THERAPEUTICS

36 Respiratory InfectionsCatherine Molyneux and Ali Robb

and bacteriologically convenient to retain a distinction between

Key points upper respiratory tract infections (URTIs) and lower respiratory
• Viral respiratory tract infections are usually mild and self- tract infections (LRTIs).
limiting, but influenza, severe acute respiratory syndrome
(SARS) and Middle East respiratory syndrome (MERS) can have
severe consequences for individuals, for public health and for
economic activity. Upper respiratory tract infections
• Exacerbations of chronic bronchitis are not always infective in Colds and flu
origin; antibiotics are used when the sputum is purulent, but
other therapeutic modalities are also valuable. URTIs with coryzal symptoms, rhinitis, pharyngitis and lar-
• Streptococcus pneumoniae remains the single most common yngitis, associated with varying degrees of systemic upset, are
cause of community-acquired pneumonia (CAP). Reduced extremely common; adults average 2–4 infections per year and
susceptibility to penicillin can complicate the management of children, 6–8, although up to 12 have been reported in some
serious pneumococcal infections, but more significant degrees groups of children (NICE, 2015a).
of resistance are currently not widespread among UK strains. These infections are usually caused by viruses. Rhinoviruses
• CAP can be caused by a variety of pathogens, and this is cause up to 50% of colds and up to 70% in the autumn. Various
reflected in the antimicrobial regimens recommended for initial other viruses, including coronaviruses and the parainluenza
treatment.
viruses, account for the rest.
• There are many potential causes of hospital-acquired (nosoco-
Most viral URTIs are mild and self-limiting. However, new
mial) pneumonia, and each unit with patients at risk will have
its own resident bacterial flora. This will strongly influence the respiratory viruses continue to be identiied, some of which pro-
choice of antibiotics for empiric therapy. duce more serious illness, for example, Middle East respiratory
• Patients with cystic fibrosis form a particularly high-risk syndrome (MERS) coronavirus, irst described in 2012, which
population. Their respiratory tract flora becomes increasingly can cause a spectrum of disease from asymptomatic infection to
abnormal with age. Colonisation with Staphylococcus aureus, respiratory failure.
Pseudomonas aeruginosa and Burkholderia cepacia complex is In general, the management of URTIs is symptomatic and con-
associated with reductions in lung function. sists of rest, adequate hydration, simple analgesics and antipyret-
• Antibiotic stewardship interventions, including close adherence ics. Apart from one or two exceptional situations, antiviral drugs
to local guidelines, are important to maintain the effectiveness
are not indicated and in most cases are not effective.
of antibiotic agents.
Antibacterial drugs have no activity against viral infections,
although in the past they were widely prescribed, sometimes with
spurious rationale, such as prophylaxis against bacterial super-
Respiratory tract infections are the most common group of infection, or simply because patients demanded them. In recent
infections seen in the UK and the commonest acute problem years, there has been heightened awareness of the adverse conse-
dealt with in primary care (National Institute for Health and quences of antibiotic overuse, the most serious of these being the
Care Excellence [NICE], 2008a). Most are viral, for which promotion of antibiotic resistance.
(with some exceptions) only symptomatic therapy is avail- Issuing antibiotic prescriptions for uncomplicated URTIs also
able, and many are self-limiting. However, the term includes reinforces the idea that these infections require medical interven-
some serious bacterial infections for which prompt treatment tion and is likely to lead to requests for an antibiotic in subsequent
is important. illnesses. This increased awareness of the harms of excessive
The respiratory tract is divided into upper and lower parts: the antibiotic prescribing has led to national campaigns aimed at dis-
upper respiratory tract consists of the sinuses, middle ear, phar- couraging the public from seeking antibiotic treatment for viral
ynx, epiglottis and larynx, whereas the lower respiratory tract infections, such as the National Health Service (NHS) antibiotic
consists of the structures below the larynx, the bronchi, bronchi- awareness campaign (Public Health England, 2015a).
oles and alveoli. Although there are anatomical and functional Unfortunately, antibiotic prescription rates in the UK have
divisions both within and between these regions, infections do plateaued after falling through the 1990s, and most people who
not always respect such boundaries. Nevertheless, it is clinically request an antibiotic for an acute uncomplicated respiratory 607
 36 THERAPEUTICS

tract infection receive one (NICE, 2008a). Therefore, further National guidelines for England recommend that NAIs can be
work to educate and change the behaviour of both patients and used in secondary care for inluenza at any time, but primary care
prescribers is required. doctors can only give NHS prescriptions for NAIs when the chief
medical oficer has conirmed that inluenza is circulating and if
the patient falls into a deined risk group (Public Health England,
Influenza
2016a).
True inluenza is caused by one of the inluenza viruses (inluenza The group eligible for prophylaxis or treatment consists of
A, B or, rarely, C). Inluenza commonly causes a syndrome of those eligible for vaccination with inactivated vaccine as listed
fever (greater than 38 °C), myalgia, headache, sore throat and previously and women who are less than 2 weeks post-partum.
cough. It is usually self-limiting in healthy adults but can cause a The patient must be able to commence treatment within a deined
severe pneumonitis and can be complicated by secondary bacte- time after the onset of symptoms or exposure to a patient with
rial infection. Serological studies in healthcare workers have sug- inluenza.
gested that 30–50% of infections in this group are asymptomatic, Prophylaxis with NAIs is only offered to patients who are not
but this may vary with strain (Public Health England, 2015b). protected by vaccination. This usually means those who have not
Inluenza tends to occur during the winter months, usually in been vaccinated, but in some years, the vaccine is poorly matched
an 8- to 10-week period; the timing, length and severity of this to the circulating strain and is therefore unlikely to be effective.
season can vary. The seasonality provides an opportunity to offer In these years, vaccinated patients are eligible for prophylaxis
preventive vaccination in the autumn. In the UK the inluenza (NICE, 2008b, 2009).
vaccination strategy has changed in recent years. In 2012 the Whether oseltamivir treatment of people with symptoms of
Joint Committee on Vaccination and Immunisation (JCVI) rec- inluenza can prevent the development of complications such as
ommended extension of the programme to children aged between pneumonia is still a matter of vigorous debate, with two recent
2 and 17. A phased extension to the programme therefore began meta-analyses coming to different conclusions (Dobson et al.,
in 2013. The eligible cohorts are published each year. Children 2015; Jefferson et al., 2014).
are vaccinated with a quadrivalent intranasal live attenuated vac- The anti-Parkinsonian drug amantadine, which has activity
cine; alternative authorised vaccines may be used for children in against the inluenza A virus, is not recommended for the treat-
clinical risk groups for whom the intranasal vaccine is unsuitable ment or prophylaxis of inluenza because resistance emerges rap-
(Public Health England, 2015b). idly, and there is a high incidence of adverse effects.
Vaccination with an inactivated quadrivalent vaccine is used in Pandemics, or global epidemics, of inluenza A occur around
patients at higher risk of severe disease and healthcare workers. every 25 years and affect huge numbers of people. The 1918
Patients at risk of severe inluenza who are eligible for inluenza ‘Spanish lu’ pandemic is estimated to have killed 20 million
vaccination in England are: people. Further pandemics took place in 1957–1958 (Asian lu),
• people older than 65 years, 1968–1970 (Hong Kong lu) and 1977 (Russian lu).
• people with chronic respiratory disease, The World Health Organization (WHO) declared a worldwide
• people with chronic kidney disease, inluenza pandemic in June 2009 after the emergence of a novel
• people with chronic liver disease, H1N1 strain of swine lineage. In the UK, NICE guidance was
• people who are immunosuppressed, superseded during the pandemic, and NAIs were given to all
• people with chronic neurological disease, individuals with lu-like illness. A vaccine was also developed.
• asplenic patients, Pandemic planning had been in operation for many years with
• pregnant women, plans for rapid vaccine development and stockpiling of antivirals.
• people with a body mass index greater than 40. However, in retrospect, infections caused by the pandemic strain
Unfortunately, the virus mutates so rapidly that the circulat- were generally associated with much milder disease than seen in
ing strains tend to change from season to season, necessitating previous pandemics, and some authorities have been accused of
annual revaccination against the prevailing virus (Public Health over-reaction.
England, 2015b). There were also adverse outcomes of the widespread use of
Inluenza A and B infections are amenable to both prevention NAIs during the 2009 pandemic. Resistance to oseltamivir
and treatment with neuraminidase inhibitors (NAIs) such as zana- emerged in some units (Gulland, 2009). Some critics argued that
mivir and oseltamivir, although there is controversy about whether the side effects of NAIs and uncertainty of beneit meant that the
the beneits justify the cost. Zanamivir is administered by dry cure was worse than the disease (Strong et al., 2009). However,
powder inhalation, whereas oseltamivir is given orally. There is an the relatively benign course of the 2009 pandemic should not
intravenous preparation of zanamivir which is unlicensed but avail- provide false reassurance regarding the potential risks associated
able on a named patient basis. Oseltamivir is the irst-line agent in with future pandemics.
most situations, but zanamivir is preferred where oseltamivir resis-
tance is suspected or for severely immunocompromised patients
Avian influenza
when H1N1 is the predominant strain of inluenza A in circula-
tion (Public Health England, 2015c). H1N1 is a strain of inluenza, An avian strain of inluenza A, H5N1, emerged in South East Asia
where the H and N refer to antigens on the virus particle, the vari- in 2003. It is now considered endemic in many parts of South
ants of which have been determined and identiied by a number. East Asia and remains a concern for public health. A second
608
 RESPIRATORY INFECTIONS 36
avian strain, H7N9, was irst detected in humans in 2013. To date, Scarlet fever, a toxin-mediated manifestation of streptococ-
human cases have only been detected in China (WHO, 2014). cal infection, is associated with a macular rash and sometimes
Person-to-person spread of these strains remains limited, but they considerable systemic illness. There has been an increased inci-
can cause severe disease, and there are concerns that they may dence of scarlet fever recently, with 14,387 cases in England
mutate to become more easily transmissible between humans. between week 37 of 2014 and week 25 of 2015. Most of these
cases were in children, with the peak incidence in those aged
1–4 (Public Health England, 2015d).
Sore throat (pharyngitis)
In the UK, there has been a recent increase in rates of group
A streptococcal infection. This includes invasive group A
Causative organisms
streptococcal infection (iGAS), associated with infection in
Pharyngitis is a common condition. In most cases, it never normally sterile sites such as blood or tissue. The UK expe-
comes to medical attention and is treated with simple therapy rienced an upsurge in invasive group A streptococcal infec-
directed at symptom relief. Many cases are not due to infection tion in 2008, and an enhanced surveillance protocol was put
at all but are caused by other factors, such as smoking. Where into place in 2009. These infections are extremely serious, and
infection is the cause, most cases are viral and form part of the prompt antibiotic treatment is vital. The serotypes involved
cold-and-lu spectrum. Epstein–Barr virus (EBV), which causes vary from year to year, with emm ST1, emm ST12 and emm
glandular fever (infectious mononucleosis), is a less common ST89 most common in the 2015–16 season (Public Health
but important cause of sore throat because it may be confused England, 2016b).
with streptococcal infection.
The only common bacterial cause of sore throat is Streptococcus
Diagnosis
pyogenes, also known as the Lanceield group A β-haemolytic
streptococcus. Other, less frequent bacterial causes include Microbiological diagnosis of the cause of pharyngitis is not usu-
Streptococcus dysgalactiae (also known as Lanceield group C/G ally required in a primary care setting. If a speciic bacterial diag-
streptococci), Arcanobacterium haemolyticum, Neisseria gonor- nosis is needed, a swab is sent for microbiological culture. Group
rhoeae and Mycoplasma sp. A β-haemolytic streptococci are usually the organism sought, but
In the past, prompt treatment of possible group A streptococ- if there is a history of treatment failure or recurrent infection, the
cal infections was considered useful to prevent suppurative and plates are incubated for 48 hours to look for Arcanobacterium
non-suppurative complications. The suppurative complications haemolyticum (Public Health England, 2015e). The main draw-
include quinsy and mastoiditis, among many others. The most back to culture methods is that the results are not available for
common non-suppurative (immune mediated) complications at least 24 hours. They also do not distinguish between infection
are rheumatic fever and glomerulonephritis, but there are oth- and carriage.
ers, including neurological complications such as Sydenham’s Rapid antigen tests (RATs) for the detection of group
chorea. A streptococcal antigens are available. Their performance
In the UK, complication rates are now low and the beneit of depends on the skill of the user. The use of rapid antigen
antibiotic treatment even in patients whose sore throat is caused tests is one of the major points of disagreement in interna-
by group A streptococci is therefore thought to be small (NICE, tional guidelines. In the UK and the Netherlands, decisions on
2008a). A cohort study in UK general practice found more than whether antibiotic treatment is appropriate depend on clinical
4000 people needed to be treated for URTI, otitis media or phar- severity, whereas in the USA, France and Finland, RATs are
yngitis to prevent one serious complication (Petersen et al., 2007). used (Pelucchi et al., 2012).
Although C. diphtheriae is rare in the UK, it should be con-
sidered when investigating travellers returning from parts of the
Treatment
world where diphtheria is common. C. ulcerans is as common a
cause of clinical diphtheria in the UK as C. diphtheriae but usu- Most people will recover from sore throat after 7 days. Analgesics
ally runs a more benign course. such as paracetamol and ibuprofen are useful for reducing pain
and fever. Under current guidance, most patients should not be
prescribed an antibiotic. Delayed antibiotic prescriptions may be
Clinical features
useful. In this scenario, the prescription is post-dated, or patients
The presenting complaint is sore throat, often associated with are advised only to use it if symptoms worsen or do not improve
fever and the usual symptoms of the common cold. The Centor (NICE, 2008a).
score is a clinical scoring system used to identify those at higher NICE (2008a) guidelines suggest that patients with a Centor
risk of bacterial infection (Centor et al., 1981). The criteria are score of 3 or 4 are considered for an immediate or delayed antibi-
the presence of tonsillar exudate, history of fever, tender ante- otic prescription. People who have marked systemic upset, those
rior surgical lymphadenopathy or adenitis and absence of cough. who are at increased risk of complications and those with valvu-
Each feature scores one point. Those with a Centor score of 3 or lar heart disease should be given an antibiotic. A low threshold
4 have a 40–60% risk of group A streptococcal infection. Those for antibiotic prescribing is also recommended for those who are
with a Centor score of zero or one are unlikely to have group A at risk of immunosuppression, those with previous rheumatic
streptococcal infection (Aalbers et al., 2011) fever and those at risk of severe disease.
609
 36 THERAPEUTICS

Penicillins such as penicillin V are recommended as irst-line

Otitis media
treatment for group A streptococcal pharyngitis. There is evi-
dence that cephalosporins may be more effective clinically and
Causative organisms
in eradicating group A streptococci from the pharynx; however,
given the higher cost and wider spectrum of activity, interna- Inlammation of the middle ear (otitis media) is seen most fre-
tional guidelines (Pelucchi et al., 2012; Shulman et al., 2012) quently in children younger than 3 years. Most cases are due to
still favour penicillin V for 10 days. Aminopenicillins such as bacteria, although viruses such as inluenza virus and rhinovi-
amoxicillin should be avoided if primary EBV infection is likely ruses have been implicated in a sizeable minority. Streptococcus
because, for reasons that are not understood, these drugs often pneumoniae and H. inluenzae are the two most commonly
cause skin rashes if used in this condition. encountered bacterial pathogens. Moraxella catarrhalis and S.
Five days of erythromycin or clarithromycin is recommended pyogenes account for a smaller proportion of cases, perhaps 10%,
for patients with penicillin allergy. This is because a review and other bacteria are rarely seen.
of antibiotics for streptococcal pharyngitis in children found
that this treatment was as effective as 10 days of penicillin V
Clinical features
(Altamimi et al., 2012).
Classically, otitis media presents with ear pain, which may be
severe. If the drum perforates, the pain is relieved, and a purulent
Acute epiglottitis
discharge may follow. There may be a degree of hearing impair-
ment plus non-speciic symptoms such as fever or vomiting.
Causative organisms
Complications include mastoiditis (which is now rare), menin-
Acute epiglottitis is a rapidly progressive cellulitis of the epi- gitis and, particularly in the case of H. inluenzae infection, sep-
glottis and adjacent structures. Previously, almost all child- ticaemia and disseminated infection. With the advent of routine
hood cases and a high proportion of adult cases were caused vaccination against H. inluenzae type b, these complications are
by Haemophilus inluenzae type b (Hib), with the rest being uncommon.
caused by other organisms such as pneumococci, streptococci
and staphylococci. With the advent of routine vaccination
Diagnosis
against H. inluenzae type b in October 1992, this disease has
become uncommon. The diagnosis of otitis media is essentially made clinically,
and laboratory investigations have little role to play. Unless
the drum is perforated, sending a swab of the external auditory
Clinical features
canal for microbiological culture is not required, and in fact, the
The typical patient is a child between 2 and 4 years old with fever results are likely to be unhelpful or misleading. For this reason,
and dificulty speaking and breathing. The patient may drool a causative organism is rarely isolated, and empirical treatment
because of impaired swallowing. Local swelling has the poten- is provided.
tial to cause rapid-onset airway obstruction, so the condition is a
medical emergency.
Treatment
There has been much debate about whether or not antibiot-
Diagnosis
ics should be used for the initial treatment of acute otitis media
The diagnosis is made clinically, and initial management (AOM). A Cochrane systematic review identiied 12 trials cover-
is concentrated on establishing or maintaining an airway. ing 3854 episodes (Venekamp et al., 2015). Antibiotic treatment
This takes priority over all other diagnostic and therapeutic led to a statistically signiicant reduction in the number of chil-
manoeuvres. Thereafter, the diagnosis may be conirmed by dren with pain in the irst 7 days; however, symptoms sponta-
visualisation of the epiglottis, typically described as ‘cherry- neously settled in 82% of children. Twenty children had to be
red’. Microbiological conirmation may be obtained by cultur- treated for one to beneit; however, one child developed diarrhoea
ing the epiglottis and the blood, but not until the airway is for every 14 treated, leaving the risk and beneit inely balanced.
secure. Antibiotics were most useful in patients under 2 with bilateral
acute otitis media and patients with perforation and discharge.
Therefore, antibiotics are currently only recommended for peo-
Treatment
ple who are systemically unwell, those who are at risk of serious
In view of the high prevalence of amoxicillin resistance among complications and those whose symptoms have lasted more than
encapsulated H. inluenzae, the treatment of choice is a cephalo- 4 days and are not improving. They should also be considered for
sporin. It is customary to use a third-generation cephalosporin children under 2 with bilateral acute otitis media and for children
such as cefotaxime or ceftriaxone, but most infections should with ear discharge (NICE, 2008a).
respond to a second-generation agent such as cefuroxime. If a If antibiotic treatment is to be given, it should be effective
sensitive organism is recovered, high-dose parenteral amoxicillin against the three main bacterial pathogens: S. pneumoniae,
may be substituted. H. inluenzae and S. pyogenes. The streptococci are usually
610
 RESPIRATORY INFECTIONS 36
sensitive to penicillins, but these are much less active against
Diagnosis
H. inluenzae, so the broader-spectrum agents amoxicillin and
ampicillin are preferred. These drugs have identical antibacte- This is usually clinical. However, in chronic cases, samples from
rial activity, but amoxicillin is recommended for oral treatment sinus washouts may be sent for bacterial culture in an attempt to
because it is better absorbed from the gastro-intestinal tract. isolate the causative organism.
About 20% of H. inluenzae strains are resistant to amoxicillin
due to production of β-lactamase, so if there is no response to
Treatment
amoxicillin, an alternative agent should be chosen.
Current national guidance suggests erythromycin or clarithro- Paracetamol or ibuprofen is used to alleviate pain. An intrana-
mycin for patients with penicillin allergy; however, these drugs sal decongestant may be useful if nasal congestion is problem-
are much less active against H. inluenzae, so alternatives to atic. Irrigating the nose with saline and applying warm face
amoxicillin should only be used if the history of penicillin allergy packs may also alleviate symptoms. If patients have severe
is convincing (NICE, 2015b). or prolonged symptoms, intranasal corticosteroids may be
Pneumococcal conjugate vaccines, which are currently given considered.
routinely in the childhood vaccination schedule, may reduce the If the patient is at high risk of complications or bacterial infec-
incidence of acute otitis media, although a review found only tion is thought likely, antibiotics should be prescribed. First-line
modest beneit when the 7-valent conjugate vaccine was used agents are amoxicillin, phenoxymethyl penicillin and doxy-
in healthy infants and no additional beneit in high-risk children cycline. If there is no response after 48 hours or if the agent is
(Fortanier et al., 2014). A small beneit was also found for inlu- poorly tolerated, second-line options include co-amoxiclav and
enza vaccination (Norhayati et al., 2015). Long-term antibiotic azithromycin (NICE, 2008a).
prophylaxis might have a role in some children, but any beneit
has to be balanced against the risks, such as the development of
antibiotic resistance and adverse effects of the antibiotics used Lower respiratory tract infections
(Leach and Morris, 2006).
Acute bronchitis
Acute bronchitis is acute inlammation of the bronchial tree lead-
Acute sinusitis
ing to cough which lasts up to 3 weeks.
Causative organisms
Causative organisms
Normally, the paranasal sinuses are sterile, but they can become
infected after damage to the mucous membrane which lines Most cases are thought to be viral, but this is uncertain because
them. This usually occurs after a viral URTI but is sometimes no cause is identiied in a large number of patients in clinical
associated with the presence of dental disease. Sinusitis is studies.
caused by a virus in 98% of cases. Bacterial acute sinusitis is
usually caused by the same organisms which cause otitis media
Clinical features
(S. pneumoniae and H. inluenzae), but occasionally other
organisms such as Staphylococcus aureus, viridans streptococci Patients may have sputum production, wheeze, dyspnoea and
(a term used to describe α-haemolytic streptococci other than S. systemic upset. There are usually no focal signs on examination
pneumoniae) and anaerobes may be found. of the chest, although wheeze may be present.

Clinical features Diagnosis

The main feature of acute sinusitis is facial pain and tenderness, Diagnosis is usually clinical; microbiological investigation is not
often accompanied by headache and a purulent nasal discharge. necessary in most cases. If symptoms persist for longer than 3
Complications include orbital involvement leading to periorbital weeks, further investigation is indicated to rule out diagnoses
cellulitis and intracranial involvement, including frontal bone such as chronic obstructive pulmonary disease (COPD) or tuber-
osteomyelitis, meningitis and brain abscess. The average dura- culosis. In smokers with persistent cough, malignancy must be
tion of the illness is 2.5 weeks, although most patients will be considered.
improving after 7–15 days (NICE, 2013a).
Bacterial infection should be suspected when three or more
Treatment
of the following criteria are present: discoloured or purulent dis-
charge greater on one side, severe local pain greater on one side, a Treatment of acute bronchitis usually consists of analgesia,
fever above 38 °C, deterioration after an initial milder illness and hydration and comfort measures. Antibiotics should be given if
a raised erythrocyte sedimentation rate (ESR) or C-reactive pro- the patient has an impaired ability to ight infection or if the acute
tein (CRP) (NICE, 2013a). The condition may become chronic bronchitis is likely to worsen a pre-existing condition. If antibiot-
with persistent low-grade pain and nasal discharge, sometimes ics are required, the irst-line agent is amoxicillin, with doxycy-
with acute exacerbations. cline as an alternative (NICE, 2015c).
611
 36 THERAPEUTICS

Pertussis Treatment
Pertussis is a highly infectious disease caused by Bordetella per- Macrolides are the mainstay of treatment. A 3-day course of
tussis. Bordetella parapertussis causes a similar although usu- azithromycin or a 7-day course of erythromycin or clarithromy-
ally milder infection. The illness classically begins with a coryza cin is recommended. Erythromycin is not used in infants under
followed by a cough that becomes paroxysmal, usually within 1 month old due to an association with pyloric stenosis. If the
1–2 weeks. The paroxysms of coughing may be followed by an patient cannot take a macrolide, then co-trimoxazole is an alter-
inspiratory whoop or by vomiting. Infants may not develop the native in patients older than 1 month. Cotrimoxazole cannot be
whoop. The disease usually lasts 2–3 months. Severe complica- used in pregnancy (Public Health England, 2013a).
tions are most common in infants under 6 months of age and Children are excluded from schools and nurseries until they
include bronchopneumonia, weight loss and cerebral hypoxia have completed a course of treatment. If the diagnosis was made
with resulting brain damage. Deaths are also most common in late and they have not been treated, they are excluded until 21
infants under 6 months. days have passed from the onset of symptoms (Public Health
Adults and older children who usually have received vac- England, 2013a).
cination or have been infected previously often lack the Because the paroxysmal cough is due to toxin-mediated dam-
classical picture of the disease. The inspiratory whoop and age, treatment does not eliminate the symptoms. The role of treat-
post-tussive vomiting are often absent, and they may simply ment is to reduce infectivity and onward transmission.
present with prolonged cough. Cases in adults and older chil-
dren are therefore often missed, increasing the risk of onward
Bronchiolitis
transmission.
In the 1950s there were more than 120,000 notiications of Bronchiolitis is characterised by inlammatory changes in the
pertussis in England and Wales. Although there were periods small bronchi and bronchioles, but not by consolidation. It is par-
of reduced vaccine uptake in the 1970s and 1980s, by 1992, ticularly recognised as a disease of infants in the irst year of life,
92% or more of children had been vaccinated by their sec- in whom a small degree of airway narrowing can have a dramatic
ond birthday, and notiications were down to fewer than 5000 effect on airlow. However, the causal organisms are equally
a year. Although vaccine coverage remained above 95%, capable of infecting adults, who may then act as reservoirs of
increased rates of pertussis were seen in 2011. This continued infection. Approximately one in three infants will develop bron-
into 2012 when a national outbreak was declared. The reasons chiolitis in their irst year of life (NICE, 2015d).
are unclear but may include the change to acellular vaccine,
better case ascertainment and genetic changes in B. pertussis
Causative organisms
(Public Health England, 2016c).
During the 2012 outbreak, the highest rates of illness were in Most cases of bronchiolitis are caused by respiratory syncy-
infants aged less than 3 months, and most became ill before they tial virus (RSV), which occurs in annual winter epidemics, but
were old enough to receive their irst vaccine. A maternal vac- human metapneumovirus (hMPV), parainluenza viruses, rhino-
cination programme was therefore introduced. Pregnant women viruses, adenoviruses and occasionally M. pneumoniae have also
were immunised, ideally at between 28 and 32 weeks of gestation been implicated.
to allow time for maternal antibody to be produced and trans-
ferred to the baby (Public Health England, 2016c).
Diagnosis
Bronchiolitis is characterised by a prodrome of fever and cory-
Diagnosis
zal symptoms which progresses to wheezing, respiratory dis-
There is a statutory duty in England to notify the local health pro- tress and hypoxia of varying degrees. Aetiological conirmation
tection team of suspected cases of pertussis to facilitate further may be made by immunoluorescence and/or viral culture of
public health action (Health Protection Agency, 2012). respiratory secretions, although increasingly the diagnosis of
Culture of a pernasal swab has traditionally been the method respiratory syncytial virus is made using rapid antigen detec-
of diagnosis in the irst 2 weeks of the illness; however, this is tion tests or by PCR.
increasingly being replaced with polymerase chain reaction
(PCR) techniques, which have increased sensitivity. Oral luid
Treatment
testing for antitoxin immunoglobulin G (IgG) can be performed
for patients between 5 and 16 years of age who have had a cough The treatment of bronchiolitis is mainly supportive and con-
for more than 2 weeks and have not been vaccinated in the last sists of oxygen, adequate hydration and ventilatory assistance if
year (Public Health England, 2013a). Serology testing for anti- required. Nebulised ribavirin for the treatment of bronchiolitis is
toxin IgG in serum samples is used to conirm the diagnosis in not mentioned in the NICE (2015d) guidelines.
adults, if the date of symptom onset is more than 2 weeks before Babies born earlier than 35 weeks of gestation or those less
the date of the test and they have not been vaccinated recently. than 6 months of age at the onset of the RSV season are at high
Serological testing is unable to distinguish between antibod- risk of the disease. Likewise, infants under 2 years old with con-
ies formed in response to disease and those formed in response genital heart disease, chronic lung disease or with severe immu-
612 to vaccination and so is unreliable in patients who have been nodeiciency are similarly at high risk. All such patients are
recently vaccinated. candidates for prophylactic treatment with palivizumab. This is
 RESPIRATORY INFECTIONS 36
a humanised monoclonal antibody used for passive immunisa- associated with quinolone use and, rarely, the development of
tion against respiratory syncytial virus (Public Health England, life-threatening hepatic toxicity and prolonged QT syndrome.
2015f). There is currently no vaccine against RSV.
Community acquired pneumonia
Exacerbations of chronic obstructive
Pneumonia is infection of the lung parenchyma. The alveoli ill
pulmonary disease
with bacteria, inlammatory cells and luid in a process called
Chronic obstructive pulmonary disease (COPD) renders patients consolidation. Mild pneumonia can be treated in the community,
more vulnerable to respiratory infection, and infectious exacer- but patients with moderate to severe disease will require hospi-
bations cause signiicant morbidity and mortality. These acute tal admission. In hospitalised patients, the diagnosis is conirmed
exacerbations of COPD are a frequent cause of morbidity and by the presence of consolidation on the chest X-ray. Diagnosing
admission to hospital. An exacerbation is deined as ‘a sustained pneumonia in primary care is more complicated. Clinical studies
worsening of the patient’s symptoms from his or her usual stable have deined community-acquired pneumonia (CAP) differently,
state that is beyond normal day-to-day variations, and is acute in but fever greater than 38 °C, pleural pain, dyspnoea, tachypnoea
onset’ (NICE, 2010). and new signs on examination of the chest seem to be useful for
separating CAP from bronchitis in the absence of a chest X-ray.
The British Thoracic Society (BTS) guidelines (BTS Community
Diagnosis
Acquired Pneumonia in Adults Guideline Group, 2009) deine
Common symptoms include worsening breathlessness, cough, CAP as symptoms of a lower respiratory tract infection (cough
increased sputum production and change in sputum colour. It is and at least one other), new focal signs on chest examination, at
important to remember that not all acute exacerbations of COPD least one systemic feature and no other explanation for the illness.
have an infective aetiology and that many infective exacerbations The NICE (2014) guidelines on community-acquired pneumonia
will be triggered by viruses. Bacterial causes include M. catarrh- suggested using a point-of-care CRP test to decide on antibiotic
alis, H. inluenzae and S. pneumoniae. treatment in adult patients with LRTI if a clinical diagnosis of
Severe exacerbations can cause marked breathlessness, confu- community-acquired pneumonia has not been made. Under these
sion, marked reduction in performance of activities of daily liv- guidelines, antibiotics would not be given if CRP is less than 20,
ing and use of accessory muscles at rest. These patients require a delayed antibiotic prescription should be considered if CRP is
hospital admission. Milder exacerbations can be managed in the greater than 20 but less than 100 and antibiotics should be offered
community. Sending sputum samples for culture as routine prac- if CRP is greater than 100 (NICE, 2014).
tice in primary care is not recommended. When community-acquired pneumonia is diagnosed clinically
in an adult in the community, the ‘CRB 65’ mnemonic score is
used to determine clinical risk. Table 36.1 describes the factors
Treatment
considered within the CRB score, where one point is scored for
NICE recommends antibiotic therapy for exacerbations of COPD each of the following: confusion, respiratory rate, blood pressure
associated with purulent sputum or where there are clinical signs and age. Patients with a CRB 65 score of 0 can be safely managed
of pneumonia or consolidation on chest X-ray (NICE, 2010). at home. Hospital assessment should be considered for patients
Recommended treatment is with an aminopenicillin (e.g. amoxi- with a score of 1 or more and especially if the score is 2 or more
cillin), a macrolide or a tetracycline, according to local guidance (NICE, 2014).
with modiication according to sputum culture results if sputum Severity scoring of community-acquired pneumonia in hospital
has been sent. However, routine sputum cultures are not recom- patients uses the ‘CURB 65’ mnemonic score, which adds blood
mended for patients managed in primary care. urea nitrogen of greater than 7 to the CRB 65 score. Patients with
Co-amoxiclav has the advantage of covering β-lactamase- a CURB 65 of 0 or 1 are low risk and suitable for treatment at
producing strains of H. inluenzae and M. catarrhalis that are home. Patients with a CURB 65 score of 2 are at intermediate
therefore resistant to amoxicillin. However, this agent has risk and should be considered for a short in-patient admission or
a greater incidence of side effects, such as a higher risk of outpatient treatment under hospital supervision. Patients with a
Clostridium (now named Clostridioides) dificile infection (CDI) CURB 65 score of 3 or more are at high risk and will require
and a much higher incidence of cholestatic jaundice. in-patient management (BTS Community Acquired Pneumonia
Numerous other drugs are promoted for the treatment of in Adults Guideline Group, 2009; NICE, 2014).
COPD exacerbations. The activity of ciproloxacin against S. In children, bacterial pneumonia should be considered where
pneumoniae is insuficient to justify its use as monotherapy there is persistent or repetitive fever of greater than 38.5 °C with
against pneumococcal infections. However, it has useful activity chest recession and a raised respiratory rate (BTS Community
against H. inluenzae and M. catarrhalis. Levoloxacin, the active Acquired Pneumonia in Children Guideline Group, 2011).
isomer of oloxacin, does not seem to offer any great microbio-
logical advantage. Moxiloxacin is a quinolone that retains activ-
Causative organisms
ity against Gram-negative organisms such as Haemophilus and
Moraxella but has greater activity against Gram-positives such The most common cause of community-acquired pneumonia is
as S. pneumoniae. It has been favourably compared with stan- S. pneumoniae. H. inluenzae (usually noncapsulate strains) are
dard treatment in exacerbations of COPD (Wilson et al., 2004). another common cause. S. aureus can cause a severe necrotis- 613
However, its use has been limited by the high incidence of CDI ing pneumonia, classically occurring after an inluenza infection.
 36 THERAPEUTICS

Table 36.1 CRB score for assessing the severity of community- Table 36.2 Empirical treatment of community-acquired
acquired pneumonia presenting in primary care pneumonia in patients with no history of penicillin
allergy
Marker Explanation of marker
CAP severity Antibiotic of choice
C Confusion defined as AMTS <8 or new disori-
entation in person, place or time Mild Amoxicillin oral

R Respiratory rate ≥30 breaths/min Moderate Amoxicillin and clarithromycin i.v. or oral

B Systolic blood pressure <90 mmHg or Severe Co-amoxiclav (i.v. until clinical improve-
diastolic <60 mmHg ment) and clarithromycin i.v. or oral

65 Age >65 CAP, Community-acquired pneumonia; i.v., intravenous.

Score Each severity marker present scores 1 point

patients with moderate- or high-severity CAP (BTS Community
0 Low risk of mortality, <1% Acquired Pneumonia in Adults Guideline Group, 2009). The
success of sputum culture depends on the quality of the sample
1–2 Intermediate risk of mortality, 1–10% because samples from the upper respiratory tract will be contami-
nated with the normal regional lora. In patients who are severely
3–4 High risk of mortality, >10%
ill and especially those requiring admission to an intensive care
AMTS, Abbreviated Mental Test Score developed and validated by unit (ICU), more invasive sampling such as bronchoalveolar
Hodkinson (1972). lavage may be required to tailor treatment.
The UK national guidelines for HIV testing in the UK recom-
mend offering an HIV test to patients with bacterial pneumo-
nia (British HIV Association et al., 2008). The BTS guidelines
recommend that patients with high-severity CAP should have
Organisms causing atypical pneumonia include Legionella pneu- Legionella urinary antigen testing (BTS Community Acquired
mophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Pneumonia in Adults Guideline Group, 2009). The NICE (2014)
Chlamydophila psittaci, Coxiella burnetii and viruses. It is not guideline extends this to patients with moderate-severity pneu-
possible to determine the microbiological cause of pneumonia monia. However, because urine antigen testing only detects
clinically or radiologically. serogroup 1 L. pneumophila, a negative test does not exclude
L. pneumophila is the cause of Legionnaire’s disease, which Legionella infection.
occurs sporadically and in outbreaks often associated with The other atypical pathogens may require serological diag-
contaminated air-conditioning or water systems. From 2002 to nosis with complement ixation tests being performed in par-
2008, there were 300–600 new cases a year reported in England allel on acute and convalescent serum. The convalescent
and Wales. Legionnaire’s disease may be rapidly progressive, sample should be taken 2 weeks after the onset of symptoms;
with very extensive consolidation and consequent respiratory however, these results are obviously too late to tailor treat-
failure. ment. Respiratory multiplex PCRs which detect agents such as
Viral infections should not be forgotten as causes of pneumo- Mycoplasma, C. pneumoniae and C. psittaci are increasingly
nia, although in practice it is unusual to make a deinitive early commonly available and allow diagnosis of atypical infection
diagnosis, so most cases are treated with antibacterials. Inluenza during the acute illness.
can cause a primary viral pneumonia and can be complicated by
secondary bacterial (particularly staphylococcal) pneumonia.
Empirical treatment
Chickenpox can be complicated by primary varicella pneumonia,
particularly in adults, and cytomegalovirus is capable of caus- Both the BTS and NICE have produced guidelines for the treat-
ing a variety of infections, including pneumonia, in patients with ment of community-acquired pneumonia in adults. The BTS
compromised cell-mediated immunity. (BTS Community Acquired Pneumonia in Adults Guideline
Group, 2009) and NICE (2014) guidelines make similar treat-
ment recommendations (Table 36.2). Local guidelines may vary
Diagnosis
depending on local resistance rates and the demographics of the
Microbiological testing is not recommended as routine practice local population.
for adults or children with low-risk disease treated in the com- For mild disease, the recommended treatment is with amoxicil-
munity. However, sputum culture may be useful in those who do lin, which provides activity against pneumococci and most strains
not respond to irst-line antibiotic treatment. of H. inluenzae. Doxycycline or clarithromycin are the preferred
Adults with moderate- or high-severity CAP should have alternatives in penicillin-allergic patients. However, for moder-
blood cultures and sputum cultures performed. The 2009 BTS ate or severe disease requiring admission to hospital, guidelines
guidelines also recommend pneumococcal antigen testing for all recommend that, until the aetiology is known, treatment should
614
 RESPIRATORY INFECTIONS 36
cover both ‘typical’ causes (e.g. S. pneumoniae and H. inluen- for Clinical Microbiology and Infectious Diseases (ESCMID)
zae) and atypical causes (e.g. M. pneumoniae, Chlamydophila guidance on the treatment of LRTI reported no documented cases
species and Legionella). For patients with moderate or severe of treatment failure with adequate doses of penicillins in extra-
CAP, the current national guidelines (BTS Community Acquired meningeal infection (Woodhead et al., 2011). A new formulation
Pneumonia in Adults Guideline Group, 2009; NICE, 2014) of amoxicillin/clavulanic acid (2 g/125 mg given 12 hourly) is
therefore recommend a combination of a β-lactam drug plus a reported to have successfully treated strains, with an amoxicillin
macrolide. For moderate disease, oral amoxicillin plus a macro- MIC of 4–8 mg/L (Woodhead et al., 2011).
lide is suggested, whereas for severe disease, a broad-spectrum M. pneumoniae does not possess a cell wall and is therefore
β-lactamase stable penicillin (co-amoxiclav) and a macrolide not susceptible to β-lactam agents. A tetracycline or a macrolide
should be given intravenously. In patients allergic to penicillin, is a suitable alternative. Tetracyclines are also effective against
a second-generation (e.g. cefuroxime) or third-generation (e.g. C. pneumoniae, C. psittaci and C. burnetii, but erythromycin
cefotaxime or ceftriaxone) cephalosporin can be used instead of is probably less effective. Quinolones are highly active against
co-amoxiclav, together with clarithromycin. For mild disease, these organisms.
the BTS guidelines (BTS Community Acquired Pneumonia in Staphylococcal pneumonia is usually treated with lucloxa-
Adults Guideline Group, 2009) suggest a 7-day course, although cillin. Meticillin-resistant S. aureus (MRSA) pneumonia is
the NICE (2014) guidance shortens this duration to 5 days. For being seen more commonly in the community and in hospital.
more severe disease, a 7- to 10-day course is suggested, but this Strains of S. aureus expressing Panton-Valentine Leukocidin,
may need to be extended, for example, if the infection was caused an exotoxin, are capable of causing a severe necrotising pneu-
by S. aureus or Gram-negative bacilli. monia and if clinically suspected should warrant urgent criti-
In children, a different approach is recommended. In the BTS cal care and specialist microbiological input.
guidance (BTS Community Acquired Pneumonia in Children Treatment recommendations for Legionnaire’s disease are
Guideline Group, 2011), amoxicillin is recommended for all chil- based on a retrospective review of the famous Philadelphia
dren, and oral administration is preferred unless the child cannot outbreak of 1976 (Fraser et al., 1977), in which two deaths
tolerate oral luids, has problematic oral absorption or is showing occurred among the 18 patients who were given erythromycin,
signs of septicaemia. The agents recommended include amoxi- compared with 16 deaths in 71 patients treated with penicil-
cillin, co-amoxiclav, cefuroxime, cefotaxime or ceftriaxone. lin or amoxicillin. This observation accords with the facts that
Macrolides may then be added if the child does not respond to Legionella is an intracellular pathogen and that macrolides pen-
irst-line treatment. etrate more eficiently than β-lactams into cells. Azithromycin
is probably the most effective of the macrolide/azalide deriva-
tives, but clinical evidence to conirm this is lacking. Other
Targeted therapy
agents with proven clinical eficacy and good intracellular
The treatment of choice for pneumococcal pneumonia is ben- activity against Legionella include rifampicin and quinolones.
zylpenicillin or amoxicillin. Erythromycin monotherapy may be There have been no randomised controlled clinical trials com-
used in penicillin-allergic patients, but resistance rates are ris- paring the new quinolones and the newer macrolides for the
ing. Macrolides are bacteriostatic rather than bactericidal, and treatment of L. pneumophila. Guidance, based on observa-
the comparative eficacy of this approach is not known. There tional studies, suggests non-severe cases should be treated with
is retrospective evidence that combination therapy using both an oral luoroquinolone (with a macrolide as an alternative).
a β-lactam and a macrolide can reduce mortality in patients Severe cases are treated with a combination of a luoroquino-
whose pneumonia is complicated by pneumococcal bacteraemia lone plus either a macrolide or rifampicin, de-escalating to a
(Martinez et al., 2003). However, a Dutch study found that nar- luoroquinolone as the sole agent after the irst few days (BTS
rowing the spectrum of antibiotic cover in patients with a pneu- Community Acquired Pneumonia in Adults Guideline Group,
mococcal bacteraemia was associated with a lower mortality rate 2009). Treatment is not recommended for the non-pneumonic
regardless of severity (Cremers et al., 2014). form of legionellosis (Pontiac fever), which presents as a self-
Pneumococci with reduced susceptibility to penicillin are limiting lu-like illness.
becoming increasingly common, particularly in continental
Europe and the USA. In the UK, about 5–10% of strains express
Prevention
‘intermediate susceptibility’ (minimum inhibitory concentration
[MIC] 0.06–2 mg/L), but high-level resistance (MIC > 2 mg/L) Pneumococcal 23-valent polysaccharide vaccine and inluenza
remains uncommon. Intermediate susceptibility may result in vaccine should be offered to all those at risk of infection. For
treatment failure in conditions such as meningitis at sites where pneumococcal infection, this includes patients who fulil the fol-
antibiotic penetration is reduced, but antibiotic penetration into lowing criteria:
the lungs is suficiently good that penicillin and amoxicillin • asplenia or dysfunction of the spleen,
remain effective for pneumonia. Strains expressing high-level • chronic respiratory disease,
resistance are unlikely to respond to penicillins. However, such • chronic heart disease,
strains are often co-resistant to macrolides and other irst-line • chronic renal disease,
agents and may require treatment with glycopeptides or line- • chronic liver disease,
zolid. The European Respiratory Society and European Society • diabetes,
615
 36 THERAPEUTICS

• immunosuppressed,
Treatment
• aged 65 years or older,
• cochlear implants, The range of organisms causing nosocomial pneumonia is very
• cerebrospinal luid leaks. large, so broad-spectrum empiric therapy is indicated. The choice
In the UK, children are immunised with the 13-serotype conju- of antibiotics will be inluenced by preceding antibiotic therapy,
gate vaccine as part of the normal childhood vaccination sched- the duration of hospital admission and, above all, by the indi-
ule. This should both protect them and reduce the circulation of vidual unit’s experience with hospital-acquired bacteria. It is
these serotypes in the community; however, there is concern that important that units maintain surveillance systems and moni-
vaccination may lead to serotype replacement, with serotypes not tor their resistance rates so that guidelines can be modiied over
included in the vaccine illing the empty ecological niche (Public time. Both the British Society for Antimicrobial Chemotherapy
Health England, 2013b). (Masterton et al., 2008) guidelines and the NICE (2014) guide-
lines recommend following local policies based on local patho-
gen and susceptibility data.
Hospital-acquired pneumonia
Co-amoxiclav is sometimes used for early HAP but lacks
Hospital-acquired pneumonia (HAP) is deined as pneumonia pseudomonal cover. Agents such as piperacillin/tazobac-
developing more than 48 hours after admission and not incubat- tam and meropenem have broad-spectrum activity including
ing at the time of admission. It is a major cause of morbidity and Pseudomonas sp. but do not cover MRSA, so an additional agent
mortality in hospital patients in the developed world. An impor- such as vancomycin or linezolid would be required in MRSA-
tant subset of HAP is ventilator-associated pneumonia (VAP), colonised patients or in units with high rates of MRSA infec-
which is deined as pneumonia occurring more than 48 hours tion. With concerns about the spread of carbapenem-resistant
after endotracheal intubation. Enterobacteriaceae, there has been a national attempt to control
The range of pathogens associated with HAP is wide. carbapenem use, with acute hospital trusts required to reduce
Traditionally, it has been divided into early infection, occurring their carbapenem prescribing below the 2014–15 baseline. The
after less than 5 days in hospital when more sensitive organ- aim is to relieve the evolutionary selective pressure driving the
isms are likely to be involved, and late infection, which carried development and spread of carbapenem resistance and therefore
a higher risk of multidrug-resistant organisms. However, these to reduce the spread of carbapenemase-producing organisms.
distinctions are not absolute. There have also been attempts to use narrower-spectrum agents
Common pathogens include Gram-negative organisms such to reduce C. dificile risk. A study using amoxicillin and temocil-
as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneu- lin has been published; however, this combination lacks P. aeru-
moniae and Acinetobacter spp. S. aureus, including MRSA is ginosa and S. aureus cover, and additional agents are therefore
the main Gram-positive organism implicated. S. pneumoniae required in some circumstances (Habayeb et al., 2015).
and Haemophilus inluenzae are sometimes found in early-onset Options in patients with type one hypersensitivity to penicil-
HAP, and the patient may have been incubating the infection at lin include aztreonam or ciproloxacin and an antibiotic with
the time of admission; they are rare in late-onset HAP. HAP may activity against Gram-positive bacteria (e.g. a glycopeptide or
be polymicrobial. It is rarely due to viruses or fungi unless the linezolid).
host is immunosuppressed. Hospital water supplies have been
implicated in sporadic cases, and occasionally there have been
Prevention
outbreaks of L. pneumophila. Therefore, this possibility should
be considered. General strategies for minimising the incidence of HAP include
early postoperative mobilisation, analgesia, physiotherapy and
promotion of rational antibiotic prescribing.
Clinical features
One of the Department of Health’s (DH’s) high-impact inter-
Nosocomial pneumonia accounts for 10–15% of all hospital- ventions (DH, 2011) is a care bundle for ventilated patients,
acquired infections, usually presenting with sepsis and/or respi- aimed at reducing the prevalence of VAP. The high-impact inter-
ratory failure. Up to 50% of cases are acquired on intensive care ventions are a set of practice interventions introduced to provide
units. Predisposing features include stroke, mechanical ventila- NHS trusts with the tools to reduce serious healthcare-associated
tion, chronic lung disease, recent surgery and previous antibiotic infections. Since 2008, the Health and Social Care Act controlling
exposure. healthcare-associated infection has been a legal requirement for
NHS trusts; it forms part of the code of practice all NHS trusts
operate under. Implementation of care bundles such as this pro-
Diagnosis
vides evidence that NHS trusts are complying with this obligation.
Sputum is commonly sent for culture, but this is sometimes The recommendations in the ventilator care bundle include
unhelpful because it may be contaminated by mouth lora. If the head-of-bed elevation, sedation holding to reduce the duration
patient has received antibiotics, the normal mouth lora is often of mechanical ventilation, aspiration of secretions every 1–2
replaced by resistant organisms such as staphylococci or Gram- hours via a subglottic port in patients who have been intubated
negative bacilli, making the interpretation of culture results more than 72 hours, limiting stress ulcer prophylaxis to high-risk
dificult. Bronchoalveolar lavage is often more helpful. Blood patients and good general hygiene of tubing management and
616 cultures may be positive. suction.
 RESPIRATORY INFECTIONS 36
Another strategy proposed for the prevention of VAP is selective
Box 36.1 Middle East respiratory syndrome coronavirus
decontamination of the digestive tract (SDD), based on the premise
epidemiological and clinical criteria
that the infecting organisms initially colonise the patient’s orophar-
ynx or intestinal tract. By administering non-absorbable antibiot-
Epidemiological criteria
ics such as an aminoglycoside or colistin to the gut and applying • Patient has lived in or travelled to an area where it could
a paste containing these agents to the oropharynx, it is proposed have been acquired in the last 14 days (as of February 2016,
that the potential causative organisms will be eradicated and the Bahrain, Jordan, Iraq, Iran, Kingdom of Saudi Arabia, Kuwait,
incidence of pneumonia thereby reduced. In some centres, an anti- Oman, Qatar, United Arab Emirates, and Yemen).
fungal agent such as amphotericin B is added; others also advocate OR
addition of a systemic broad-spectrum agent such as cefotaxime. • The patient has had close contact with a patient with MERS in
the 14 days before the patient became ill and that patient had
The role of selective decontamination of the digestive tract symptoms at the time of contact.
remains controversial. A Cochrane review suggested that it did OR
reduce respiratory tract infections, although mortality was only • The patient is a healthcare worker on ICU caring for patients
reduced if systemic antibiotics were also given (Di’Amico et al., with respiratory distress.
2009). However, questions remain about longer-term beneits OR
and the potential effects on antibiotic resistance. The use of aero- • The patient is part of a cluster of epidemiologically linked
cases requiring ICU admission.
solised antibiotics in this context has been considered; agents
AND
which would be suitable for administration by this route and with
the appropriate antimicrobial spectrum include aminoglycosides Clinical case description
(particularly tobramycin) and the polymyxin drug colistin. There • The patient has a fever >38 °C or history of fever and cough
and has evidence of disease of the lung parenchyma (e.g.
are no published data available at present, and therefore this
chest X-ray changes) with no alternative explanation.
approach cannot be universally recommended.
ICU, Intensive care unit; MERS, Middle East respiratory syndrome.
From Public Health England, 2018
Aspiration pneumonia
One further condition which may be seen either in hospital or in
the community is aspiration pneumonia, initiated by inhalation of Americas, Europe and Asia. The outbreak terminated that year,
stomach contents contaminated by bacteria from the mouth. Risk with only small numbers of cases occurring since. Many experts
factors include alcohol, hypnotic drugs and general anaesthesia; predict that SARS will re-emerge.
all of these may induce a patient to vomit while unconscious.
Gastric acid is very destructive to lung tissue and leads to severe
Middle East respiratory syndrome coronavirus
tissue necrosis. Damaged tissue is then prone to secondary infec-
tion, often with abscess formation. Anaerobic bacteria are par- This novel coronavirus was irst identiied in 2012 and causes
ticularly implicated, but these are often accompanied by aerobic Middle East respiratory syndrome (MERS). The clinical picture
organisms such as viridans streptococci. ranges from asymptomatic infection to severe respiratory distress
and death. Common symptoms include fever, cough and short-
ness of breath (Box 36.1). Some patients have gastro-intestinal
Treatment
symptoms such as diarrhoea; pneumonia is common but not uni-
Treatment with amoxicillin and metronidazole is usually ade- versal. In 36% of identiied cases, the patients have died (WHO,
quate. However, broader-spectrum drugs may be used if there are 2017). Camels appear to be a common host. Human-to-human
reasons to suspect Gram-negative involvement, for example, if transmission requires close contact, but there has been trans-
the patient has been in hospital or has previously been exposed mission to healthcare workers, and there have been nosocomial
to antibiotics. Options for treatment in such patients include co- outbreaks (WHO, 2017). The risk in these patients is low, but
amoxiclav, piperacillin/tazobactam and carbapenems. they should be tested to exclude the possibility (Public Health
England, 2018). Treatment is still under investigation and is cur-
rently supportive and includes supplemental oxygen and ventila-
Novel coronaviruses
tion if required. No antiviral drugs are recommended at present.
Most coronaviruses cause mild URTIs, but two have emerged in
recent years which are more serious.
Cystic fibrosis
Cystic ibrosis (CF) is an inherited, autosomal-recessive disease
Severe acute respiratory syndrome
which, at the cellular level, is caused by a defect in the transport
Clinically, the severe acute respiratory syndrome (SARS) coro- of ions in and out of cells. This leads to changes in the consis-
navirus causes pneumonitis, presenting with a lu-like prodrome tency and chemical composition of exocrine secretions. In the
and progressing to dyspnoea, dry cough and often adult respira- lungs, this is manifest by the production of very sticky, tenacious
tory distress syndrome, requiring ventilatory support. Treatment mucus which is dificult to clear by mucociliary action. The pro-
of SARS is largely supportive. It was irst described in 2003 duction of such mucus leads to airway obstruction and infection.
after a large outbreak originating in China spread throughout the These repeated infections lead to lung damage and bronchiectasis, 617
 36 THERAPEUTICS

which in turn predisposes to further infection. The pattern in CF vital, and because biochemical methods are unreliable, PCR
is of a progressive decline in lung function with episodes of acute methods are recommended (Cystic Fibrosis Trust Microbiology
worsening known as pulmonary exacerbations. The features of Laboratory Standards Working Group, 2010). The impact of other
these exacerbations include increased cough, increased sputum Gram-negative bacteria and also of organisms such as anaerobes
production, shortness of breath, chest pain, loss of appetite and which had traditionally not been thought to be pathogenic is still
decline in respiratory function. unresolved.
In recent years there has been an increase in the number of
patients in Europe and the USA found to be colonised with non-
Infective organisms
tuberculous mycobacteria. Transmission of Mycobacterium
It had been thought that the microbiology of respiratory infec- abscessus complex has been recorded (Cystic Fibrosis Trust
tions in cystic ibrosis involved a few key pathogens, but this is Mycobacterium abscessus Infection Control Working Group,
now acknowledged over recent years to be increasingly complex. 2013). Poorer outcomes after lung transplantation have been
H. inluenzae is frequently encountered in early childhood and described in patients colonised with M. abscessus (Floto et al.,
has been reported to be the most common organism at 1 year 2015). The Mycobacterium avium complex is most frequently
of age. LRTI is sometimes dificult to distinguish from upper isolated, but the number of M. abscessus complex isolated is
respiratory tract colonisation. As in healthy children, most of the increasing rapidly. There are concerns that this may be related to
infections in children with cystic ibrosis are with non-capsulate widespread use of azithromycin prophylaxis. Consensus guide-
strains. S. aureus is a common pathogen and may be isolated lines from the European Cystic Fibrosis Society and the US
from early infancy. In the UK, continuous anti-staphylococcal Cystic Fibrosis Foundation recommend annual screening for car-
prophylaxis is recommended up to the age of 3, although some riage of non-tuberculous mycobacteria and strict infection con-
centres continue beyond this time. Prophylaxis has been with trol precautions (Floto et al., 2015).
lucloxacillin, but MRSA rates vary between units and this may Fungi have also been increasingly recognised as important
affect the choice of agent. pathogens in cystic ibrosis. Aspergillus colonisation leading
P. aeruginosa is the most common pathogen isolated from to allergic bronchopulmonary aspergillosis (ABPA) has been
people with cystic ibrosis, and its prevalence increases with recognised for many years, but it has now also been suggested
age. It is possible to clear 80% of early infections with aggres- that it can cause exacerbations by producing a fungal bronchitis.
sive antibiotic therapy (e.g. ciproloxacin and an inhaled amino- Scedosporium apiospermum and Wangiella (Exophiala) derma-
glycoside) and so delay the onset of chronic colonisation. Once titidis are being isolated more commonly (Cystic Fibrosis Trust
chronic colonisation with P. aeruginosa is established, it is asso- Antibiotic Working Group, 2009).
ciated with faster decline in lung function, increased hospitalisa-
tion and reduced survival. Long-term suppressive therapy with
Treatment
inhaled antibiotics is used in these patients to slow the decline in
lung function. Although this section concentrates on antibiotic therapy, it should
An important feature of those P. aeruginosa strains which be noted that other treatments such as physiotherapy play a vital
infect patients with cystic ibrosis is their production of large part. In addition, lung transplantation can be lifesaving.
amounts of alginate, a polymer of mannuronic and glucuronic Acute respiratory exacerbations of CF caused by P. aerugi-
acid. This seems to be a virulence factor for the organism nosa are usually treated with dual antibiotic therapy with two
because it inhibits opsonisation and phagocytosis and enables agents that act by different mechanisms (Table 36.3). The length
the bacteria to adhere to the bronchial epithelium, thus inhibit- of treatment course is usually 2 weeks. Sensitivity testing of
ing clearance. It does not confer additional antibiotic resistance. Pseudomonas spp. and other non-fermenting Gram-negative
Strains which produce large amounts of alginate have a wet, bacilli should not be used in isolation to guide treatment because
slimy appearance on laboratory culture media and are termed it is frequently unreliable in this setting. The choice of antibiotics
‘mucoid’ strains. will therefore be guided by the patient’s response.
P. aeruginosa acquisition by CF patients had been thought to B. cepacia complex is often very dificult to treat, and strains
involve sporadic acquisition of environmental strains. However, may be resistant to all available antibiotics. Under these circum-
some strains of P. aeruginosa are transmissible between CF stances, combination therapy is often required.
patients. Guidelines recommend molecular ingerprinting to iden- The use of inhaled (usually nebulised) antibiotics as an adjunct
tify these epidemic strains (Cystic Fibrosis Trust Microbiology to parenteral therapy has attracted attention, both for treatment
Laboratory Standards Working Group, 2010). of acute exacerbations and for longer-term use in an attempt to
Other Gram-negative bacteria can also infect the lungs of reduce the pseudomonal load. Agents which have been admin-
patients with CF, with the Burkholderia cepacia complex being istered in this way include colistin, aminoglycosides and aztre-
the most important. Outbreaks of these organisms occurred in CF onam. The best evidence that long-term administration can be
centres in the 1980s and 1990s, leading to many deaths. Therefore, beneicial comes from a large multi-centre trial of nebulised
interaction between non-related CF patients, either socially or in tobramycin (Moss, 2001). Patients were randomised to receive
healthcare settings, is strongly discouraged. Colonisation with once-daily nebulised tobramycin or placebo in on–off cycles
genomovar IIIA of the B. cepacia complex (cenocepacia) pre- for 24 weeks, followed by open-label tobramycin to complete 2
cludes lung transplantation because of high postoperative mor- years of study. Nebulised tobramycin was safe and well toler-
618 tality rates. Correct identiication of the organism is therefore ated and was associated with a reduction in hospitalisation and
 RESPIRATORY INFECTIONS 36
Table 36.3 Antibiotics with activity against Pseudomonas

Antibiotic Comment

β-Lactams and related drugs

Ureidopenicillins Piperacillin, formulated in combination with the β-lactamase inhibitor tazobactam, is the only one of these
agents currently available in the UK.

Cephalosporins Ceftazidime is the third-generation cephalosporin active against Pseudomonas; it is very active against other
Gram-negative bacilli but has rather lower activity against Gram-positive bacteria. Ceftobiprole is a new
cephalosporin with activity against Pseudomonas and MRSA.

Carbapenems Broad-spectrum agents with good Gram-negative activity. Imipenem was the first of these drugs, but CNS
toxicity and its requirement for combination with the renal dipeptidase inhibitor cilastatin have largely led
to its replacement by meropenem. Doripenem is a newer carbapenem with similar activity to meropenem.
Ertapenem has poor activity against Pseudomonas aeruginosa.

Monobactams Aztreonam is the only monobactam available and offers good activity against Gram-negative organisms but
no activity against Gram-positive organisms.

Other antibiotic classes

Aminoglycosides Gentamicin and tobramycin have very similar activity against Pseudomonas; tobramycin is perhaps slightly
more active. Netilmicin is less active, whereas amikacin may be active against some gentamicin-resistant
strains.

Quinolones Ciprofloxacin can be given orally and parenterally, but as with ceftazidime, resistance can develop while the
patient is on treatment. Other quinolones, such as ofloxacin, its L-isomer levofloxacin, and moxifloxacin, have
better Gram-positive spectrum but concomitantly less activity against Pseudomonas.

Polymyxins Colistin (polymyxin E) can be given by inhalation and intravenously; it is usually reserved for more resistant
cases due to its toxicity.

CNS, Central nervous system; MRSA, meticillin-resistant Staphylococcus aureus.

improvements in lung function. This was at the expense of a

degree of tobramycin resistance, although this did not appear to Answers
be clinically signiicant. In patients who are intolerant of nebu- 1. A viral aetiology is the most likely cause. These are usually the same
lised treatment, tobramycin and colistin dry powder inhalers can viruses that cause colds. Bacterial infection with group A strepto-
be used (NICE, 2013b). cocci usually presents with a more severe infection. The Centor
score can be used to help determine whether bacterial infection is
likely; because there is no tonsillar exudate, history of fever, tender
Case studies anterior surgical lymphadenopathy or adenitis and no cough, the
score would be 0, indicating that bacterial infection is unlikely.
2. Antibiotics are not recommended for routine use. Treatment is
Case 36.1 directed at symptomatic relief, and most people recover within
7 days.
A 40-year-old woman, Mrs LH, presents to her primary care 3. The likely cause is of Mrs LH’s symptoms is oral candidiasis. The
doctor with a 1-week history of sore throat. She is normally presence of dysphagia is concerning and raises the question of
fit and well and has had no other symptoms other than some oesophageal involvement. If the dysphagia is significant, hospital
lethargy. admission may be indicated, and endoscopy may be required to
elucidate the extent of the infection.
4. Mrs LH maybe immunocompromised, and this must be consid-
ered. Therefore, all patients with oral candidiasis should be offered
Questions
HIV testing (British HIV Association et al., 2008).
1. What are the likely causes of Mrs LH’s sore throat?
2. Should Mrs LH be prescribed antibiotics?
The primary care doctor decides to prescribe a 10-day course of Case 36.2
penicillin V to cover a possible streptococcal infection. Two weeks
later, the patient returns. Mrs LH is feeling worse and is now expe- A 65-year-old man, Mr. NP, is found collapsed at home. He is
riencing difficulty in swallowing. Examination of her throat reveals brought into hospital. His family said that he complained of flu-
widespread white plaques. like symptoms a few days before. Mr. NP is pyrexial, tachypnoeic,
3. What is the likely diagnosis? tachycardic and hypoxic. On examination, he is found to have
4. What other investigations might be indicated? reduced air entry at the right base. 619
 36 THERAPEUTICS

depending on weight, would be the usual therapy for a severe

Questions group A streptococcal infection. Because the patient has pre-
sented in septic shock, a broader-spectrum combination such
1. What is the likely diagnosis?
as piperacillin and tazobactam and clindamycin would be used
2. What are the possible infecting organisms?
until the causative organism had been identified. The clindamy-
3. What empirical antibiotics would you choose?
cin could be stopped once the patient has stabilised, usually
after 48–72 hours.
Answers If a group A streptococcus is isolated from clinical samples, the
therapy can be rationalised to amoxicillin. Amoxicillin would usu-
1. Mr NP is likely to have community-acquired pneumonia. ally be given for 10 days, but this could be switched to oral therapy
2. The most likely causative organisms are S. pneumoniae and H. once the patient has been afebrile for 24 hours, his haemodynamic
influenzae. However, S. aureus should also be considered in post– parameters have returned to normal, and his inflammatory mark-
influenza pneumonia. ers are falling.
3. The choice of treatment for Mr NP should be guided by the ‘CURB’ 3. Intravenous immunoglobulin has been used in group A strep-
65 score. Given the history, the CURB 65 score is likely to be at tococcal infection causing toxic shock. A single dose of 2 g/kg
least 3, indicating severe disease. A broad-spectrum β-lactam, should be prescribed.
such as co-amoxiclav, and a macrolide antibiotic are usually used.
The β-lactam should be given intravenously initially.
Case 36.5
Case 36.3 A 72-year-old man, Mr AD, with a known history of COPD
presents at the hospital emergency department with increas-
A 4-year-old girl, Miss GR, attends an appointment with her ing breathlessness. Mr AD has a productive cough of cream-
primary care doctor. Her mother explains that Miss GR is com- coloured sputum, which is normal for him. He has not noticed
plaining of ear pain over the past 2 days. She is systemically an increase in purulence or volume. Chest X-ray showed hyper-
well and playing in the consultation room. On examination she inflated lungs but no focal consolidation, and a diagnosis of
is afebrile, but the tympanic membrane is inflamed. acute exacerbation of COPD was made.

Questions
Questions
1. What is the likely diagnosis?
2. Should Miss GR be prescribed antibiotics? 1. Does Mr AD require antibiotics?
2. What investigations would inform the diagnosis?

Answers
Answers
1. It is likely that Miss GR has otitis media.
2. Immediate antibiotic treatment should not be necessary given 1. Many exacerbations of COPD are non-infective. Therefore, anti-
that the infection is unilateral and the patient is over 2 years old. biotics should be reserved for when sputum has become more
However, a delayed prescription could be considered, dated for purulent.
2 days after the consultation if the girl has not improved. Amoxicillin 2. The diagnosis of an exacerbation of COPD is clinical. Sputum
for 7 days would be a reasonable choice. The dose would depend cultures should only be performed if antibiotics are required
on the patient’s weight. and if the patient is unwell enough to require referral to second-
ary care or if an initial empirical course of treatment has been
ineffective.
Case 36.4
A 30-year-old man, Mr SH, is found collapsed at home. He had
complained of a sore throat over the past few days. On arrival
Case 36.6
at hospital, Mr SH is pyrexial (38.5 °C), hypotensive with a
A 7-year-old girl, Miss TL, is seen in the hospital paediatric out-
blood pressure of 80/50 mmHg and tachycardic with a heart
patient clinic for a routine appointment. She is known to have
rate of 130 beats/min.
cystic fibrosis and has had several exacerbations in the past
which have been treated with flucloxacillin. On this visit, Miss
Questions TL is stable, but the report of sputum culture received 2 days
after the clinic shows a growth of P. aeruginosa.
1. What is the likely diagnosis?
2. What antibiotics should be prescribed for Mr SH?
3. What other treatments could be considered?
Questions
1. What treatment should be started?
Answers 2. What other options are available?
3. One week later, you receive a telephone call from Miss TL’s parents
1. Invasive group A streptococcal infection seems the most likely
that she has become unwell. They suspect Miss TL has another
diagnosis based on the clinical presentation.
chest infection. What agents might be appropriate for treating this
2. A β-lactam antibiotic, for example, amoxicillin 1 g three times
infection?
a day i.v. and clindamycin up to 1200 mg four times a day
620
 RESPIRATORY INFECTIONS 36
Answers Questions
1. Pseudomonas colonisation is associated with more rapid decline in 1. What is the likely diagnosis?
lung function, and therefore decolonisation should be attempted, 2. What treatment should Master SW be offered?
for example, using ciprofloxacin 20 mg/kg twice a day for 14 days 3. What public health measures are necessary?
and an inhaled aminoglycoside.
2. Non-pharmacological measures such as physiotherapy should also
be included. Answers
3. Combination treatment is usually favoured, depending on indi-
1. Pertussis should be considered as a possible diagnosis. This could
vidual susceptibility results. This might include a β-lactam antibi-
be confirmed by culture or PCR if Master SW has been unwell for
otic such as ceftazidime or piperacillin/tazobactam in combination
less than 2 weeks or by oral fluid IgG testing if he has been unwell
with an aminoglycoside such as tobramycin. In this case, Miss TL
for more than 2 weeks.
became unwell while on the original decolonisation regime; there-
2. A 3-day course of azithromycin or a 7-day course of erythromycin
fore, an alternative regime would be indicated.
or clarithromycin is the usual treatment for pertussis.
3. Pertussis is a notifiable disease, and in England, the local health
Case 36.7 protection team should be informed when the diagnosis is sus-
pected. Because pertussis is highly infectious, Master SW should
A 4-year-old boy, Master SW, presents with bouts of paroxys- be excluded from nursery until 5 days after he starts treatment or
mal coughing which often end in vomiting. The previous week, 21 days after the cough started in line with Public Health England
Master SW had been unwell, with coryzal symptoms. Master SW (2016c) guidance.
has missed several of his standard vaccinations because his par-
ents were concerned about ‘overloading’ his immune system.

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Further reading
Bennett, J.E., Dolin, R., Blaser, M.J. (Eds.), 2015. Mandell, Douglas and Kalil, A.C., Meterski, M.L., Klompas, M., et al., 2016. Management of adults
Bennett’s Principles and Practice of Infectious Disease, eighth ed. Elsevier, with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical
New York, pp. 748–885. Practice Guidelines by the Infectious Diseases Society of America and the
American Thoracic Society. Clin. Infect. Dis. 63 (5), e61–e111.
622
THERAPEUTICS

37 Urinary Tract Infections

Neil J. B. Carbarns

Key points normally considered to be urethral contaminants unless there

are exceptional clinical circumstances, such as a sick immu-
• Urinary tract infection (UTI) is one of the most common com-
nosuppressed patient.
plaints seen in general practice, is one of the most common
reasons for prescribing antibiotics and accounts for about one-
• Asymptomatic bacteriuria: signiicant bacteriuria in the
third of hospital-acquired infections. absence of symptoms in the patient.
• Escherichia coli is the most frequent pathogen, accounting for • Cystitis: a syndrome of frequency, dysuria and urgency, some-
more than three-quarters of community-acquired UTIs. times with suprapubic tenderness, which usually suggests
• Antimicrobial sensitivity patterns are changing. E. coli and infection restricted to the lower urinary tract, that is, the blad-
other bacteria are becoming increasingly resistant to amoxicil- der and urethra.
lin, cephalosporins, trimethoprim and the quinolones, both in • Urethral syndrome: a syndrome of frequency and dysuria in the
healthcare-related and community-acquired infection. absence of signiicant bacteriuria with a conventional pathogen.
• Symptoms are variable; many UTIs are asymptomatic and some • Acute pyelonephritis: an acute infection of one or both kid-
present atypically, particularly in children and the elderly. neys with lank pain, tenderness and fever. Usually, the lower
• The concept of significant bacteriuria (at least 100,000 organ- urinary tract is also involved.
isms/mL of urine) is generally used to distinguish between
• Chronic pyelonephritis: a potentially confusing term used in
contamination and infection, but fewer organisms than this can
still cause symptoms and disease. One-third of young women
different ways. It can refer to continuous excretion of bacteria
with cystitis have lower counts. from the kidney, to frequent, recurring infection of the renal
• Asymptomatic UTI should be treated in children and preg- tissue or to a particular type of pathology of the kidney seen
nant women, but first it should be confirmed by having two microscopically or by radiographic imaging, which may or
urine cultures with significant numbers of the same pathogen. may not be caused by infection. Although chronic infections
Treatment options are reduced because some antibiotics are of renal tissue are relatively rare, they do occur in the presence
contraindicated in these patient groups. of kidney stones and in tuberculosis.
• Catheter-related UTI should be treated only when the patient • Relapse and reinfection: relapse is recurrence of a UTI caused
has systemic evidence of infection. by the same organism that caused the original infection.
• A 3-day treatment course is usually sufficient in uncomplicated Reinfection is recurrence caused by a different organism and
lower UTI in women. Longer, 7- to 14-day courses are recom-
is, therefore, a new infection.
mended for men, children and pregnant women.
• Urosepsis: includes clinical evidence of UTI with two or more
• Although it is not always necessary to send urine samples for
laboratory analysis unless empirical treatment fails, they pro-
criteria of a systemic inlammatory response, for example,
vide local epidemiology and antibiotic resistance data. Urine abnormal temperature, white blood cell count, heart rate or
dipsticks for pyuria and bacteriuria are useful screening tests. respiratory rate.
• Antibiotic prophylaxis may be beneficial in women with recur-
rent UTIs and in children with structural or functional abnormali-
ties. Non-antimicrobial prevention measures include probiotics
and cranberry products. Epidemiology
UTIs are among the most common infectious diseases occurring in
The term urinary tract infection (UTI) usually refers to the pres- either the community or healthcare setting. Uncomplicated UTIs
ence of organisms in the urinary tract together with symptoms, typically occur in healthy adult non-pregnant women, whereas
and sometimes signs, of inlammation. However, it is more pre- complicated UTIs are found in either sex and at any age, frequently
cise to use one of the following terms. associated with structural or functional urinary tract abnormalities.
• Signiicant bacteriuria: deined as the presence of at least
100,000 bacteria/mL urine. A quantitative deinition such as
Infants
this is needed because small numbers of bacteria are nor-
mally found in the anterior urethra and may be washed out UTI is a problem in all age groups, although its prevalence varies
into urine samples. Counts of fewer than 100 bacteria/mL are markedly. In infants up to 6 months of age, symptomatic UTI has 623
 37 THERAPEUTICS

a prevalence of about 2 cases per 1000 and is much more com- Recurrent and complicated UTIs associated with underlying
mon in boys than in girls. In addition to these cases, asymptom- structural abnormalities, such as congenital anomalies, neu-
atic UTI is much more common than this, occurring in around 2% rogenic bladder and obstructive uropathy, are often caused by
of boys in their irst few months of life. more resistant organisms such as Pseudomonas aeruginosa,
Enterobacter and Serratia species. In complicated UTI there is an
increased rate of isolation of multiple organisms. Organisms such
Children
as these are also more commonly implicated in hospital-acquired
In preschool children, UTIs become more common and the sex urinary infections, including those in patients with poor urinary
ratio reverses, such that the prevalence rate is 5% in girls and catheter care, which are an important source of cross-infection.
0.5% in boys. In older children, the prevalence of bacteriuria Rare causes of urinary infection, nearly always in association
falls to 1.2% among girls and 0.03% among boys. Overall, about with structural abnormalities or catheterisation, include anaero-
3–5% of girls and 1–2% of boys will experience a symptom- bic bacteria and fungi. Urinary tract tuberculosis is an infrequent
atic UTI during childhood. However, in girls, about two-thirds but important diagnosis that may be missed through lack of clini-
of UTIs are asymptomatic. The occurrence of bacteriuria during cal suspicion. A number of viruses are excreted in urine and may
childhood appears to correlate with a higher incidence of bacte- be detected by culture or nucleic acid ampliication methods,
riuria in adulthood. but symptomatic infection is conined to immunocompromised
patients, particularly children following peripheral blood stem
cell transplant, in whom adenoviruses and polyomaviruses such
Adults
as BK virus are associated with haemorrhagic cystitis.
When women reach adulthood, the prevalence of bacteriuria In hospitals, a major predisposing cause of UTI is urinary cath-
rises to between 3% and 5%. Each year, about a quarter of these eterisation. With time, even with closed drainage systems and
women with bacteriuria clear their infections spontaneously and scrupulous hygiene, bacteria can be found in almost all catheters,
are replaced by an equal number of newly infected women, who and this is a risk of the development of symptomatic infection.
are often those with a history of previous infections. On aver-
age, about 10% of adult women have a symptomatic UTI each
year, and more than half of adult women report that they have
had a symptomatic UTI at some time. Two to ive percent of Pathogenesis
women have recurrent UTIs, with the peak age of incidence in
their early 20s and with a genetic predisposition. UTI is uncom- There are three possible routes by which organisms might reach
mon in young healthy men, with 0.5% of adult men having the urinary tract: the ascending, blood-borne and lymphatic
bacteriuria. Structural or functional abnormality is associated routes. There is little evidence for the last route in humans.
with UTI in men. The rate of symptomatic UTI in men rises Blood-borne spread to the kidney can occur in bacteraemic ill-
progressively with age, from 1% annually at age 18 to 4% at nesses, most notably Staphylococcus aureus septicaemia, but by
age 60 years. far the most frequent route is the ascending route.
In women, UTI is preceded by colonisation of the vagina,
perineum and periurethral area by the pathogen, which then
Elderly
ascends into the bladder via the urethra. Uropathogens colonise
In the elderly of both sexes, the prevalence of bacteriuria increases the urethral opening of men and women. That the urethra in
dramatically, reaching at least 20% among women and 10% women is shorter than in men and the urethral meatus is closer to
among men. Asymptomatic bacteriuria in older persons does not the anus are probably important factors in explaining the prepon-
seem to have any harmful effects, and there is no evidence that derance of UTI in females. Further, sexual intercourse appears
treating it is beneicial, including no decrease in urinary inconti- to be important in forcing bacteria into the female bladder, and
nence. Therefore, routine treatment of asymptomatic bacteriuria this risk is increased by the use of diaphragms and spermicides,
in older persons is not indicated (Nicolle, 2009). which have both been shown to increase E. coli growth in the
vagina. Whether circumcision reduces the risk of infection in
adult men is not known, but it markedly reduces the risk of UTI
in male infants.
Aetiology and risk factors
Organism
More than 95% of uncomplicated UTIs are caused by a single
bacterial species. In acute uncomplicated UTI acquired in the E. coli causes most UTIs, and although there are many serotypes
community, Escherichia coli is by far the most common caus- of this organism, only a few of these are responsible for a dis-
ative bacterium, being responsible for about 80% of infections. proportionate number of infections. Although there are as yet no
The remaining 20% are caused by other Gram-negative enteric molecular markers that uniquely identify uropathogenic E. coli,
bacteria such as Klebsiella and Proteus species, and by Gram- some strains possess certain virulence factors that enhance their
positive cocci, particularly enterococci and Staphylococcus sap- ability to cause infection, particularly infections of the upper
rophyticus. The latter organism is almost entirely restricted to urinary tract. Recognised factors include bacterial surface struc-
624 infections in young, sexually active women. tures called P-imbriae, which mediate adherence to glycolipid
 URINARY TRACT INFECTIONS 37
receptors on renal epithelial cells, possession of the iron-scav- is associated with future complications such as chronic pyelone-
enging aerobactin system, and increased amounts of capsular K phritis in adulthood, hypertension and renal failure. It is therefore
antigen, which mediates resistance to phagocytosis. vital to make the diagnosis early, and any child with a suspected
UTI should receive urgent expert assessment.
Host
Children
Although many bacteria can readily grow in urine, and Louis
Pasteur used urine as a bacterial culture medium in his early Children older than 2 years with UTI are more likely to pres-
experiments, the high urea concentration and extremes of osmo- ent with some of the classic symptoms such as frequency, dys-
lality and pH inhibit growth. Other defence mechanisms include uria and haematuria. However, some children present with acute
the lushing mechanism of bladder emptying, because small num- abdominal pain and vomiting, and this may be so marked as to
bers of bacteria inding their way into the bladder are likely to be raise suspicions of appendicitis or other intra-abdominal pathol-
eliminated when the bladder is emptied. Moreover, the bladder ogy. Again, however, it is extremely important that the diagno-
mucosa, by virtue of a surface glycosaminoglycan, is intrinsically sis of UTI is made promptly to pre-empt the potential long-term
resistant to bacterial adherence. Presumably, in suficient num- consequences. National guidance has been published in the UK
bers, bacteria with strong adhesive properties can overcome this on paediatric UTIs to promote a more consistent clinical practice
defence. Finally, when the bladder is infected, white blood cells by ensuring prompt, accurate diagnosis and appropriate manage-
are mobilised to the bladder surface to ingest and destroy invad- ment (National Institute for Health and Care Excellence [NICE],
ing bacteria. The role of humoral antibody-mediated immunity 2007). A key feature of the guidance is that children with unex-
in defence against infection of the urinary tract remains unclear. plained fever should have their urine tested within 24 hours and
Genetic susceptibility of individual patients to UTI has been attention is given to avoiding over- or under-diagnosis, appropri-
reviewed (Lichtenberger and Hooton, 2008). ate investigation and the prompt start of antibiotic treatment.

Abnormalities of the urinary tract Adults

Any structural abnormality leading to the obstruction of uri- In adults, the typical symptoms of lower UTI include frequency,
nary low increases the likelihood of infection. Such abnormali- dysuria, urgency and haematuria. Acute pyelonephritis (upper
ties include congenital anomalies of the ureter or urethra, renal UTI) usually causes fever, rigors and loin pain in addition to
stones and, in men, enlargement of the prostate. Renal stones lower tract symptoms. Systemic symptoms may vary from insig-
can become infected with bacteria, particularly Proteus and niicant to extreme malaise. Importantly, untreated cystitis in
Klebsiella species, and thereby become a source of ‘relapsing’ adults rarely progresses to pyelonephritis, and bacteriuria does
infection. Vesicoureteric relux is a condition caused by failure of not seem to carry the adverse long-term consequences that it does
physiological valves at the junction of the ureters and the bladder in children.
which allows urine to relux towards the kidneys when the blad- In about 40% of women with dysuria, urgency and frequency,
der contracts. It is probable that vesicoureteric relux plays an the urine sample contains fewer than 100,000 bacteria/mL. These
important role in childhood UTIs that lead to chronic renal dam- patients are said to have the urethral syndrome. Some have a true
age (scarring) and persistence of infection. If there is a dimin- bacterial infection but with relatively low counts (100–1000 bac-
ished ability to empty the bladder such as that due to spinal cord teria/mL). Some have urethral infection with Chlamydia tracho-
injury, there is an increased risk of bacteriuria. matis, Neisseria gonorrhoeae, mycoplasmas or other ‘fastidious’
organisms, any of which might give rise to symptoms indistin-
guishable from those of cystitis. In others, no known cause can
be found by conventional laboratory techniques. It is important
Clinical manifestations to consider the possibility of urinary tract tuberculosis, because
special methods are necessary for its detection. Sometimes the
Most UTIs are asymptomatic. Symptoms, when they do occur, symptoms are of non-infectious origin, such as menopausal oes-
are principally the result of irritation of the bladder and urethral trogen deiciency or allergy. However, most cases of urethral syn-
mucosa. However, the clinical features of UTI are extremely drome will respond to standard antibiotic regimens as used for
variable and to some extent depend on the age of the patient. treating conirmed UTI.

Infants Elderly
Infections in newborns and infants are often overlooked or mis- Although UTI is frequent in the elderly, most cases are asymp-
diagnosed because the signs may not be referable to the urinary tomatic, and even when present, symptoms are not diagnostic
tract. Common but non-speciic presenting symptoms include because frequency, dysuria, hesitancy and incontinence are fairly
failure to thrive, vomiting, fever, diarrhoea and apathy. Further, common in elderly people without infection. Further, there may
conirmation may be dificult because of problems in obtaining be non-speciic systemic manifestations such as confusion and
adequate specimens. UTI in infancy and childhood is a major falls, or alternatively the infection may be the cause of dete-
risk factor for the development of renal scarring, which in turn rioration in pre-existing conditions such as diabetes mellitus or 625
 37 THERAPEUTICS

congestive cardiac failure, whose clinical features might pre- are concerns that these are reliable only when applied to fresh
dominate. UTI is one of the most frequent causes of admission to urine samples tested at the point of care. Assessment of colour
hospital among the elderly. changes on dipsticks can be subjective, and automated reading
systems have been developed to assist interpretation. Generally,
the negative predictive value is better than the positive predictive
value, so their preferred use is as screening tests to identify those
Investigations specimens which are least likely to be infected and which there-
fore do not require culture. A perfectly valid alternative is just to
The key to successful laboratory diagnosis of UTI lies in obtain- hold the specimen up to the light: Specimens that are visibly clear
ing an uncontaminated urine sample for microscopy and cul- are very likely to be sterile.
ture. Contaminating bacteria can arise from skin, vaginal lora The leucocyte esterase test detects enzyme released from leu-
in women and penile lora in men. Patients therefore need to be cocytes in urine and is approximately 90% sensitive at detecting
instructed in how to produce a midstream urine sample (MSU). white blood cell counts greater than 10/mm3. It will be posi-
For women, this requires careful cleansing of the perineum and tive even if the cells have been destroyed because of delays in
external genitalia with soap and water. Uncircumcised men transport to a laboratory. However, vitamin C and antibiotics in
should retract the foreskin. This is followed by a controlled mic- the urine such as cephalosporins, gentamicin and nitrofurantoin
turition in which about 20 mL of urine from only the middle por- may interfere with the reaction. Although the presence of leu-
tion of the stream is collected, the initial and inal components cocytes is common in UTIs, it may also occur in other condi-
being voided into the toilet or bedpan. Understandably, this is not tions. Particularly in children, white blood cells can be present for
always possible and many so-called MSUs are in fact clean-catch many reasons, including fever alone.
specimens in which the whole urine volume is collected into a The nitrite test (also called the Griess test) detects urinary
sterile receptacle and an aliquot transferred into a specimen pot nitrite made by bacteria that can convert excreted dietary nitrate
for submission to the laboratory. These are more likely to contain used as a food preservative to nitrite. Although the coliform bac-
urethral contaminants. In very young children, special collection teria that commonly cause UTI can be detected in this way, some
pads for use inside nappies or stick-on bags are useful ways of organisms cannot, for example, enterococci, group B strepto-
obtaining a urine sample. Occasionally, in-and-out diagnostic cocci, Pseudomonas, because they do not contain the convert-
catheterisation or even suprapubic aspiration directly from the ing enzyme. In addition, the test depends on suficient nitrate in
bladder is necessary. the diet and on allowing enough time, at least 4 hours, for the
For primary care doctors located some distance from a labo- chemical conversion to occur in the urine. Performance of the
ratory, transport of specimens is a problem. Specimens must dipstick test is generally less diagnostic in infants and younger
reach the laboratory within 1–2 hours or should be refrigerated; children than in the older age groups, and this may relate in part
otherwise, any bacteria in the specimen will multiply and might to the small capacity and frequent emptying of the infant bladder,
give rise to a false-positive result. Methods of overcoming bacte- resulting in lower numbers of organisms and less pyuria. The use
rial multiplication in urine include the addition of boric acid to of dipsticks alone for the diagnosis of UTI is not recommended
the container and the use of dip-slides, in which an agar-coated for children younger than 3 years (NICE, 2007). The inability of
paddle is dipped into the urine and submitted directly to the lab- the test to detect group B streptococci also makes it a relatively
oratory for incubation. Both of these alternatives have dificul- inappropriate test for screening for asymptomatic bacteriuria in
ties. For the boric acid technique, it is important that the correct pregnancy, in which this organism assumes particular importance
amount of urine is added to the container to achieve the appropri- as a cause of neonatal sepsis.
ate concentration of boric acid (1.8% w/v), because the chemi- Although a negative dipstick test for leucocytes and nitrites can
cal has signiicant antibacterial activity when more concentrated. quite accurately predict absence of infection, their absence does
When the dip-slide is used, no specimen is available on which to not necessarily predict non-response to antibiotic treatment, and
do cell counts. further research is needed on this. Some experts consider that
Concerns about the relative expense and slow turnaround time detection of nitrites in a symptomatic patient should prompt initi-
of urine microscopy and culture have stimulated interest in alter- ation of treatment (Gopal Rao and Patel, 2009). An algorithm for
native diagnostic strategies. Some advocate a policy of empirical the use of dipstick testing in uncomplicated UTI in adult women
antimicrobial treatment in the irst instance and reserve investiga- is set out in Fig. 37.1.
tion only for those cases who do not respond. Others are in favour There are other rapid methods for detecting bacteriuria, such as
of using cheaper, more convenient screening tests, for example, tests for interleukin-8, and no shortage of data concerning their
urine dipsticks. It is important to be aware that there is no rapid sensitivity and speciicity, but the optimal strategy will always
screening test that will reliably detect all UTIs. Urine microscopy be a compromise between accuracy, speed, convenience and
and culture remain the standard by which other investigations are cost, and is likely to be very different for different settings and
measured. populations.

Dipsticks Microscopy
Dipsticks for rapid near-patient testing for urinary blood, protein, Microscopy is the irst step in the laboratory diagnosis of UTI
626 nitrites and leucocyte esterase are usually used, although there and can be readily performed in practice. A drop of uncentrifuged
 URINARY TRACT INFECTIONS 37
Symptoms of UTI

Perform near-
patient dipstick
test

Nitrite positive Nitrite negative Nitrite negative Nitrite negative

Leucocytes Leucocytes Leucocytes Leucocytes

positive or negative negative positive negative

Protein Protein Protein or blood

positive or negative negative positive

Blood negative

Probable UTI UTI very unlikely UTI or urethral Consider other

syndrome diagnosis
Possibly urethral
syndrome

Treat empirically Reassure and give Review symptoms Review symptoms

with first-line advice on managing
antibiotic symptoms Treat if clinically Treat if clinically
appropriate appropriate
Do not routinely
Send urine for Send urine for
send urine for
culture culture
culture unless
symptoms recur

Fig. 37.1 Algorithm for diagnosis of acute uncomplicated urinary tract infection (UTI) in adult women.

urine is placed on a slide, covered with a coverslip and examined particularly at the extremes of age, in pregnancy and in pyelo-
under a 40× objective. Excess white cells are usually seen in the nephritis. Red blood cells may be seen, as may white cell casts,
urine of patients with symptomatic UTI, and more than 10 per which are suggestive of pyelonephritis. As a rule of thumb,
high-power ield is abnormal. Notably, there are other methods the presence of at least one bacterium per ield correlates with
in common use, and laboratories may report white cell counts per 100,000 bacteria/mL.
microlitre (mm3) of urine or per millilitre. Automated machinery
for microscopy of urine is increasingly used and offers increased
Culture
precision and handling capacities of more than 100 specimens/h.
Although there is a substantial capital cost to such equipment, it Bladder urine is normally sterile, but when passed via the urethra,
is offset by savings in labour and bacterial culture materials. One it is inevitable that some contamination with the urethral bacte-
feature of this equipment is that it is generally much more sensi- rial lora will occur. This is why it is important that laboratories
tive in detecting cells, so much so that laboratories using such sys- quantify the number of bacteria in urine specimens. In work car-
tems will have a much higher number for signiicant results (e.g. ried out more than 40 years ago, it was demonstrated that patients
greater than 50 rather than greater than 10 white cells per mm3). with UTI usually have at least 100,000 bacteria/mL, whereas in
It is important not to be too rigid in the interpretation of patients without infection, the count is usually less than 1000
the white cell count. UTI may occur in the absence of pyuria, bacteria/mL. Between these igures lies a grey area, and it should 627
 37 THERAPEUTICS

be appreciated that the MSU is not an infallible guide to the pres-

Table 37.1 Common management problems with urinary tract
ence or absence of urinary infection. True infections may be asso-
infections
ciated with low counts, particularly when the urine is very dilute
because of excessive luid intake or where the pathogen is slow Problem Comments
growing. Although the quantitative criterion for ‘signiicant’ bac-
teriuria is generally taken as greater than 100,000/mL, in some Asymptomatic Asymptomatic bacteriuria should be
infection treated where there is a risk of serious con-
speciic groups, it is less: for men, it is greater than 1000/mL,
sequences (e.g. in childhood), where there
and for women with symptoms of UTI, it is greater than 100/mL is renal scarring, and in pregnancy. Other-
(Scottish Intercollegiate Guidelines Network [SIGN], 2012). wise, treatment is not usually required.
Most genuine infections are caused by one single bacterial spe-
cies; mixed cultures usually suggest contamination. If a patient is Catheter in situ, Systemic symptoms may result from
taking an antibiotic when a urine specimen is obtained for cul- patient unwell catheter-associated UTI and should respond
ture, growth of bacteria may be inhibited. The laboratory may to antibiotics, although the catheter is likely
to remain colonised. Local symptoms such
perform a test to detect antimicrobial substances in the urine, and as urgency are more likely to reflect urethral
this may be useful information to clarify circumstances in which irritation than infection.
the culture is negative but a signiicant pyuria is present.
Catheter in situ, Unless the patient is systemically unwell,
urine cloudy or antibiotics are unlikely to achieve much and
smelly may give rise to resistance. Interventions of
uncertain benefit include bladder washouts
Treatment or a change of catheter.

Although many, and perhaps most, cases clear spontaneously Penicillin allergy Clarify ‘allergy’: vomiting or diarrhoea
given time, symptomatic UTI usually merits antibiotic treat- are not allergic phenomena and do not
ment to eradicate both symptoms and pathogen. Asymptomatic contraindicate penicillins. Penicillin-induced
bacteriuria may or may not need treatment depending upon the rash is a contraindication to amoxicillin, but
circumstances of the individual case. Bacteriuria in children cephalosporins are likely to be tolerated.
Penicillin-induced anaphylaxis suggests
and in pregnant women requires treatment, as does bacteriuria
that all β-lactams should be avoided.
present when surgical manipulation of the urinary tract is to be
undertaken, because of the potential complications. On the other Symptoms of UTI, Exclude urethritis, candidosis, etc.
hand, in non-pregnant, asymptomatic bacteriuric adults without but no bacteriuria Otherwise, likely to be urethral syndrome,
any obstructive lesion, screening and treatment are probably which usually responds to conventional
unwarranted in most circumstances. Unnecessary treatment antibiotics.
will lead to selection of resistant organisms and puts patients
Bacteriuria, but no May suggest contamination. However,
at risk of adverse drug effects including bowel infection with
pyuria pyuria is not invariable in UTI and may be
Clostridium dificile, which has been particularly associated absent particularly in pyelonephritis, preg-
with the use of quinolones, cephalosporins and co-amoxiclav. nancy, neonates, the elderly, and Proteus
A number of common management problems are summarised infections.
in Table 37.1.
Pyuria but no Usually, the patient has started antibiotics
bacteriuria before taking the specimen. Rarely, a fea-
Non-specific treatments ture of unusual infections (e.g. anaerobes,
tuberculosis).
Advising patients with UTI to drink a lot of luids is common prac-
tice on the theoretical basis that more infected urine is removed Urine grows Usually reflects perineal candidosis and
by frequent bladder emptying. This is plausible, although not Candida contamination. True candiduria is rare and
evidence based. Some clinicians recommend urinary analgesics may reflect renal candidosis or systemic
such as potassium or sodium citrate, which alkalinise the urine, infection with candidaemia.
but these should be used as an adjunct to antibiotics. They should
Urine grows two or Mixed UTI is unusual; mixed cultures are
not be used in conjunction with nitrofurantoin, which is active more organisms likely to reflect perineal contamination.
only at acidic pH. A repeat should be sent unless this is
impractical (e.g. frail elderly patients), in
which case best guess treatment should be
Antimicrobial chemotherapy instituted if clinically indicated.
The principles of antimicrobial treatment of UTI are the same
Symptoms recur May represent relapse or reinfection. A
as those of the treatment of any other infection: From a group
repeat urine culture should be performed
of suitable drugs chosen on the basis of eficacy, safety and shortly after treatment.
cost, select the agent with the narrowest possible spectrum
and administer it for the shortest possible time. In general, UTI, Urinary tract infection.
628 there is no evidence that bactericidal antibiotics are superior
 URINARY TRACT INFECTIONS 37
to bacteriostatic agents in treating UTI, except perhaps in effective for UTI because it is chemically unstable in the urinary
relapsing infections. Blood levels of antibiotics appear to be tract (Kumarasamy et al., 2010).
unimportant in the treatment of lower UTI; what matters is
the concentration in the urine. However, blood levels probably
Uncomplicated lower urinary tract infections
are important in treating pyelonephritis, which may progress
to bacteraemia. Drugs suitable for the oral treatment of cystitis The problem with empirical treatment is that more than 10% of
include trimethoprim; the β-lactams, particularly amoxicillin, the healthy adult female population would receive an antibiotic
co-amoxiclav and cefalexin; luoroquinolones such as cipro- each year. The use of antibiotics to this extent in the population
loxacin, norloxacin and oloxacin; and nitrofurantoin. Where has implications for antibiotic resistance, a major focus of pub-
intravenous administration is required, suitable agents include lic health policy worldwide. This highlights the tension between
β-lactams such as amoxicillin and cefuroxime, quinolones, and maximising the beneit for individuals and minimising antibiotic
aminoglycosides such as gentamicin. resistance at a population level. Strategies have included diag-
In renal failure, it may be dificult to achieve adequate ther- nostic algorithms to predict more precisely who has a UTI, as
apeutic concentrations of some drugs in the urine, particularly well as issuing delayed prescriptions (Mangin, 2010).
nitrofurantoin and quinolones. Further, accumulation and toxic- Therapeutic decisions should be based on accurate, up-to-date
ity may complicate the use of aminoglycosides. Penicillins and antimicrobial susceptibility patterns. Among almost 2500 E. coli
cephalosporins attain satisfactory concentrations and are rela- isolates in a European multicentre survey, the resistance rates
tively non-toxic, and are therefore the agents of choice for treat- were 30% for amoxicillin, 15% for trimethoprim, 3.4% for co-
ing UTI in the presence of renal failure. amoxiclav, 2.3% for ciproloxacin, 2.1% for cefadroxil and 1.2%
for nitrofurantoin (Kahlmeter, 2003). These igures are lower
than most routine laboratory data would suggest, but it should
Antibiotic resistance
be remembered that the experience of diagnostic laboratories is
Antimicrobial resistance is a major concern worldwide. The sus- likely to be biased by the overrepresentation of specimens from
ceptibility proile of commonly isolated uropathogens has been patients in whom empirical treatment has already failed. It is
constantly changing. Highly antibiotic-resistant organisms such important to be aware of local variations in sensitivity pattern
as Acinetobacter and coliform bacteria of many species that and to balance the risk of therapeutic failure against the cost of
produce extended-spectrum β-lactamase (ESBL) enzymes have therapy.
emerged in recent years. They are particularly of concern as a
cause of UTI in community-based patients because oral treatment
Adults
options are limited. Previously, most ESBL-producing bacteria
were hospital-acquired and occurred in specialist units. The preference for best guess therapy would seem to be a choice
ESBL-producing bacteria are clinically important because between trimethoprim, an oral cephalosporin such as cefalexin,
they produce enzymes that destroy almost all commonly used co-amoxiclav or nitrofurantoin, with the proviso that therapy can
β-lactams except the carbapenem class, rendering most penicil- be reined once sensitivities are available. The quinolones are
lins and cephalosporins largely useless in clinical practice. Some best reserved for treatment failures and more dificult infections,
ESBL enzymes can be inhibited by clavulanic acid, and com- because overuse of these important agents is likely to lead to
binations of an agent containing it, for example, co-amoxiclav, an increase in resistance, as has been seen in countries such as
with other oral broad-spectrum β-lactams, for example, ceixime Spain and Portugal. These recommendations are summarised in
or cefpodoxime, have been used to treat UTIs caused by ESBL- Table 37.2.
producing E. coli. These combinations are unlicensed and their Other drugs that have been used for the treatment of UTI
effectiveness is variable. include co-trimoxazole, pivmecillinam, fosfomycin and earlier
In addition, many ESBL-producing bacteria are multiresis- quinolones such as nalidixic acid. Co-trimoxazole was recognised
tant to non-β-lactam antibiotics as well, such as quinolones, as a cause of bone marrow suppression and other haematological
aminoglycosides and trimethoprim, narrowing treatment side effects, and in the UK, its use is greatly restricted. Further,
options. ESBL E. coli is often pathogenic, and a high propor- despite superior activity in vitro, there is no convincing evidence
tion of infections result in bacteraemia with resultant mortality. that it is clinically superior to trimethoprim alone in the treatment
Some strains cause outbreaks both in hospitals and in the com- of UTI caused by strains susceptible to both. Pivmecillinam is an
munity. Empirical treatment strategies may need to be reviewed oral prodrug that is metabolised to mecillinam, a β-lactam agent
in settings where ESBL-producing strains are prevalent, and it with a particularly high afinity for Gram-negative penicillin-
may be considered appropriate to use a carbapenem in seriously binding protein 2 and a low afinity for commonly encountered
ill patients until an infection has been proved not to involve an β-lactamases, and which therefore has theoretical advantages in
ESBL producer. the treatment of UTI. Pivmecillinam has been extensively used
Recently, even more resistant strains have emerged in India for cystitis in Scandinavian countries, where it does not seem to
and Pakistan, with subsequent transfer to the UK, that carry a have led to the development of resistance, and for this reason,
gene for a novel New Delhi metallo-β-lactamase-1 that also con- there have been calls for wider recognition of its usefulness, par-
fers resistance to carbapenems. This blaNDM-1 gene was mostly ticularly for UTI caused by ESBL-producing strains. Fosfomycin
found among E. coli and Klebsiella, which were highly resistant is a broad-spectrum antibiotic with pharmacokinetic and pharma-
to all antibiotics except to colistin and tigecycline, which is not codynamic properties that favour its use for treatment of cystitis 629
 37 THERAPEUTICS

Table 37.2 Oral antibiotics used for lower urinary tract infections

Antibiotic Dose (adult) Side effects Contraindications Comments

Amoxicillin 250–500 mg three times Nausea, diarrhoea, allergy Penicillin hypersensitivity High levels of resistance (>50%)
a day in Escherichia coli not used
empirically

Co-amoxiclav 375–625 mg three times See amoxicillin See amoxicillin Amoxicillin in combination with
a day clavulanic acid

Cefalexin 250–500 mg four times Nausea, diarrhoea, allergy Cephalosporin hypersensitiv-

a day ity, porphyria

Trimethoprim 200 mg twice a day Nausea, pruritus, allergy Pregnancy, neonates, folate
deficiency, porphyria

Nitrofurantoin 50 mg four times a day Nausea, allergy, rarely Renal failure, neonates, Modified-release form may be
pneumonitis, pulmonary porphyria, glucose-6- given as 100 mg twice daily;
fibrosis, neuropathy phosphate dehydrogenase inactive against Proteus
deficiency

Ciprofloxacin 100–500 mg twice a day Rash, pruritus, tendinitis Pregnancy, children Reserve for difficult cases

with a single oral dose (Falagas et al., 2010). Finally, older qui- Renal scarring occurs in 5–15% of children with UTI, who
nolones such as nalidixic acid and cinoxacin were once widely should be identiied so that appropriate treatment can be insti-
used, but generally these agents have given ground to the more tuted. Unfortunately, the subgroup at high risk cannot be pre-
active luorinated quinolones. dicted, and for this reason, many clinicians choose to investigate
all children with UTI, for example, using ultrasound and radio-
isotope scanning.
Duration of treatment
The question of duration of treatment has received much atten-
Acute pyelonephritis
tion. Traditionally, a course of 7–10 days has been advocated, and
this is still the recommendation for treating men, in whom the pos- Patients with pyelonephritis may be severely ill and, if so, will
sibility of occult prostatitis should be borne in mind. For women, require admission to hospital and initial treatment with a par-
though, there has been particular emphasis on the suitability of enteral antibiotic. Suitable agents with good activity against
short-course regimens such as 3-day or even single-dose therapy. E. coli and other Gram-negative bacilli include cephalosporins
The consensus of an international expert working group was that such as cefuroxime and ceftazidime, some penicillins such as
3-day regimens are as effective as longer regimens in the cases of co-amoxiclav, quinolones, and aminoglycosides such as gen-
trimethoprim and quinolones. β-Lactams have been inadequately tamicin (Table 37.3). A irst-choice agent would be parenteral
investigated on this point, but short courses are generally less cefuroxime, gentamicin or ciproloxacin. When the patient is
effective than trimethoprim and quinolones, and nitrofurantoin improving, the route of administration may be switched to oral
requires further study before deinite conclusions can be drawn. therapy, typically using a quinolone. Conventionally, treatment
Single-dose therapy, with its advantages of cost, adherence and is continued for 10–14 days, although shorter courses of 7 days
the minimisation of side effects, has been used successfully in have been proven effective in patients who are less severely ill
many studies but in general is less effective than when the same at the outset.
agent is used for a longer period. In hospital-acquired pyelonephritis, there is a risk that the
In the urethral syndrome, it is worth trying a 3-day course of infecting organism may be resistant to the usual irst-line drugs.
one of the agents mentioned earlier. If this fails, a 7-day course In such cases it may be advisable to start a broad-spectrum agent
of tetracycline could be tried to deal with possible chlamydia or such as ceftazidime, ciproloxacin or meropenem.
mycoplasma infection.
Relapsing urinary tract infection
Children
The main causes of persistent relapsing UTI are renal infec-
In children, the risk of renal scarring is such that UTI should be tion, structural abnormalities of the urinary tract and, in men,
diagnosed and treated promptly, even if asymptomatic. The drugs chronic prostatitis. Patients who do not respond positively on a
of choice include β-lactams, trimethoprim and nitrofurantoin. 7- to 10-day course should be given a 2-week course, and if that
Quinolones are relatively contraindicated in children because fails, a 6-week course can be considered. Structural abnormalities
of the theoretical risk of causing cartilage and joint problems. may need surgical correction before a cure can be maintained. It
630 Children should be treated for 7–10 days. is essential that prolonged courses (i.e. >4 weeks) are managed
 URINARY TRACT INFECTIONS 37
Table 37.3 Parenteral antibiotics used for pyelonephritis

Antibiotic Dose (adult) Side effects Contraindications Comments

Cefuroxime 750 mg three times a day Nausea, diarrhoea, allergy Cephalosporin hypersensitivity, Implicated in Clostridium
porphyria difficile diarrhoea

Ceftazidime 1 g three times a day See cefuroxime See cefuroxime See cefuroxime

Co-amoxiclav 1.2 g three times a day Nausea, diarrhoea, allergy Penicillin hypersensitivity

Gentamicin 80–120 mg three times a Nephrotoxicity, ototoxicity Pregnancy, myasthenia gravis Monitor levels
day or 5 mg/kg once daily

Ciprofloxacin 200–400 mg twice a day Rash, pruritus, tendinitis Pregnancy, children Implicated in Clostridium
difficile diarrhoea

Piperacillin with 4.5 g three times a day Nausea, allergy Penicillin hypersensitivity
tazobactam

Meropenem 500 mg three times a day Nausea, rash, convulsions Reserve for multiresistant
cases

under bacteriological control, for example, with monthly cultures. to a decreased incidence of bacteriuria and symptomatic infec-
In men with prostate gland infection, it is appropriate to select tion. Several studies of the effect of incorporating antibiotics
antibiotics with good tissue penetration such as trimethoprim and such as rifampicin and minocycline or silver-based alloys into
the luoroquinolones. the catheter have shown beneit. Although clearly more costly
than standard catheters, economic evaluation shows silver
alloy catheters to be cost eficient when used in patients who
Catheter-associated infections
need catheterisation for several days. The effect of these cath-
In most large hospitals, 10–15% of patients have an indwelling eters on clinical outcomes such as bacteraemia remains to be
urinary catheter. Even with the very best catheter care, most will determined.
have infected urine after 10–14 days of catheterisation, although
most of these infections will be asymptomatic. Antibiotic treat-
Bacteriuria of pregnancy
ment will often appear to eradicate the infecting organism, but
as long as the catheter remains in place, the organism, or another The prevalence rate of asymptomatic bacteriuria of pregnancy
more resistant one, will quickly return. The principles of antibi- is about 5%, and about a third of these women proceed to
otic therapy for catheter-associated UTI are therefore as follows: development of acute pyelonephritis, with its attendant conse-
• Do not treat asymptomatic infection. quences for the health of both mother and pregnancy. Further,
• If possible, remove the catheter before treating symptomatic there is evidence that asymptomatic bacteriuria is associated
infection. with low birth weight, prematurity, hypertension and pre-
Although it often prompts investigation, cloudy or strong- eclampsia. For these reasons, it is recommended that screening
smelling urine is not per se an indication for antimicrobial ther- be carried out, preferably by culture of a properly taken MSU,
apy. In these situations, saline or antiseptic bladder washouts which should be repeated if positive for conirmation (NICE,
are often performed, but there is little evidence that they make 2008).
a difference. Similarly, encrusted catheters are often changed on Rigorous meta-analysis of published trials has shown that anti-
aesthetic grounds, but it is not known whether this reduces the biotic treatment of bacteriuria in pregnancy is effective at clearing
likelihood of future symptoms. bacteriuria, reducing the incidence of pyelonephritis and reduc-
Following catheter removal, bacteriuria may resolve sponta- ing the risk of preterm delivery. The drugs of choice are amoxi-
neously, but more often it persists (typically for longer than 2 cillin or cefalexin or nitrofurantoin, depending on the sensitivity
weeks in more than half of patients) and may become symp- proile of the infecting organism. Co-amoxiclav is cautioned
tomatic, although usually it will respond well to short-course in pregnancy because of relative lack of clinical experience in
treatment. pregnant women. Trimethoprim is contraindicated without folate
supplementation (particularly in the irst trimester) because of
its theoretical risk of causing neural tube defects through folate
Antimicrobial catheters
antagonism. Nitrofurantoin should be avoided close to the time
Several different types of novel catheters with anti-infective of expected delivery because of a risk of haemolysis in the baby.
properties have been developed with the aim of reducing the Ciproloxacin is contraindicated because it may affect the grow-
ability of bacteria to adhere to the material, which should lead ing joints. There are insuficient data concerning short-course 631
 37 THERAPEUTICS

therapy in pregnancy, and 7 days of treatment remains the stan- infection with strains intrinsically resistant to the chosen prophy-
dard. Patients should be followed up for the duration of the lactic antibiotic is possible.
pregnancy to conirm cure and to ensure that any reinfection is
promptly addressed. Children
In children, recurrence of UTI is common and the complications
potentially hazardous, so many clinicians recommend antimicro-
Prevention and prophylaxis bial prophylaxis following documented infection. The evidence
in favour of this practice is not strong, and although it has been
There are a number of folklore and naturopathic recommenda- shown to reduce the incidence of bacteriuria, there is no good-
tions for the prevention of UTI. Most of these have not been quality evidence that prophylactic antibiotics are effective in pre-
put to statistical study, but at least they are unlikely to cause venting further symptomatic UTIs, and they have not been shown
harm. to reduce the incidence of renal scarring complications, which
are the most important outcomes for the patient (Mori et al.,
2009). Further, important variables remain to be clariied, such
Cranberry juice as when to begin prophylaxis, which agent to use and when to
Cranberry juice (Vaccinium macrocarpon) has long been thought stop. Guidelines have abandoned the time-honoured recommen-
to be beneicial in preventing UTI, and this has been studied in a dation for routine antibiotic prophylaxis following a irst infec-
number of clinical trials. Cranberry is thought to inhibit adhesion tion, although it may be considered when there is recurrent UTI
of bacteria to urinary tract cells on the surface of the bladder. In (NICE, 2007).
sexually active women, a daily intake of 750 mL of cranberry Although evidence is limited for some recommendations, there
juice was associated with a 40% reduction in the risk of symp- are many common-sense general measures aimed at reducing the
tomatic UTI in a double-blinded 12-month trial. Many studies risk of recurrence of infection, particularly in girls. They include
have been criticised for methodological laws, and currently advice on regular bladder emptying, cleaning the perineal/anal
there is only limited evidence that cranberry juice is effective at area from front to back after urinating, treating constipation ade-
preventing recurrent UTI. There have been no randomised con- quately and avoiding both bubble baths and washing the hair in
trolled trials of the use of cranberry products (juice, tablets or the bath.
capsules) in the treatment of established infection, or compar-
ing it with established therapies such as antibiotics for prevent- Case studies
ing infection. In spite of the suggestive in vitro data and early
reviews that suggested a beneit of cranberry for UTI, recent
meta-analyses are conlicting in their support of its eficacy. A Case 37.1
Cochrane review of 24 studies concluded that there was only a
slight but nonsigniicant reduction in the occurrence of symp- Mr FG, a 70-year-old man, has consulted his primary care doctor
three times in the past 3 months and seems to have the same
tomatic UTI overall (Jepson et al., 2012). However, another
E. coli infection on each occasion. A short course of antibiotics
review of 13 studies concluded that cranberry-containing clears up the symptoms, but a clinical relapse is soon appar-
products are associated with a protective effect against UTIs ent. Mr FG is admitted to hospital for transurethral resection of
(Wang et al., 2012). the prostate and 2 days after the operation he becomes unwell
A hypothetical beneit in using cranberry instead of antibiotics with rigors, fever and loin pain. Microscopy of his urine shows
for this purpose is a reduced risk of the development of antibi- more than 200 white cells/mm3. Blood cultures are taken and
otic-resistant bacteria. A signiicant hazard is an interaction of rapidly become positive, with Gram-negative bacilli seen on
microscopy.
cranberry with warfarin, with a risk of bleeding episodes, and
available products are not available in standardised formulations.
Further, cranberry juice is unpalatable unless sweetened with Questions
sugar and therefore carries a risk of tooth decay, although ironi-
1. Is there any way of predicting which UTIs are likely to go on to
cally it is reported to prevent dental caries by blocking adherence cause further problems such as pyelonephritis or prostatitis?
of plaque bacteria to teeth. 2. What antibiotic therapy is indicated now?

Antibiotic prophylaxis Answers

In some patients, mainly women, reinfections are so frequent 1. Progression of a simple UTI is much more common in patients other
that long-term antimicrobial prophylaxis with speciic antibiot- than young women. Foreign bodies such as catheters and stents,
ics is indicated. If the reinfections are clearly related to sexual or physiological problems such as neurogenic bladder increase
the risk of a complicated UTI. In men, persistent or recurrent infec-
intercourse, then a single dose of an antibiotic after intercourse is
tion with the same organism is highly suggestive of prostatitis and
appropriate. In other cases, long-term, low-dose prophylaxis may should prompt an extended course of treatment. Pyelonephritis is
be beneicial. One dose of trimethoprim (100 mg) or nitrofuran- more difficult to predict. Frequency, dysuria and haematuria indi-
toin (50 mg) at night will sufice. These drugs are unlikely to lead cate lower tract infection. Fever, vomiting, rigors and flank pain are
632 to the emergence of resistant bacteria, although breakthrough more suggestive of upper renal tract involvement.
 URINARY TRACT INFECTIONS 37
2. Mr FG should be started on intravenous antibiotic therapy for
presumed prostatitis or pyelonephritis and consequent bacte- Case 37.4
raemia. The antibiotic should cover Gram-negative organisms
found in the hospital environment such as Klebsiella, Enterobacter Mrs EH, a 62-year-old woman, has been troubled by recurrent
and Pseudomonas. Appropriate agents would be piperacillin-tazo- symptoms of UTI. She has been taking an oral oestrogen prepara-
bactam, ceftazidime, ciprofloxacin or meropenem. An alternative tion for menopausal symptoms for some years. She is currently on
would be an aminoglycoside such as gentamicin, provided the an orthopaedic ward and catheterised because of incontinence.
patient has satisfactory renal function. Mrs EH is afebrile but has been confused since her hip replacement
5 days earlier; she remains on cefuroxime, which was started as
prophylaxis at the time of the operation. The urine in her catheter
Case 37.2 bag is cloudy, has a high white cell count and grows Enterococcus
faecalis sensitive to amoxicillin but resistant to cephalosporins.
A pregnant woman, Ms SL, aged 26 years is found to have
bacteriuria at her first antenatal visit. No white or red cells are
seen in her urine. Urine culture demonstrates E. coli at a count Questions
of more than 100,000 bacteria/mL, sensitive to trimethoprim,
nitrofurantoin and cefalexin, but resistant to amoxicillin. Other 1. How should Mrs EH be managed?
than a degree of urinary frequency, which Ms SL ascribes to the 2. In older women, is there any association with the use of different
pregnancy itself, the patient does not complain of any urinary types of oestrogen delivery systems and UTIs?
symptoms.

Answers
Question 1. Mrs EH’s confusion may have a number of causes, including her
recent surgery, sleep disturbance, drug toxicity, deep venous
Does Ms SL need antibiotic treatment, and if so, which medicines
thrombosis or infection. If, following clinical examination and
could be safely prescribed?
investigation, which should include blood cultures, her catheter-
associated infection is thought to be contributing to her systemic
problems, it should be treated with amoxicillin. If possible, the
Answer
catheter should be removed, even if this is inconvenient for the
Ms SL may be correct that her urinary frequency is a consequence nursing staff. Unless it has been prescribed for another indication,
of pregnancy. However, because of the consequences of untreated the cefuroxime is achieving nothing and may be stopped.
infection during pregnancy, even asymptomatic bacteriuria should be 2. In post-menopausal women, there have been trials assessing the
treated. A repeat urine specimen should be obtained to confirm the merits of topical oestrogen creams. Topical intravaginal oestriol
persistent finding of more than 100,000 bacteria/mL, and treatment cream has significant benefits in reducing the number of UTIs in those
started with either cefalexin or co-amoxiclav for 7 days. Trimethoprim suffering recurrent infections. In a placebo-controlled trial, the rate of
should be avoided during early pregnancy because of its theoreti- UTI was 12-fold less in the group receiving active oestrogen cream.
cal risk of teratogenicity, and nitrofurantoin should be avoided in This effect is not seen with oral oestrogens (Perrotta et al., 2008).
late pregnancy because it may cause neonatal haemolysis. Following
treatment, Ms SL should be reviewed throughout the pregnancy to
ensure eradication of the bacteriuria and to permit early treatment of Case 37.5
any relapse or reinfection.
Ms MD, a 45-year-old woman, suffers from recurrent episodes of
cystitis. Examination is unremarkable. On the occasions when a
Case 37.3 specimen has been sent, the urine has contained few white cells
and no significant growth of organisms.
A 2-year-old boy is admitted to hospital with vomiting and
abdominal pain. His mother reports that he was treated for a UTI
6 months previously but was not investigated further at the time. Question
A clean-catch urine sample shows more than 50 white cells/mm3, How should the patient be managed?
and bacteria are seen on microscopy.

Answer
Question
Ms MD is suffering from the urethral syndrome, in which symptoms
What action should be taken? of infection are not associated with objective evidence of UTI. It may
be felt necessary to investigate her to exclude less common causes
of UTI such as herpes simplex virus, Chlamydia trachomatis, Neisseria
Answer gonorrhoeae, Gardnerella vaginalis, Mycoplasma hominis and Lactobacilli.
Otherwise, her symptoms are likely to respond to conventional
It seems that this child is suffering from a recurrent UTI. An intrave- courses of antibiotics. Consider non-infective causes, for example,
nous antibiotic such as cefuroxime should be started, because the psychological factors or trauma from intercourse.
child will not tolerate oral antibiotics at present. If the organism
proves to be sensitive to amoxicillin, the treatment could be changed
accordingly. Further investigations, for example, ultrasonography and Case 37.6
radioisotope scan, may be carried out to determine any underlying
cause of the infection and to look for already established renal scar- Ms LT, a 23-year-old woman, has recurrent symptoms of UTI tem-
ring. The child may require long-term prophylaxis to prevent a further porally related to sexual intercourse, despite following advice to 633
recurrence. empty her bladder as soon as possible after sex.
 37 THERAPEUTICS

severe symptoms of UTI and is admitted to hospital with a diag-

Question nosis of ‘urosepsis’.
What do you think of the use of antibiotics such as trimethoprim for
women who get recurrent problems after sexual intercourse? Question
What particular consideration is there in relation to the potential for
Answer Mrs DG’s UTI to be an antibiotic-resistant strain?
Post-coital voiding does not have any prospective data to support
it, but it is a simple, harmless intervention. Long-term continuous Answer
antimicrobial prophylaxis is unquestionably an effective treatment
but may be overtreating those in whom UTIs follow intercourse. Post- Hospitalised patients in a number of countries are at risk of becom-
coital prophylaxis, a single dose within 2 hours of intercourse, has ing colonised with coliform bacteria that are extremely resistant to
the advantage of using less antibiotic overall. One small, placebo- commonly used antibiotics, as well as to those that are often used
controlled, double-blind trial assessed the efficacy of post-coital co- empirically for patients with sepsis. In the Indian subcontinent there
trimoxazole in preventing recurrent UTI and found that 12% of the have been particular problems with strains that are resistant to
active treatment patients developed a UTI in 6 months, compared the carbapenem class of antibiotics such as meropenem, because
with 82% of the control group. Other studies have shown nitrofuran- the bacteria produce a transmissible hydrolyzing carbapenemase
toin, cefalexin and ciprofloxacin also to be effective. enzyme. Such strains are usually resistant to virtually all classes of
antibiotics and it may be necessary to administer intravenous com-
bination therapy including colistin or fosfomycin. Patients who have
Case 37.7 been hospitalised in areas where such resistant strains are prevalent
should be screened for potential carriage of the organism if readmit-
A 45-year-old woman, Mrs DG, was hospitalised in India a few ted to hospital so that assiduous infection control precautions can
weeks ago while undergoing cosmetic surgery. She now has be implemented.

References
Falagas, M.E., Vouloumanou, E.K., Togias, A.G., et al., 2010. Fosfomy- Mori, R., Fitzgerald, A., Williams, C., et al., 2009. Antibiotic prophylaxis
cin versus other antibiotics for the treatment of cystitis: a meta- for children at risk of developing a urinary tract infection: a systematic
analysis of randomized controlled trials. J. Antimicrob. Chemother. review. Acta Paediatrica. 98, 1781–1786.
65, 1862–1877. National Institute for Health and Care Excellence (NICE), 2007. Urinary
Gopal Rao, G., Patel, M., 2009. Urinary tract infection in hospitalized elderly tract infection in children: diagnosis, treatment and long-term manage-
patients in the United Kingdom: the importance of making an accurate ment. NICE, London. Available at: http://www.nice.org.uk/nicemedia/
diagnosis in the post broad-spectrum antibiotic era. J. Antimicrob. pdf/CG54fullguideline.pdf.
Chemother. 63, 5–6. National Institute for Health and Care Excellence (NICE), 2008. Antenatal
Jepson, R.G., Williams, G., Craig, J.C., 2012. Cranberries for prevent- care for uncomplicated pregnancies. NICE, London. Available at: http://
ing urinary tract infections. Cochrane Database Syst. Rev. 2012 (10), www.nice.org.uk/guidance/cg62.
CD001321. https://doi.org/10.1002/14651858.CD001321.pub5. Nicolle, L.E., 2009. Urinary tract infections in the elderly. Clin. Geriatr.
Kahlmeter, G., 2003. An international survey of the antimicrobial suscepti- Med. 25, 423–436.
bility of pathogens from uncomplicated urinary tract infections: the ECO Perrotta, C., Aznar, M., Mejia, R., et al., 2008. Oestrogens for preventing recurrent
SENS Project. J. Antimicrob. Chemother. 51, 59–76. urinary tract infection in postmenopausal women. Cochrane Database Syst.
Kumarasamy, K.K., Toleman, M.A., Walsh, T.R., et al., 2010. Emergence of Rev. 2008 (2), CD005131. https://doi.org/10.1002/14651858.CD005131.pub2.
a new antibiotic resistance mechanism in India, Pakistan, and the UK: a Scottish Intercollegiate Guidelines Network (SIGN), 2012. Management of
molecular, biological, and epidemiological study. Lancet Infect. Dis. 10, suspected bacterial urinary tract infection in adults. SIGN, Edinburgh.
597–602. Available at: http://www.sign.ac.uk/guidelines/fulltext/88/index.html.
Lichtenberger, P., Hooton, T.M., 2008. Complicated urinary tract infections. Wang, C.H., Fang, C.C., Chen, N.C., et al., 2012. Cranberry-containing
Curr. Infect. Dis. Rep. 10, 499–504. products for prevention of urinary tract infections in susceptible popula-
Mangin, D., 2010. Urinary tract infection in primary care. Br. Med. J. 340, tions: a systematic review and meta-analysis of randomized controlled
373–374. trials. Arch. Intern. Med. 172, 988–996.

Further reading
Hooton, T.M., 2015. Nosocomial urinary tract infections. In: Mandell, G.L., non-pregnant women. NHS Scotland, Glasgow. Available at: https://www.
Bennett, J.E., Dolin, R. (Eds.), Principles and Practice of Infectious scottishmedicines.org.uk/iles/sapg1/Management_of_recurrent_lower_
Diseases, eighth ed. Elsevier, London, pp. 3334–3346. UTI_in_non-pregnant_women.pdf.
Sobel, J.D., Kaye, D., 2015. Urinary tract infections. In: Mandell, G.L., Bennett, National Institute for Health and Care Excellence, 2015. Urinary tract infec-
J.E., Dolin, R. (Eds.), Principles and Practice of Infectious Diseases, eighth tions in adults: quality standard QS90. NICE, London. Available at: https:
ed. Elsevier, London, pp. 886–913. //www.nice.org.uk/guidance/qs90.
Scottish Medicines Consortium and Scottish Prescribing Advisory Group,
2016. Guidance on management of recurrent urinary tract infection in

634
THERAPEUTICS

38 Gastro-Intestinal Infections
Jim Gray

Key points Infections are rarely severe, and the vast majority of cases never
reach medical attention. Nevertheless, they are of considerable
• There are many different microbial causes of gastro-intestinal
economic importance. In the UK, viruses, especially noroviruses,
infections.
are the most common cause of gastroenteritis. Campylobacter,
• Gastroenteritis is the most common syndrome of gastro-intestinal
infection, but some gastro-intestinal pathogens can cause sys-
followed by non-typhoidal serovars of Salmonella enterica, are
temic infections. the most common reported causes of bacterial gastroenteritis.
• Fluid and electrolyte replacement is the mainstay of manage- Cryptosporidiosis is the most commonly reported parasitic infec-
ment of gastroenteritis. tion. In developing countries, the incidence of gastro-intestinal
• Antibiotic resistance in gastro-intestinal pathogens is an esca- infection is at least twice as high and the range of common patho-
lating problem. gens is much wider. Infections are more often severe and repre-
• Most cases of gastroenteritis that occur in developed countries sent a major cause of mortality, especially in children.
are mild and self-limiting and do not require antibiotic therapy. Gastro-intestinal infections can be transmitted by consumption
Unnecessary use of antibiotics simply promotes antibiotic of contaminated food or water or by direct faecal–oral spread.
resistance. Airborne spread of viruses that cause gastroenteritis also occurs.
• Antibiotic therapy should be considered for patients with The most important causes of gastro-intestinal infection, and their
underlying conditions that predispose to serious or complicated usual modes of spread, are listed in Table 38.1. In developed coun-
gastroenteritis, or where termination of faecal excretion of
pathogens is desirable to prevent further spread of the infection.
tries, the majority of gastro-intestinal infections are food-borne.
Farm animals are often colonised by gastro-intestinal pathogens,
• Clostridium difficile is a very important cause of diarrhoea in
hospitals. Strict control measures are required; cases are usually especially Salmonella and Campylobacter. Therefore, raw foods
initially treated with oral metronidazole or oral vancomycin. such as poultry, meat, eggs and unpasteurised dairy products
• Fidaxomicin is a new treatment for C. difficile that may be asso- are commonly contaminated and must be thoroughly cooked to
ciated with a lower recurrence rate. Faecal microbiota transplan- kill such organisms. Raw foods also represent a potential source
tation is another treatment option that is becoming mainstream. of cross-contamination of other foods, through hands, surfaces
• Antibiotic therapy is also essential for life-threatening systemic or utensils that have been inadequately cleaned. Food handlers
infections, such as enteric fever. who are excreting pathogens in their faeces can also contaminate
• Where possible, antibiotic therapy should be delayed until a food. This is most likely when diarrhoea is present, but continued
microbiological diagnosis has been established. excretion of pathogens during convalescence also represents a
risk. Food handlers are the usual source of Staphylococcus aureus
food poisoning, where toxin-producing strains of S. aureus car-
Gastro-intestinal infections represent a major public health and ried in the nose or on skin are transferred to foods. Bacterial
clinical problem worldwide. Many species of bacteria, viruses and food poisoning is often associated with inadequate cooking and/
protozoa cause gastro-intestinal infection, resulting in two main or prolonged storage of food at ambient temperature before con-
clinical syndromes. Gastroenteritis is a non-invasive infection of sumption. Water-borne gastro-intestinal infection is primarily a
the small or large bowel that manifests clinically as diarrhoea and problem in countries without a sanitary water supply or sewer-
vomiting. Other infections are invasive, causing systemic illness, age system, although outbreaks of water-borne cryptosporidiosis
often with few gastro-intestinal symptoms. Helicobacter pylori occur from time to time in the UK. The spread of pathogens such as
and its association with gastritis, peptic ulceration and gastric Shigella or enteropathogenic Escherichia coli (E.coli) by the fae-
carcinoma are discussed in Chapter 12. cal–oral route is favoured by over-crowding and poor standards of
personal hygiene. Such infections in developed countries are
most common in children and can cause troublesome outbreaks
in paediatric wards, nurseries and residential children’s homes.
Epidemiology and aetiology Treatment with broad-spectrum antibiotics alters the bowel
lora, creating conditions that favour superinfection with micro-
In Western countries, the average person probably experiences organisms (principally Clostridium dificile) that can cause diar-
one or two episodes of gastro-intestinal infection each year. rhoea. C. dificile infection (CDI) may be associated with any 635
 38 THERAPEUTICS

Table 38.1 Important causes of gastro-intestinal infection, their modes of spread and pathogenic mechanisms

Causative agent Chief mode(s) of spread Pathogenic mechanisms

Bacteria

Campylobacter Food, especially poultry, milk Mucosal invasion, enterotoxin

Salmonella enterica, non-typhoidal serovars Food, especially poultry, eggs, meat Mucosal invasion, enterotoxin

Salmonella enterica serovars Typhi and Paratyphi Food, water Systemic invasion

Shigella Faecal–oral Mucosal invasion, enterotoxin

Escherichia coli

Enteropathogenic Faecal–oral Mucosal adhesion

Enteroaggregative Faecal–oral, food Mucosal toxicity

Enterotoxigenic Faecal–oral, food, water Enterotoxin

Enteroinvasive Faecal–oral, food Mucosal invasion

Verotoxin-producing Food, especially meat Verotoxin

Staphylococcus aureus Food, especially meats, dairy produce Emetic toxin

Clostridium perfringens Food, especially meat Enterotoxin

Bacillus cereus

Short incubation period Food, especially rice Emetic toxin

Long incubation period Food, especially meat and vegetable dishes Enterotoxin

Vibrio cholerae O1, O139 Water Enterotoxin

Vibrio parahaemolyticus Seafoods Mucosal invasion, enterotoxin

Clostridium difficile Faecal–oral (nosocomial) Cytotoxin, enterotoxin

Clostridium botulinum Inadequately heat-treated canned/preserved Neurotoxin

foods

Protozoa

Giardia lamblia Water Mucosal invasion

Cryptosporidium Water, animal contact Mucosal invasion

Entamoeba histolytica Food, water Mucosal invasion

Viruses

Rotavirus, norovirus, astrovirus, sapovirus, adenovirus Food, faecal–oral, respiratory secretions Small-intestinal mucosal damage

antibiotic, but clindamycin, the cephalosporins and the luoro- Pathophysiology

quinolones are most commonly implicated. CDI is most common
in patients with serious underlying disease and in the elderly. Development of symptoms after ingestion of gastro-intestinal
Although some sporadic cases are probably due to overgrowth pathogens depends on two factors. First, suficient organisms
of endogenous organisms, person-to-person transmission also must be ingested and then survive host defence mechanisms;
occurs in hospitals and care homes, sometimes resulting in large and second, the pathogens must possess one or more virulence
636 outbreaks. mechanisms to cause disease.
 GASTRO-INTESTINAL INFECTIONS 38
Host factors bacteria produce enterotoxins, including enterotoxigenic E. coli
and Clostridium perfringens. The emetic toxins of S. aureus and
Healthy individuals possess a number of defence mechanisms Bacillus cereus are neurotoxins that induce vomiting by an action
that protect against infection by enteropathogens. Therefore, on the central nervous system. The symptoms of botulism are
large numbers of many pathogens must be ingested for infection mediated by a neurotoxin that blocks release of acetylcholine at
to ensue; for example, the infective dose for Salmonella is typi- nerve endings. Cytotoxins cause mucosal destruction and inlam-
cally around 105 organisms. Other species, however, are better mation (see later). The pathogenicity of C. dificile is mediated by
able to survive host defence mechanisms; for example, infection two exotoxins, TcdA and TcdB, both of which are potent cytotoxic
with Shigella or verotoxin-producing E. coli (VTEC) can result enzymes that damage the human colonic mucosa. Verotoxins are
from ingestion of fewer than 100 organisms. VTEC (principally potent cytotoxins that cause direct damage to small-vessel endo-
E. coli O157) are especially important because of the risk of thelial cells, which is exacerbated by stimulation of production
the life-threatening complication haemolytic uraemic syndrome of inlammatory mediators by non-endothelial cells. This causes
(HUS). multiorgan microvascular injury, expressed most commonly as
haemorrhagic colitis and HUS.
Gastric acidity
Mucosal damage
Most microorganisms are rapidly killed at normal gastric pH.
Patients whose gastric pH is less acidic, as, for example, fol- Cytotoxins are important in mediating mucosal invasion, but other
lowing treatment with antacids or ulcer-healing drugs, are more mechanisms are also involved. Enteropathogenic E. coli causes
susceptible to gastro-intestinal infections. There is a particularly diarrhoea by damaging microvilli when it adheres to the intestinal
strong association between proton pump inhibitor use and CDI. mucosa. Organisms such as Shigella and enteroinvasive E. coli
express surface proteins that facilitate mucosal invasion. Diarrhoea
due to mucosal damage may be caused by reduction in the absorp-
Intestinal motility
tive surface area or the presence of increased numbers of immature
It is widely held that intestinal motility helps to rid the host of enterocytes which are secretory rather than absorptive.
enteric pathogens, and that anti-motility agents are therefore
potentially hazardous in patients with infective gastroenteritis.
Systemic invasion
Despite this, self-medication with antidiarrhoeals is commonly
practised, and in otherwise healthy individuals is probably safe. The lipopolysaccharide outer membrane and possession of an
antiphagocytic outer capsule are important virulence factors in
invasive Salmonella infections.
Resident microflora
The resident microlora of the lower gastro-intestinal tract,
largely composed of anaerobic bacteria, help to resist colonisa-
tion by enteropathogens. Clinical manifestations
Many cases of gastro-intestinal infection are asymptomatic or
Immune system
cause subclinical illness. Gastroenteritis is the most common
Phagocytic, humoral and cell-mediated elements are important syndrome of gastro-intestinal infection, presenting with symp-
in resistance to different pathogens. Individuals with inherited or toms such as vomiting, diarrhoea and abdominal pain. The term
acquired immunodeiciencies are therefore susceptible to speciic ‘dysentery’ is sometimes applied to infections with Shigella (bac-
gastro-intestinal infections, depending on which components of illary dysentery) and Entamoeba histolytica (amoebic dysentery),
their immune system are affected. where severe colonic mucosal inlammation causes frequent diar-
rhoea with blood and pus. Table 38.2 lists the most important
causative agents of gastroenteritis together with a brief descrip-
Organism factors
tion of the typical illness that each causes. However, the symp-
The irst requirement of gastro-intestinal pathogens is that they toms experienced by individuals infected with the same organism
are able to adhere to the gut wall and colonise the intestine. The can differ considerably. This is important because it means that it
symptoms of gastro-intestinal infection can then be mediated by is rarely possible to diagnose the cause of gastroenteritis on clini-
various mechanisms (see Table 38.1). cal grounds alone.
Gastro-intestinal manifestations of infection with VTEC range
from non-bloody diarrhoea to haemorrhagic colitis. In addition,
Toxins
VTEC are the most important cause of HUS, a serious complica-
Toxins produced by gastro-intestinal pathogens can be classiied tion which is most common in young children and the elderly.
as enterotoxins, neurotoxins and cytotoxins. Enterotoxins act on HUS is deined by the triad of microangiopathic haemolytic
intestinal mucosal cells to cause net loss of luid and electrolytes. anaemia, thrombocytopenia and acute renal dysfunction. The
The classic enterotoxin-mediated disease is cholera, the result of mortality rate is about 5%, and up to half of the survivors suffer
infection with toxigenic serotypes of Vibrio cholerae. Many other long-term renal damage. 637
 38 THERAPEUTICS

Table 38.2 Characteristic clinical features of various causes of gastroenteritis

Causative agent Incubation period Symptoms (syndrome)

Campylobacter 2–5 days Bloody diarrhoea

Abdominal pain
Systemic upset

Salmonella 6–72 h Diarrhoea and vomiting

Fever; may be associated bacteraemia

Shigella 1–4 days Diarrhoea, fever (bacillary dysentery)

Escherichia coli

Enteropathogenic 12–72 h Infantile diarrhoea

Enteroaggregative 1–3 days Childhood diarrhoea, traveller’s diarrhoea

Enterotoxigenic 1–3 days Traveller’s diarrhoea

Enteroinvasive 1–3 days Similar to Shigella

Verotoxin-producing 1–3 days Bloody diarrhoea (haemorrhagic colitis)

Haemolytic uraemic syndrome

Staphylococcus aureus 4–8 h Severe nausea and vomiting

Clostridium perfringens 6–24 h Diarrhoea

Bacillus cereus

Short incubation period 1–6 h Vomiting

Long incubation period 6–18 h Diarrhoea

Vibrio cholerae O1, O139 1–5 days Profuse diarrhoea (cholera)

Vibrio parahaemolyticus 12–48 h Diarrhoea, abdominal pain

Clostridium difficile Usually occurs during/just after antibiotic Diarrhoea, abdominal pain, pseudomembranous
therapy enterocolitis

Giardia lamblia 1–2 weeks Watery diarrhoea

Cryptosporidium 2 days to 2 weeks Watery diarrhoea

Entamoeba histolytica 2–4 weeks Diarrhoea with blood and mucus (amoebic dysentery),
liver abscess

Viruses 1–2 days Vomiting, diarrhoea

Systemic upset

The clinical spectrum of CDI ranges from asymptomatic car- gradually increases, but the pulse characteristically remains slow.
riage to life-threatening pseudomembranous colitis (so called Without treatment, during the second and third weeks, the symp-
because yellow-white plaques or membranes consisting of ibrin, toms become more pronounced. Diarrhoea develops in about half
mucus, leucocytes and necrotic epithelial cells are found adherent of cases. Examination usually reveals splenomegaly, and a few
to the inlamed colonic mucosa). erythematous macules (rose spots) may be found, usually on the
Enteric fever, resulting from infection with S. enterica serovars trunk. Serious gastro-intestinal complications such as haemor-
Typhi and Paratyphi, presents with symptoms such as headache, rhage and perforation are most common during the third week.
malaise and abdominal distension after an incubation period of Symptoms begin to subside slowly during the fourth week. In
638 3–21 days. During the irst week of the illness, the temperature general, paratyphoid fever is less severe than typhoid fever.
 GASTRO-INTESTINAL INFECTIONS 38
Symptoms of acute
gastroenteritis

Ensure adequate hydration

– Frequent small volumes of fluid
– Rehydration drinks or intravenous
fluids if required

Nausea and vomiting Diarrhoea Diarrhoea with blood

predominant symptoms without blood or and/or serious systemic upset
– Probable viral gastroenteritis serious systemic upset

Take paracetamol or ibuprofen Test for C. difficile if patient

as required hospitalised and at risk
Manage conservatively unless
positive for C. difficile

Symptoms usually improve Symptoms not improved

within 48–72 h or worsening after
48–72 h

Send faeces sample for

mircrobiological examination
Symptoms usually resolve Consider antibiotic therapy
within 48–72 h once results are availablea

a
Antibiotic therapy may have to be commenced empirically if patient has serious systemic upset

Fig. 38.1 Pathway for the investigation and management of patients with symptoms of acute gas-
troenteritis.

Botulism typically presents with autonomic nervous system there are public health concerns (e.g. if the sufferer works in the
effects, including diplopia and dysphagia, followed by symmetri- food industry) and for gastro-intestinal infections in hospital-
cal descending motor paralysis. There is no sensory involvement. ised patients.
Gastro-intestinal infections are often followed by a period of The mainstay of investigation of diarrhoeal illness is examina-
convalescent carriage of the pathogen. This usually lasts for no tion of faeces. Conventional faecal microbiology is one of the
more than 4–6 weeks but can be for considerably longer, espe- most complex aspects of diagnostic microbiology. A range of dif-
cially for Salmonella. ferent, often labour-intensive techniques have been required to
test for different bacteria, viruses and protozoa. However, labora-
tory diagnostic strategies are changing; increasingly laboratories
are using molecular methods (e.g. multiplex polymerase chain
Investigations reaction [PCR]) to detect the full range of enteric pathogens (bac-
teria, viruses and parasites) more quickly and more accurately
Many cases of gastroenteritis outside hospital are mild and than by conventional methods. Results can be available in as
short-lived, and microbiological investigation may not be little as an hour, compared with 2 or more days with conventional
necessary. However, investigations are always recommended methods, which can assist with antibiotic stewardship and infec-
where antibiotic therapy is being considered (Fig. 38.1), where tion prevention and control. 639
 38 THERAPEUTICS

Conventionally, bacterial infections have been diagnosed by Antiemetics and antidiarrhoeal drugs are discussed in Chapters
stool culture. Various selective culture media designed to sup- 35 and 14, respectively. This chapter focuses on the place of anti-
press growth of normal faecal organisms and/or enhance the biotic therapy in gastro-intestinal infections.
growth of a particular pathogen are used. When sending speci-
mens to the laboratory, it is important that details of the age of
Antibiotic therapy
the patient, the clinical presentation and recent foreign travel are
provided so that appropriate media for the likely pathogens can The requirement for antibiotic treatment in gastro-intestinal infection
be selected. depends on the causative agent, the type and severity of symptoms,
A two-stage approach is recommended for diagnosis of CDI. and the presence of underlying disease. Antibiotics are ineffective in
Diarrhoeal stools are screened for the presence of glutamate some forms of gastroenteritis, including bacterial intoxications and
dehydrogenase (GDH) antigen, an inexpensive, sensitive, but viral infections. For many other infections, such as salmonellosis
non-speciic test; PCR is also suitable as an initial screening and campylobacteriosis, effective agents are available, but antimi-
test, but it is more expensive. Samples that are positive for crobial therapy is often not clinically necessary. Serious infections,
GDH, or by PCR, are then tested for C. dificile toxin. Patients such as enteric fever, always require antibiotic therapy.
who are toxin-positive have CDI; those who are GDH- or PCR-
positive are C. dificile excretors. C. dificile excretors are at
Conditions for which antibiotic therapy is not
risk of development of CDI, especially if they are exposed to
available or not usually required
antibiotics; they also present an infection-control risk because
they may spread toxigenic C. dificile to other patients who may The symptoms of S. aureus and short incubation period B. cereus
develop CDI. Sigmoidoscopy is used to diagnose pseudomem- food poisoning and botulism are usually caused by ingestion of
branous colitis. preformed toxin, and therefore antibiotic therapy would not inlu-
Various other procedures are sometimes useful in investigating ence the illness. Pathogens such as C. perfringens, Vibrio para-
patients with suspected bacterial gastroenteritis. Blood cultures haemolyticus, and enteropathogenic E. coli usually cause a brief,
should be taken from patients with severe systemic upset and are self-limiting illness that does not require speciic treatment.
especially important when enteric fever is suspected. In enteric None of the presently available antiviral agents are useful in
fever, the causative organism may also be cultured from urine gastroenteritis caused by viruses such as rotaviruses or norovi-
or bone marrow. In S. aureus and B. cereus food poisoning, the ruses. Although most viral infections are self-limiting, chronic
pathogen can sometimes be isolated from vomitus. In cases of infections can occur in immunocompromised patients. Where pos-
food poisoning, suspect foods may also be cultured. In general, sible, immunosuppression should be reduced. Immunoglobulin-
serological investigations are of little value in the diagnosis of containing preparations, administered orally or directly into the
bacterial gastroenteritis. However, demonstration of serum anti- duodenum via a nasogastric tube, have also been reported to be
bodies to E. coli O157 can be helpful in conirming the cause effective in managing chronic viral gastroenteritis in immuno-
of the HUS. Botulism is diagnosed by demonstration of toxin in compromised patients. As well as human serum immunoglobulin,
serum. antibodies from other species (e.g. immunised bovine colos-
Parasitic infestations are conventionally detected by micro- trum) have been used. Immunotherapy of viral gastroenteritis
scopic examination of faeces, but PCR appears to be more sen- for severely immunocompromised patients remains experimen-
sitive. Molecular methods have to a large extent superseded tal. Where these preparations are used, dosages and frequency of
electron microscopy and immunological tests for detection of administration of immunoglobulin preparations must be deter-
enteric viruses. mined locally, based on expert opinion (Pammi and Haque, 2011).
Occasionally, where viruses such as cytomegalovirus or adenovi-
ruses cause enteritis in immunocompromised patients, antiviral
treatment, under specialist supervision, may be indicated.
Treatment At least one study has found that the risk of HUS in chil-
dren with diarrhoea caused by VTEC was much higher in those
Many gastro-intestinal infections are mild and self-limiting who received antibiotics (Wong et al., 2000). On that basis, it
and never reach medical attention. Where treatment is is advised in the UK that antibiotics are contraindicated in chil-
required, there are three main therapeutic considerations. Fluid dren with VTEC infection (National Collaborating Centre for
and electrolyte replacement is the cornerstone of treatment of Women’s and Children’s Health, 2009). However, it has been
diarrhoeal disease. Most patients can be managed with oral suggested that some antibiotics, especially fosfomycin and qui-
rehydration regimens, but severely dehydrated patients require nolones, may prevent the development of HUS, and these treat-
rapid volume expansion with intravenous luids. Symptomatic ments are used in some other countries (Corogeanu et al., 2012).
treatment with antiemetics and anti-motility (antidiarrhoeal)
agents is sometimes used, especially as self-medication.
Conditions for which antimicrobial therapy may be
Antimicrobial agents may be useful both in effecting symptom-
considered
atic improvement and in eliminating faecal carriage of patho-
gens, and therefore reducing the risk of transmitting infection The place for antibiotics in the management of uncompli-
to others. cated gastroenteritis due to bacteria such as Salmonella and
640
 GASTRO-INTESTINAL INFECTIONS 38
Campylobacter is not clear-cut. Certain antibiotics are reason- Ciproloxacin given orally at a dosage of 500–750 mg twice
ably effective in reducing the duration and severity of clinical daily in adults (7.5–12.5 mg/kg twice daily in children) or 200 mg
illness and in eradicating the organisms from faeces. However, intravenously twice daily in adults (5–7.5 mg/kg twice daily in
many microbiologists are cautious about the widespread use of children) is recommended for invasive salmonellosis. Alternative
antibiotics in diarrhoeal illness because of the risk of promoting agents include ampicillin or amoxicillin, trimethoprim or chlor-
antibiotic resistance (Pollack et al., 2013). Another dificulty with amphenicol (see later section Enteric Fever). However, resistance
respect to antibiotic prescribing is that it is not usually possible to to these agents is more common than resistance to ciproloxacin,
determine the aetiological agent of diarrhoea on clinical grounds, and they are not recommended as empiric therapy.
and stool culture takes at least 48 hours. Although an aetiological E. coli infections. Most cases of enteropathogenic E. coli–
diagnosis can be established much faster using PCR, antibiotic associated diarrhoea are self-limiting and are managed conser-
susceptibility results are not provided. Patients with severe ill- vatively; indeed, until recently few microbiology laboratories in
ness, especially systemic symptoms, may require antibiotic ther- Western countries have tested for these bacteria. However, increas-
apy before the aetiological agent, or its antibiotic susceptibilities, ingly laboratories are using PCR tests to investigate samples from
are established. In such circumstances, a luoroquinolone antibi- patients with diarrhoea, and some of the commercially available PCR
otic such as ciproloxacin would usually be the most appropriate panels test for enteropathogenic E. coli. Consequently, some patients
empiric agent, at least in patients in whom CDI is considered with chronic diarrhoea are now being reported to have enteropatho-
unlikely or has been excluded. Otherwise, it is reasonable to limit genic E. coli, the signiicance of which is uncertain (Duda-Madej
antibiotic use to microbiologically proven cases where there is et al., 2013). Specialist advice should be obtained before consid-
serious underlying disease and/or continuing severe symptoms. ering treatment of such patients. On the basis that enteroinvasive
Antibiotics may also be used to try to eliminate faecal carriage, E. coli are closely related to Shigella and cause a similar clinical syn-
for example, in controlling outbreaks in institutions, or in food drome, similar therapy may be appropriate. Antibiotic therapy for
handlers who may be prevented from returning to work until they traveller’s diarrhoea caused by enterotoxigenic or enteroaggregative
are no longer excreting gastro-intestinal pathogens. E. coli infections is often unnecessary, but troublesome symptoms
Campylobacteriosis. Erythromycin is effective in terminating will often respond to a single dose of ciproloxacin or azithromycin;
faecal excretion of Campylobacter. Some studies have shown that the need for further doses depends on clinical response. Alternatively,
treatment commenced within the irst 72–96 hours of illness can also a 3- to 5-day course of trimethoprim may be given, although resis-
shorten the duration of clinical illness, especially in patients with tance is becoming increasingly common in some areas. Rifaximin
severe dysenteric symptoms. The recommended dosage for adults is a new non-absorbable antibiotic that is available in a number of
is 250–500 mg four times a day orally for 5–7 days, and for children countries. It appears to be as effective as ciproloxacin in treating
30–50 mg/kg/day in four divided doses. Clarithromycin 250–500 mg E. coli–predominant traveller’s diarrhoea but is ineffective in patients
(children <1 year of age, 7.5 mg/kg; 1–2 years, 62.5 mg; 3–6 years, with inlammatory or invasive enteropathogens (Hopkins et al.,
125 mg; 7–9 years, 5–7 days) twice a day orally or azithromycin 2014). The dosage for adults is 200 mg three times per day for 3 days.
500 mg (children 10 mg/kg) once daily for 3 days is also effective.
Ciproloxacin, at a dosage of 500 mg twice daily orally for adults,
Conditions for which antimicrobial therapy
may also be effective in Campylobacter enteritis. However, resis-
is usually indicated
tance rates to erythromycin have generally remained less than 5%,
whereas resistance to ciproloxacin has emerged, exceeding 10% in Shigellosis. Shigella sonnei, which accounts for most cases
the UK and 50% in some other countries (Dingle et al., 2005). of shigellosis in the UK and most other industrialised countries,
Salmonellosis. Most cases of Salmonella gastroenteritis are usually causes a mild, self-limiting illness. Even if not required
self-limiting, and antibiotic therapy is unnecessary. However, on clinical grounds, antibiotic therapy for shigellosis is usually
antimicrobial therapy of salmonellosis is routinely recom- recommended to eliminate faecal carriage, and therefore pre-
mended for infants younger than 6 months and immunocompro- vent person-to-person transmission. In contrast with salmonel-
mised patients, who are susceptible to complicated infections. losis, a number of antibiotics may be effective in shortening
Most antibiotics, even those with good in vitro activity, do not the duration of illness and terminating faecal carriage. This is
alter the course of uncomplicated Salmonella gastroenteritis. especially true of strains of S. sonnei that are endemic in indus-
However, the luoroquinolones, such as ciproloxacin, can often trialised countries, whereas in developing countries, Shigella
shorten both the symptomatic period and the duration of faecal species that are multiple antibiotic resistant are an increasing
carriage. Ciproloxacin resistance is now seen in up to 10% of problem. The luoroquinolones are highly effective in shigello-
non-typhoidal serovars of S. enterica in some countries but is sis, and resistance is rare; therefore, they are often considered to
still uncommon in the UK (Al-Mashhadani et al., 2011). The rec- be the treatment of choice, especially in adults and/or for treat-
ommended dosage of ciproloxacin for adults is 500 mg twice ing imported infections. The dosage of ciproloxacin is 500 mg
daily orally for 1 week. Fluoroquinolones are not licensed for twice daily orally in adults (7.5 mg/kg twice daily in children).
this indication in children, although there is increasing evidence Amoxicillin is an alternative irst-line drug for S. sonnei infec-
that they can safely be given to children. The recommended dos- tions acquired in the UK, where around 90% of isolates are sus-
age of ciproloxacin in childhood is 7.5 mg/kg twice daily orally. ceptible. The dosage of amoxicillin is 250–500 mg three times
Trimethoprim at a dosage of 25–100 mg twice daily orally may daily in adults and 62.5–125 mg three times daily in children.
be used in children if it is preferred not to use a luoroquinolone. Azithromycin (doses as for campylobacteriosis) is increasingly
641
 38 THERAPEUTICS

recommended as an alternative agent for shigellosis, especially intrinsically resistant to furazolidone and trimethoprim. The
in children (Jain et al., 2005). Third-generation cephalosporins choice of antibiotics is therefore governed by knowledge of
such as ceftriaxone are another option for severe shigellosis. local resistance patterns, which may vary between outbreaks.
Trimethoprim resistance is now common, so this agent can no Tetracycline 250 mg four times daily or doxycycline 100 mg
longer be recommended as empiric therapy. Antibiotic therapy is once daily by mouth is probably the most widely used therapy
usually given for a maximum of 5 days. in adults. Ampicillin, amoxicillin or erythromycin is generally
Enteric fever. Treatment should be commenced as soon as the preferred agent for children. Although clinical cure can be
a clinical diagnosis of enteric fever is made. Fluoroquinolones achieved after a single dose of antibiotics, treatment is usu-
have been widely used as the irst-choice treatment for typhoid ally given for 3–5 days to ensure eradication of V. cholerae
and paratyphoid fevers. When treating isolates that are fully from faeces.
sensitive, the clinical response is at least as rapid as with the C. dificile infection. The irst objective is to diagnose CDI
older treatments, there is a lower relapse rate and convalescent as soon as possible so that appropriate treatment and infection
faecal carriage is shortened. However, the proportion of isolates control measures can be put in place. Clinicians must consider
with reduced susceptibility to luoroquinolones has increased the diagnosis in any patient in whom there is no clear alternative
to around 75%. Although most of these isolates have minimum diagnosis for his or her diarrhoea. Stool samples must be sent to
inhibitory concentration values below those regarded as fully the laboratory immediately, and the laboratory must make test-
resistant, treatment failures have been reported. For this rea- ing available 7 days per week. Once the diagnosis is conirmed,
son, luoroquinolones are no longer recommended as irst-line attention must be paid to the patient’s hydration and nutrition,
treatment unless it is known that the isolate is fully sensitive. non-essential antibiotic therapy or gastro-intestinal active drugs
Resistance to other antibiotics that have been commonly used must be stopped and the patient’s condition closely monitored.
to treat enteric fever, such as co-trimoxazole, chloramphenicol Although mild cases may resolve without speciic therapy, treat-
and ampicillin, is now frequent. These agents therefore can- ment of all hospitalised patients with diarrhoea due to C. dificile
not be recommended as alternatives to luoroquinolones for is recommended, to shorten the duration of illness and to reduce
empiric treatment of enteric fever, but may be useful in patients environmental contamination and, therefore, the risk of nosoco-
with bacterial isolates that are conirmed as sensitive. Doses of mial transmission.
ciproloxacin are as outlined for non-typhoidal salmonellosis. Oral metronidazole 400 mg three times daily for 10 days is
The usual dosage of chloramphenicol is 50 mg/kg/day in four widely used as the irst-line treatment for mild-to-moderate CDI.
divided doses, and for ampicillin 100 mg/kg/day in four divided For severe CDI, oral vancomycin is recommended at a dosage of
doses. Two weeks of antibiotic therapy is usually recommended, 125 mg four times daily for 10 days. In patients who are unable
although shorter courses of ciproloxacin (7–10 days) may be as to take oral medication, either drug can be administered via a
effective. nasogastric tube. However, there is growing evidence that vanco-
The majority of cases of enteric fever diagnosed in the UK mycin is superior to metronidazole in CDI of all grades of sever-
are related to travel to the Indian subcontinent, where multi- ity (Nelson et al., 2017). Where there is no response to initial
drug resistance is common (Wain et al., 2015). Third-generation treatment, the dosage of vancomycin can be increased up to 500
cephalosporins are the recommended irst-choice agents to treat mg four times daily, together with intravenous metronidazole 500
such infections, for example, cefotaxime (100–150 mg/kg daily mg three times daily. Oral idaxomicin 200 mg twice a day for
in two to four divided doses in children; 6–8 g daily in three to 10 days was approved for CDI treatment in Europe in 2012. This
four divided doses in adults) or ceftriaxone (50–80 mg/kg/day in drug is considerably more expensive than vancomycin, which is
children; 1–2 g/day in adults). Alternative agents for multidrug- itself more expensive than metronidazole. Fidaxomicin has been
resistant strains are intravenous carbapenems or oral azithromy- shown in clinical trials to be at least non-inferior to vancomycin
cin at a dosage of 20 mg/kg/day (maximum 1000 mg) for at least for the initial cure of CDI, but is clearly associated with a lower
5 days. Time taken for clearance of bacteraemia may be longer rate of recurrence. It is therefore recommended for treatment of
with azithromycin, but the relapse rate appears to be lower than patients deemed to be at high risk of recurrence; individual hos-
with β-lactam antibiotics. pitals must make their own assessment of the cost-effective use
Chronic carriers of Salmonella. Patients may become of idaxomicin (Wilcox, 2013).
chronic carriers after Salmonella infection, especially in the pres- Recurrence of symptoms occurs in about 20% of patients
ence of underlying biliary tract disease. Oral ciproloxacin 500– treated for CDI. Although some recurrences are due to germina-
750 mg twice daily continued for 2–6 weeks is usually effective tion of spores that have persisted in the colon since the origi-
in eradicating carriage and has largely superseded the use of oral nal infection, it is recognised that some of these cases are due
amoxicillin at a dosage of 3 g twice daily. to reinfection, rather than relapse caused by the original strain
Cholera. Fluid and electrolyte replacement is the key (Loo et al., 2004). Most recurrences do respond to a further 10- to
aspect of the management of cholera. However, antibiotics 14-day course of metronidazole or vancomycin, but increasingly
do shorten the duration of diarrhoea, and therefore reduce the idaxomicin is seen as irst-line treatment for this indication. A
overall luid loss, and rapidly terminate faecal excretion of the few patients experience repeated recurrences. Faecal microbi-
organism. Effective agents include tetracyclines, erythromy- ota transplantation is being increasing used in managing these
cin, trimethoprim, ampicillin or amoxicillin, chloramphenicol, patients. However, questions remain concerning regulatory mat-
ciproloxacin and furazolidone. However, antibiotic resistance ters, donor selection, the optimal mixture of the transplant and the
642 is being increasingly seen; in particular, V. cholerae O139 is preferred route of administration.
 GASTRO-INTESTINAL INFECTIONS 38
Pharmaceutical approaches to managing patients with multiple amoebic liver abscess. The dosage for adults is 800 mg (children
recurrences where idaxomicin has failed include: 100–400 mg) three times daily for 5–10 days. To eradicate cysts,
• a supervised trial of anti-motility agents alone (if there are no metronidazole therapy is followed by a 5-day course of diloxanide
abdominal symptoms or signs of severe CDI), furoate 500 mg three times daily (20 mg/kg daily in three divided
• tapering or pulse therapy with oral vancomycin given for 4–6 doses for children). Tinidazole has been shown to reduce clinical
weeks, failure and be better tolerated than metronidazole (Gonzales et al.,
• a 2-week course of oral vancomycin 125 mg four times daily 2009). The dosage of tinidazole for adults is 2 g daily for 2–3 days,
and oral rifampicin 300 mg twice daily, and for children is 50–60 mg/kg daily for 3 days.
• intravenous immunoglobulin, especially if the patient’s albu- Asymptomatic excretors of cysts living in areas with a high
min status worsens. prevalence of E. histolytica infection do not merit treatment
Trial data do not currently support the use of probiotics for because most individuals quickly become reinfected. However,
the treatment or prevention of CDI (Department of Health and asymptomatic excretors of cysts in Europe or North America are
Health Protection Agency, 2009). usually treated with diloxanide furoate for 5–10 days; metroni-
Cryptosporidiosis. Cryptosporidiosis in immunocompetent dazole and tinidazole are relatively ineffective in this situation.
individuals is generally self-limiting. However, in immunosup-
pressed patients, severe diarrhoea can persist indeinitely and can
even contribute to death. HIV-infected patients who are receiv-
ing highly active antiretroviral therapy now have a much lower Patient care
incidence of cryptosporidiosis due to immune reconstitution and
possibly a direct anti-cryptosporidium effect of protease inhibi- Individuals who are excreting gastro-intestinal pathogens are
tors. There is no reliable antimicrobial therapy. Azithromycin, potentially infectious to others. Liquid stools are particularly
which is readily prescribable, is partially effective at a dosage of likely to contaminate the hands and the environment. All cases of
500 mg once daily (10 mg/kg once daily in children). Treatment gastro-intestinal infection should be excluded from work or school
should be continued until Cryptosporidium oocysts are no lon- at least until the patients are symptom free; hospitalised patients
ger detectable in faeces (typically 2 weeks), to minimise the should be isolated in a single room. Patients should be advised on
risk of relapse post-treatment. Occasionally, therapy has to be general hygiene, and in particular, on thorough handwashing and
continued indeinitely to prevent relapse. Most other agents that drying after visiting the toilet and before handling food.
have been recommended for treatment of cryptosporidiosis, for In most countries, many gastro-intestinal infections are statu-
example, nitazoxanide, spiramycin, paromomycin and letrazuril, torily notiiable. Following notiication, the authorities will judge
are not licensed in the UK. These can usually be sourced from whether the implications for public health merit investigation of
special-order manufacturing or importing companies (Smith and the source of infection, contact screening or follow-up clearance
Corcoran, 2004). Of these agents, nitazoxanide has US Food and stool samples from the original case.
Drug Administration approval in the USA and has been shown Common therapeutic problems in the management of gastro-
to be effective in clinical trials at a dosage of 500 mg twice daily intestinal infection are summarised in Table 38.3. Problems asso-
(adults and children aged ≥12 years) for 3 days (children 1–3 ciated with speciic gastro-intestinal infections are summarised
years: 100 mg twice daily; 4–11 years: 200 mg twice daily). in Table 38.4.
Clinical cure rates of 72–88% have been reported in immuno-
competent patients (Fox and Saravolatz, 2005), but are probably
lower in immunosuppressed patients. Case studies
Giardiasis. Metronidazole is the treatment of choice for giar-
diasis. Various oral regimens are effective, for example, 400 Case 38.1
mg three times daily (7.5 mg/kg in children) for 5 days, or 2 g/
day (children: 500 mg to 1 g) for 3 days. Alternative treatments A 12-year-old boy, Master RH, is admitted to hospital with a
are tinidazole 2 g as a single dose, or mepacrine hydrochloride history of fever, weight loss and malaise 1 week after return-
100 mg (2 mg/kg in children) three times daily for 5–7 days. ing from visiting relatives in Pakistan. Whilst there he was diag-
Nitazoxanide is a new thiazolide antiparasitic drug (discussed in nosed as having typhoid fever, and although details are sketchy,
it seems that Master RH received treatment with ciprofloxacin.
the earlier Cryptosporidiosis section) that has also been licensed
The only other medical history of note is that he experienced an
for treatment of giardiasis in some countries, but is not currently anaphylactic reaction after taking penicillin 4 years ago. Twenty-
available in the UK. A single course of treatment for giardiasis four hours after admission, S. enterica serovar Typhi is isolated
has a failure rate of up to 10%. A further course of the same or from a blood culture.
another agent is often successful. Sometimes repeated relapses
are due to reinfection from an asymptomatic family member.
In such cases, all affected family members should be treated Questions
simultaneously.
1. Why might Master RH not have fully responded to the treatment
Amoebiasis. The aim of treatment in amoebiasis is to kill all veg-
given in Pakistan?
etative amoebae and also to eradicate cysts from the bowel lumen. 2. Which antibiotic would now be most appropriate as empiric
Metronidazole is highly active against vegetative amoebae and is therapy?
commonly the treatment of choice for acute amoebic dysentery and 643
 38 THERAPEUTICS

Table 38.3 Practice points: general problems with treatment of gastro-intestinal infections

Problems Resolution

Difficult or impossible to make a rapid aetiological New rapid and more sensitive diagnostic techniques (polymerase chain reaction) are
diagnosis being introduced
Hospital laboratories are expected to offer rapid testing for Clostridium difficile
7 days per week

Antibiotic resistance in bacterial causes of gastroen- With no or few antibiotic agents on the horizon, good antibiotic stewardship
teritis is increasing in prevalence is essential to preserve the effectiveness of existing treatments

Clinical effectiveness and cost-effectiveness of Without reliable data showing benefit, antimicrobial therapy is not used in the
antibiotic therapy for many bacterial gastro-intesti- majority of infections
nal infections are not clearly established

No specific therapies for viral gastroenteritis Infections in otherwise healthy individuals are generally self-limiting

Up to 20% of patients with C. difficile infection Fidaxomicin is a new treatment for C. difficile infection that may be associated with a
experience at least one recurrence lower rate of recurrence

Few other recent improvements in the diagnosis of Various non-evidence-based experimental treatments have been used to manage im-
bacterial or parasitic infections munocompromised patients with protracted diarrhoea; faecal microbiota transplanta-
tion is being increasingly used to manage C. difficile infection

Acute illness may be followed by a period of Cautious use of antidiarrhoeal medication may be indicated at this stage
non-infective diarrhoea

Table 38.4 Practice points: problems with treatment of specific gastro-intestinal infections

Infection Antibiotic Problems Resolution

Campylobac- Macrolides (e.g. Not always effective, especially if commenced Reserve therapy for cases where symptoms are
teriosis erythromycin) >72 h after onset of symptoms severe or worsening at time of diagnosis

Ciprofloxacina Up to 50% of strains are resistant Use only as a second-line agent for isolates
that have been shown to be sensitive

Salmonellosis Ciprofloxacina Not always effective Reserve therapy for cases where symptoms are
Resistance is increasing severe or worsening at time of diagnosis

Enteric fever Ciprofloxacina Resistance is increasing None of these agents is now considered to be
a suitable first-line therapy for enteric fever in
Ampicillin or Resistance to these agents is now common the UK
amoxicillin

Chloramphenicol Higher incidence of chronic carriage and relapse

than with ciprofloxacin
Resistance is now common

Shigellosis Trimethoprim Resistance is increasing Therapy should be guided by antibiotic

sensitivities of the isolate; most trimethoprim-
resistant strains are ciprofloxacin sensitive

Clostridium Metronidazole Relapse rate up to 20% Repeat course of treatment, or treatment with
difficile another agent, e.g. fidaxomicin, or consider
faecal microbiota transplantation

Vancomycin (oral) More expensive than metronidazole Reserve for more serious cases; in the
Risk of promoting vancomycin-resistant case of relapse, repeat course of treat-
enterococci ment, or treatment with another agent, e.g.
Relapse rate up to 20% fidaxomicin, or consider faecal microbiota
transplantation

644 Cryptosporidi- Azithromycin or nita- Not always effective Long-term therapy may be required to control
osis zoxanide symptoms
aCiprofloxacin is not licensed for general paediatric use; it is widely used to treat gastro-intestinal infections in children.
 GASTRO-INTESTINAL INFECTIONS 38
Answers Answer
1. Strains of S. enterica serovar Typhi that have reduced susceptibil- There is no reliable antimicrobial therapy for cryptosporidiosis.
ity to fluoroquinolones are common in the Indian subcontinent. Azithromycin is readily prescribable, and as such may be used at a
Although these strains are not usually fully fluoroquinolone resis- dosage of 500 mg once daily as a first-choice agent. If symptoms
tant, treatment failures have been reported, even when an appropri- do abate, treatment should be continued until Cryptosporidium
ate dose regimen has been used. In this case, there is not even any oocysts are no longer detectable in faeces (typically 2 weeks), to
assurance that the treatment regimen in Pakistan was adequate. minimise the risk of relapse post-treatment. Occasionally, ther-
2. Given the lack of assurance of the adequacy of the ciprofloxacin apy has to be continued indefinitely to prevent relapse. Of the
treatment in Pakistan, one option would be to re-treat with cipro- alternative agents for treatment of cryptosporidiosis, nitazoxanide
floxacin. However, given the high likelihood that the strain will have appears to be the most effective. Although not licensed in the
reduced susceptibility to ciprofloxacin, it would be more logical to UK, it can usually be sourced from special-order manufacturing or
use an alternative agent. Of those, carbapenems and cephalospo- importing companies. However, nitazoxanide treatment is also not
rins are β-lactam antibiotics that would be best avoided, given the always effective in patients who are unable to mount an appropri-
history of anaphylaxis following penicillin exposure. Azithromycin ate immune response.
would appear therefore to be the empiric treatment of choice in
this case. If the patient was seriously unwell and/or unable to take
oral medication, then a carbapenem antibiotic might have to be Case 38.4
used under specialist supervision.
A businessman, Mr JM, is planning a short trip to Egypt. During
previous visits to the area, he has experienced troublesome
Case 38.2 diarrhoea despite being careful about hygiene. Although the
diarrhoea has not made him seriously unwell, it has caused him
A mother brings her 6-year-old daughter, Miss MF, to her pri- considerable inconvenience during business discussions.
mary care doctor because she has a 2-day history of bloody
diarrhoea and abdominal pain. The family had been on a farm
visit the previous weekend and had eaten food when there. The Question
mother is anxious for her child to be treated with antibiotics
Are there any antimicrobials that Mr JM could take to prevent this
because they will be going on their summer holiday in 1 week.
problem?

Questions
Answer
1. Give three possible infective causes of Miss MF’s symptoms.
Although traveller’s diarrhoea is not usually serious, it can cause con-
2. How should the primary care doctor respond to the mother’s
siderable inconvenience whether the sufferer is travelling for leisure
request for antibiotics?
or business reasons. Simple measures that can help prevent traveller’s
diarrhoea include taking care with food and drinks (only bottled water
from reputable sources should be used). There are two approaches
Answers
to antibiotic use in traveller’s diarrhoea. Either the drug can be taken
1. The two commonest bacterial gastro-intestinal infections, campy- prophylactically to try to prevent development of diarrhoea, or treat-
lobacteriosis and salmonellosis, can both present in this way. Many ment can be commenced with the onset of diarrhoea. The latter
other bacterial and protozoan causes of gastroenteritis can also approach is generally preferred because it limits unnecessary expo-
cause similar symptoms. One bacterium that is especially impor- sure to antibiotics, and the response to treatment is usually rapid.
tant to consider in this case, where there is a history of a farm However, there are instances such as in this case where the inconve-
visit, is E. coli O157. Every effort should be made to obtain a stool nience of even short-lived diarrhoea may be great enough to justify
sample from the patient for microbiological examination. use of prophylaxis.
2. It would not be appropriate to treat Miss MF’s symptoms empiri- The choice of antibiotics for traveller’s diarrhoea has been made
cally with antibiotics for a number of reasons. Firstly, antibiotic more complicated by the increasing prevalence of antibiotic resis-
therapy may make no difference to the speed of clinical resolution. tance in many developing countries. Drugs such as amoxicillin or
Secondly, where antibiotics are justified, the choice of drug will trimethoprim no longer have a role. A fluoroquinolone, such as cip-
depend on the aetiological agent. Thirdly, antibiotics are contra- rofloxacin, still represents a reasonable first choice, with azithromycin
indicated in infection with E. coli O157, which must feature in the as a possible alternative in areas where fluoroquinolone resistance is
differential diagnosis in this case. known to be common. For travellers from countries where it can be
prescribed, rifaximin may be the agent of choice. For travellers to
areas where infections such as amoebic dysentery or giardiasis are
Case 38.3 common, it may be appropriate to take a supply of metronidazole
that can be started if there is no response to the first-line antibacterial
An adult liver transplant patient, Mr EJ, presented with diar- prophylaxis.
rhoea (up to 15 times per day), which has been ongoing for
10 days since he returned from a camping holiday. The micro-
biology laboratory has just called to say that Cryptosporidium
Case 38.5
oocysts were seen in his faeces sample.
A 75-year-old woman, Mrs CS, on an elderly care ward experi-
ences watery diarrhoea and abdominal pain 4 days after com-
Question mencing therapy with ciprofloxacin for a urinary tract infection.
C. difficile toxin is detected in a stool sample. She has had two 645
What treatment management can be offered to Mr EJ? previous episodes of CDI in the past year.
 38 THERAPEUTICS

the preferred first-line treatment for mild-to-moderate CDI, whereas

Question oral vancomycin would be a more expensive, but possibly more
effective, alternative; either treatment would be on option here.
How should Mrs CS be managed?
However, because Mrs CS has recurrent CDI, many prescribers
would now choose to treat with fidaxomicin. Although fidaxomicin
Answer is much more expensive, it is associated with a lower risk of CDI
recurrence. Another treatment option that would be considered in
Firstly, treatment with ciprofloxacin should be discontinued. Four- some centres is faecal microbiota transplantation. Mrs CS should be
day antibiotic therapy for a urinary tract infection will often suffice, closely monitored for the frequency and severity of the diarrhoea to
but if further treatment is required, an antibiotic that is less likely ensure that she does not experience life-threatening complications
to disturb the bowel flora should be prescribed. Secondly, Mrs CS of CDI. Finally, the patient should be isolated to reduce the risk of
requires treatment for her CDI. Metronidazole is often regarded as spread of the infection.

References
Al-Mashhadani, M., Hewson, R., Vivancos, R., et al., 2011. Foreign travel of interpreting in vitro azithromycin susceptibility. Pediatr. Infect. Dis. J.
and decreased ciproloxacin susceptibility in Salmonella enterica infec- 24, 494–497.
tions. Emerg. Infect. Dis. 17, 123–125. Loo, V.G., Libman, M.D., Miller, M.A., et al., 2004. Clostridium dificile: a
Corogeanu, D., Willmes, R., Wolke, M., et al., 2012. Therapeutic concentra- formidable foe. Can. Med. Assoc. J. 171, 47–48.
tions of antibiotics inhibit Shiga toxin release from enterohemorrhagic National Collaborating Centre for Women’s and Children’s Health, 2009.
E. coli O104:H4 from the 2011 German outbreak. BMC Microbiol. 12, 160. Diarrhoea and vomiting caused by gastroenteritis: diagnosis, assessment
Department of Health and Health Protection Agency, 2009. Clostridium and management in children younger than 5 years. RCOG Press, London.
dificile infection: how to deal with the problem. Department of Health, Nelson, R.L., Suda, K.J., Evans, C.T., 2017. Antibiotic treatment for
London. Clostridium dificile-associated diarrhoea in adults. Cochrane Database
Dingle, K.E., Clarke, L., Bowler, I.C., 2005. Ciproloxacin resistance among Syst. Rev. 2017 (3), CD004610. https://doi.org/10.1002/14651858.
human Campylobacter isolates 1991–2004: an update. J. Antimicrob. CD004610.pub5.
Chemother. 55, 395–396. Pammi, M., Haque, K.N., 2011. Oral immunoglobulin for the prevention of
Duda-Madej, A., Gościniak, G., Andrzejewska, A., et al., 2013. Association rotavirus infection in low birth weight infants. Cochrane Database Syst.
of untypeable enteropathogenic Escherichia coli (EPEC) strains with Rev. 2011 (11), CD003740. https://doi.org/10.1002/14651858.CD003740.
persistent diarrhea in children from the region of lower Silesia in Poland. pub2.
Pol. J. Microbiol. 62, 461–464. Pollack, L.A., Gould, C.V., Srinivasan, A., 2013. If not now, when? Seizing
Fox, L.M., Saravolatz, L.D., 2005. Nitazoxanide: a new thazolide antipara- the moment for antibiotic stewardship. Infect. Control. Hosp. Epidemiol.
sitic agent. Clin. Infect. Dis. 40 (8), 1173–1180. 34, 117–118.
Gonzales, M.L.M., Dans, L.F., Martinez, E.G., 2009. Antiamoebic drugs Smith, H.V., Corcoran, G.D., 2004. New drugs and treatment for crypto-
for treating amoebic colitis. Cochrane Database Syst. Rev. 2009 (2), sporidiosis. Curr. Opin. Infect. Dis. 17, 557–564.
CD006085. https://doi.org/10.1002/14651858.CD006085.pub2. Wain, J., Hendriksen, R.S., Mikoleit, M.L., et al., 2015. Typhoid fever.
Hopkins, K.L., Mushtaq, S., Richardson, J.F., et al., 2014. In vitro activity of Lancet 385, 1136–1145.
rifaximin against clinical isolates of Escherichia coli and other enter- Wilcox, M., 2013. Updated guidance on the management and treatment of
opathogenic bacteria isolated from travellers returning to the UK. Int. J. Clostridium dificile infection. Public Health England, London.
Antimicrob. Agents 43, 431–437. Wong, C.S., Jelacic, S., Habeeb, R.L., et al., 2000. The risk of the hemolytic
Jain, S.K., Gupta, A., Glanz, B., et al., 2005. Antimicrobial-resistant Shigella uremic syndrome in children during a large outbreak of Escherichia coli
sonnei: limited antimicrobial treatment options for children and challenges O175:H7 infections. N. Engl. J. Med. 342, 1930–1936.

Further reading
DuPont, H.L., 2005. What’s new in enteric infectious diseases at home and Lübbert, C., 2016. Antimicrobial therapy of acute diarrhoea: a clinical
abroad. Curr. Opin. Infect. Dis. 18, 407–412. review. Expert. Rev. Anti Infect. Ther. 14, 193–206.
Florez, I.D., Al-Khalifah, R., Sierra, J.M., et al., 2016. The effectiveness Mohan, P., Haque, K., 2002. Oral immunoglobulin for the prevention of
and safety of treatments used for acute diarrhea and acute gastroenteritis rotavirus infection in low birth weight infants. Cochrane Database Syst.
in children: protocol for a systematic review and network meta-analysis. Rev. 2002 (3), CD003740. https://doi.org/10.1002/14651858.CD003740.
Syst. Rev. 5, 14. Munnink, B.B., Hoek, L.V., 2016. Viruses causing gastroenteritis: the
Goldenber, S.D., 2016. Faecal microbiota transplantation for recurrent known, the new and those beyond. Viruses 8 (2), 42.
Clostridium dificile infection and beyond: risks and regulation. J. Hosp. Toaimah, F.H., Mohammad, H.M., 2016. Rapid intravenous rehydration
Infect. 92, 115–116. therapy in children with acute gastroenteritis: a systematic review.
Pediatr. Emerg. Care 32, 131–135.

Useful websites
National Institute for Health and Care Excellence. Clinical Knowledge Sum- Public Health England. Gastrointestinal infections: guidance, data and
maries: Gastroenteritis: https://cks.nice.org.uk/gastroenteritis analysis: https://www.gov.uk/government/collections/gastrointestinal-infe
ctions-guidance-data-and-analysis

646
THERAPEUTICS

41 Tuberculosis Toby Capstick and Paul Whitaker

Key points In 2006, the emergence of extensively drug-resistant tuberculosis

(XDR-TB) was also reported. The treatment of drug-resistant TB
• Clinical manifestations of active tuberculosis (TB) disease are
is complex, costlier and of a longer duration than drug-suscepti-
varied because Mycobacterium tuberculosis can infect any
organ in the body, but common non-specific symptoms include ble cases.
malaise, weight loss, fever and night sweats. Adequate and effective treatment is essential, both clinically
• Diagnosis of TB is based on the context of clinical signs and for patients and also to control TB, because the Bacille Calmette-
symptoms and investigations such as radiography and micro- Guérin (BCG) vaccine does not prevent infection. Successful
biological results. control depends on a close working collaboration between clini-
• Risk factors for TB include close contact with an infectious cal, microbiological, pharmacy, infection control and public
person, living in a country with a high incidence of TB, immu- health teams in managing patients and their contacts.
nocompromise because of drugs or disease and previous
under-treatment of TB.
• Treatment of active TB with single anti-TB drugs must never be
attempted, and a single drug must never be added to a failing
regimen, because of the risks for development of further drug Epidemiology
resistance.
• Adherence to the full treatment course is essential to achieve The global incidence of TB has declined steadily with rates now
cure, prevent relapse, prevent the development of drug resis- around 18% lower than in 2000. Reporting of patients with TB to
tance and prevent transmission to other people. national surveillance systems is variable between countries, but
• Fixed-dose combination drugs are preferred to using separate it is estimated that 10.4 million people experienced symptoms
drugs because they reduce pill burden and prevent selective of TB worldwide in 2016 (World Health Organization [WHO],
non-adherence. 2017); this number includes more than 1 million children. Ten
• Adverse effects of anti-TB drugs are common. Patients should percent of all patients were also positive for HIV. In 2016, despite
be advised on common and serious adverse drug reactions, the fact that all patients can potentially be cured, 1.3 million peo-
how to manage them and when to refer to their named health-
ple died. In addition, a further 374,000 had TB-HIV co-infection
care professional.
(deaths among HIV-positive TB cases are classiied as HIV
• All patients should have a risk assessment for their likely adher-
deaths according to International Classiication of Diseases, 10th
ence, and Directly Observed Therapy should be considered for
patients thought likely to be non-adherent. Revision). Alongside HIV, TB remains a leading cause of death
• The management of drug-resistant TB is highly complex and worldwide.
should only be managed by a multidisciplinary team with expe- The highest annual incidence of TB (>100 cases per 100,000
rience in managing such cases. population) is seen in sub-Saharan Africa, India and Southeast
Asia. Intermediate rates of TB (26–100 cases/100,000) occur
in China, South America, Eastern Europe and northern Africa.
Lower rates (<25 cases per 100,000 inhabitants) occur in the
Introduction USA, Western Europe, Canada, Japan and Australia.
In 2016, it was estimated that 490,000 cases of MDR-TB
Tuberculosis (TB) is a bacterial infection caused by occurred; however, only about a quarter of these were detected
Mycobacterium tuberculosis complex. It is a global problem and and reported. Almost half of all of these cases occurred in India,
still accounts for millions of deaths every year. Unfortunately, China and the Russian Federation. In some areas of the world
the burden of TB disproportionately affects developing countries, more than one in four people have drug-resistant TB; this is a
and this effect is also compounded by co-infection with HIV. problem especially in Eastern European countries such as Belarus
Advances in diagnostics and treatment have led to a reduction in and Lithuania.
TB mortality by 47% since 1990, with an estimated 53 million A total of 5664 TB cases were reported in England during 2016
lives saved between 2000 and 2016. However, many new chal- (Public Health England, 2017). The overall incidence across all
lenges are facing healthcare systems. The biggest concern has population groups was 10.2 per 100,000 population. This rate has
been the increase in multidrug-resistant tuberculosis (MDR-TB). declined over the past 5 years because of a reduction in migrants 673
 41 THERAPEUTICS

from high-incidence countries, as well as improved pre-entry TB Zumla, 2011). Although this accounts for the majority of cases,
screening. The majority of TB cases in the UK were in the popu- between 10% and 40% of individuals can have extrapulmo-
lation born outside of the UK. The incidence amongst UK-born nary disease. In these patients they will often have the systemic
individuals remains stable at around 3.2 per 100,000 population. symptoms of TB, such as weight loss and sweats, but will have
focal signs and symptoms elsewhere. Common sites for extra-
pulmonary TB include the lymph nodes, pleura, skeletal sites,
abdominal sites and the central nervous system (CNS). In the
Aetiology UK the commonest sites for extrapulmonary TB are the lymph
nodes in the neck and the chest. Miliary TB is the widespread
M. tuberculosis complex contains ive different species; however, dissemination throughout the body due to spread through the
it is M. tuberculosis, M. bovis and M. africanum that are asso- bloodstream and is seen in around 3% of TB cases. It is more
ciated with human disease. M. tuberculosis is the most notable common in infants and the elderly, as well as immunocompro-
cause of TB and accounts for the majority of cases worldwide. mised individuals. In miliary TB the CNS is affected in around
M. africanum is responsible for up to half of the cases of TB in 20% of cases.
West Africa but is not a major pathogen outside of this geographi- In patients with HIV the manifestations of TB can be atypi-
cal area. M. bovis is the causative organism in bovine TB and cal. Extrapulmonary disease is more common, and patients with
accounts for between 5% and 10% of human TB. Its impact has advanced HIV can have very few signs and symptoms despite
fallen since the introduction of pasteurised milk. Both M. bovis extensive and disseminated TB.
and M. africanum can give rise to clinical features of disease that
are indistinguishable from M. tuberculosis.
TB is an airborne disease, and the source of infection is from
another individual with active pulmonary disease. Patients should
Diagnosis
be considered infectious if they have sputum smear-positive pul-
Latent infection
monary disease (i.e. they produce sputum containing suficient
tubercle bacilli to be seen on microscopic examination of a Screening for latent M. tuberculosis infection is indicated for
sputum smear) or laryngeal TB. Patients with smear-negative groups in which the prevalence of latent infection is high or in
pulmonary disease, on three sputum samples, are less infectious those who are at higher risk of reactivation. High-risk groups
than those who are smear positive. When coughing, droplets include foreign-born persons from endemic areas and contact
containing the tubercle bacilli are aerosolised and subsequently screening during an investigation of an active TB case. The diag-
inhaled by other people. The greatest risk is to prolonged, mainly nosis and treatment of latent TB is important because this will
household contacts. result in a reduction in the numbers of active infectious cases in
Inhalation of M. tuberculosis and deposition in the lungs leads to the future.
one of three possible outcomes: immediate clearance of the organ- There are two ways of identifying latent TB: the irst is a
ism, primary active disease, or latent infection (with or without tuberculin skin test and the second an interferon-γ release assay
subsequent reactivation of disease). Active TB develops in around (IGRA). Both methods are a test of the person’s immunological
10% of patients who do not clear the organism, and latent TB memory against TB.
develops in around 90%. In latent TB the infectious bacilli trigger The only tuberculin skin test now used is the Mantoux test. The
an immune response and T lymphocytes become sensitised to the standard Mantoux test consists of an intradermal injection of 2 TU
mycobacterium. The immune system forms granulomas around the of Statens Serum Institute tuberculin RT23 in 0.1 mL of solution
infection to limit spread, and these latent bacilli can remain in this for injection. The results are read 48–72 hours later, although a
state for a long period. If there is a change in the inlammatory valid reading can be obtained up to 96 hours later. The transverse
response, then the latent bacilli can be released, triggering reactiva- diameter of the area of induration is measured with a ruler and the
tion of disease. It is estimated that there are 2 billion people world- result recorded in millimetres. A diameter of induration ≥5 mm is
wide who have latent TB and are at risk of reactivation. There is considered positive and represents an immune response against
a 10% lifetime risk that latent TB will reactivate; however, fac- the tuberculin (National Institute for Health and Care Excellence
tors that further increase the risk include HIV, immunosuppressant [NICE], 2016). A false-positive result can be caused by previous
drugs, diabetes mellitus, chronic kidney disease and poor nutri- BCG vaccination or nontuberculous environmental mycobacte-
tion. The estimated annual risk of TB in those with HIV infection rium. A false-negative result can occur if the patient has a lowered
and TB co-infection is around 10%, as opposed to a 10% lifetime immune system and cannot mount an inlammatory response.
chance in someone infected with TB, but not HIV. The IGRA measures the immune response following the expo-
sure of the patient’s blood cells to proteins from M. tuberculosis.
After incubation for 16–24 hours the levels of interferon-γ are
quantiied. The advantages include that it is not affected by prior
Clinical features BCG vaccination and no second visit is required to read the test.
If either the tuberculin skin test or the IGRA is positive, an
The classic symptoms related to TB are those of prolonged assessment of the patient has to be made to ensure he or she
(>2 weeks) respiratory symptoms. These usually include chronic has no features of active TB. Only when it is conirmed that the
674 cough, weight loss, fevers and night sweats. Patients can be pro- patient is symptom free and has a normal chest radiograph can he
ductive of purulent sputum as well as haemoptysis (Lawn and or she be conirmed as having latent disease.
 TUBERCULOSIS 41
Active tuberculosis
Awareness of TB amongst healthcare professionals is essential for
its control. Early diagnosis, especially of pulmonary TB, followed
by prompt commencement of treatment can reduce the period of
infectivity to other people, especially susceptible contacts, who
might be at risk of the more serious forms of TB disease. TB should
be considered part of the differential diagnosis in a range of clinical
presentations. These include cough, pleural effusions, lymphade-
nopathy, skeletal pain, abdominal pain and fever of unknown origin.
Basic investigations include sputum microbiology, as well as
chest radiograph; however, with the complexity of presentations
many patients will require more extensive diagnostics to conirm
TB. Conirmation is important to avoid unnecessary treatment, as
well as to obtain appropriate specimens for testing drug suscep-
tibilities. At present there is only a limited role for IGRAs and
tuberculin skin testing in the diagnosis of active disease.
Fig. 41.1 Chest radiograph of a 45-year-old male patient with spu-
Microbiological testing tum heavily smeared positive for Mycobacterium tuberculosis. Chest
radiograph shows increased airspace shadowing in both upper lobes
Sputum microscopy and mycobacterial culture are considered to with a cavity in the right upper lobe.
be the gold standard tests for the diagnosis of pulmonary disease.
The staining and microscopy of the sputum smear is a reliable
and cost-effective way of identifying a patient with active TB.
If positive, there is usually a high burden of disease, and these
patients are more infectious. A negative smear cannot be relied
upon and, in many cases, because M. tuberculosis is a slow-growing
organism, culture positivity can take several weeks. A minimum
of three sputum samples, one of which needs to be from early
morning, should be collected from patients with suspected
pulmonary TB. In many patients, treatment will be commenced
on clinical suspicion before cultures become positive.
If conventional culture methods are used, such as the
Lowenstein–Jensen medium, growth may take between 3 and
8 weeks. Modern liquid cultures can produce results more
quickly, often in 1–3 weeks. Once the culture does become posi-
tive it allows for drug-susceptibility patterns to be identiied, Fig. 41.2 Computed tomography (CT) of a 45-year-old male patient
with sputum heavily smeared positive for Mycobacterium tuberculo-
allowing appropriate treatment.
sis. CT scan shows thick-walled 4-cm cavity and nodular inflammation
More recently, polymerase chain reaction–based tests can also in the right upper lobe.
detect M. tuberculosis complex in clinical specimens. These
assays use nucleic acid probes to amplify speciic target RNA lobes, often with cavitation and lymph node enlargement (Fig. 41.1).
or DNA. Using these probes, it is possible, with high sensitivity, However, in many cases, the features are not typical and may pres-
to identify both M. tuberculosis and rifampicin resistance muta- ent with masses, nodules and pleural effusions. In patients with
tions (rpoB gene). These tests do not replace routine culture, but HIV atypical chest radiograph appearances are common.
they may shorten the time interval before effective treatment is Chest computed tomography (CT) is more sensitive than plain
commenced. chest radiography and has a role in the atypical or the subtler
In patients who do not have pulmonary TB, samples can be cases (Fig. 41.2). In these cases the CT scan may indicate further
collected and processed in a similar way. These may include investigations, such as bronchoscopy, to obtain microbiological
luid from pleural effusions or tissue biopsies, for example, from samples.
lymph nodes. In tissue biopsies it is also possible to send them Further imaging may also be required depending upon the pre-
for histological diagnosis, and the typical features seen in TB are sentation or symptoms, for example, a CT or magnetic resonance
those of caseating granulomatous inlammation. imaging scan of the brain in someone with neurological symptoms.

Radiology
Chest radiography is an essential part of the diagnostic workup in Public health action
TB. It is important both for the initial diagnosis as well as to risk
stratify, to determine how infectious the patient may be. Classic TB is a statutorily notiiable communicable disease in the UK. 675
features on chest radiograph include focal iniltration of the upper Cases should be notiied on clinical suspicion by the attending
 41 THERAPEUTICS

doctor to the local authority or a local Public Health England of fully sensitive TB requires the use of four irst-line anti-TB
centre for communicable disease control. Notiication enables drugs: isoniazid, rifampicin, pyrazinamide and ethambutol
public health action to be initiated and involves investigation (NICE, 2016). Streptomycin was previously used as an alterna-
of prolonged, close contacts who might be at risk of infection, tive to ethambutol but is no longer recommended for uncompli-
mainly those living in the same household as the patient, to assess cated cases.
them for latent or active TB disease. It may also enable the source Isoniazid and rifampicin are the most effective bactericidal
of the infection to be found and treated. drugs, and they are most effective at preventing the emergence
Latent TB infection is not infectious and does not require of drug resistance. Rifampicin and pyrazinamide have sterilising
notiication. activity and kill semi-dormant persistent bacteria, and pyrazin-
amide is particularly effective in acid environments. Ethambutol
is bacteriostatic and may prevent or delay the emergence of resis-
tant strains.
Bacille Calmette-Guérin Vaccination Most patients with a fully sensitive strain of TB (including
adults and children regardless of whether they are HIV positive)
The BCG vaccine contains a live attenuated strain of M. bovis require a 6-month course of isoniazid and rifampicin, supple-
and is 70–80% effective against the most severe forms of TB, mented with pyrazinamide and ethambutol for the irst 2 months
such as TB meningitis in children, but is less effective in adults. (NICE, 2016). This is often referred to as the ‘standard recom-
The current (Public Health England, 2013) UK vaccination mended regimen’, and the use of ixed-dose combination (FDC)
strategy targets the at-risk population rather than the entire UK regimens (e.g. Voractiv, Rifater and Riinah) is recommended to
population. In brief, BCG immunisation is offered to infants reduce pill burden and improve adherence. The recommended
at high risk of TB exposure (e.g. those living in local areas doses of irst-line drugs are listed in Table 41.1.
of high incidence or with close relatives from high-incidence
countries), children (where active TB is excluded) who are
Active tuberculosis without central nervous system
contacts of people diagnosed with pulmonary TB and people
involvement
younger than 35 years who are at occupational risk of TB (e.g.
healthcare workers, veterinary staff, prison staff and staff of The ‘standard recommended regimen’ is recommended for all
hostels for homeless people). people with active TB without CNS involvement. This includes
pulmonary TB, which is deined as TB affecting the lungs, pleu-
ral cavity, mediastinal lymph nodes or larynx, and those with
all forms of extrapulmonary TB, for example, peripheral lymph
Treatment node, bone and joint, pericardial and disseminated (including
miliary) TB.
The aims of TB treatment are the following: Glucocorticoids are also recommended in the treatment of
• cure the patient of TB disease, pericardial TB (at an initial dosage of prednisolone 60 mg daily
• prevent death from active TB, (1 mg/kg/day in children) and then gradually tapered after 2–3
• prevent relapse of disease, weeks (NICE, 2016).
• prevent development of drug resistance,
• prevent the transmission of the disease to other patients or
Active tuberculosis with central nervous system
contacts.
involvement
M. tuberculosis is a slow-growing obligate pathogen that
exists in different populations, making it dificult to target with Active TB affecting the CNS is associated with high rates
antibacterials. It exists mostly as extracellular actively growing of morbidity and mortality, and thus treatment is extended
organisms, slowly growing organisms within macrophages under to 12 months, that is, 12 months of isoniazid and rifampicin,
microaerobic and acidic conditions, and as dormant organisms in supplemented with pyrazinamide and ethambutol for the irst
anaerobic conditions. The presence of organisms in pulmonary 2 months. Rifampicin, isoniazid and ethambutol penetrate the
cavities, caseous necrotic foci or pus may reduce antibiotic pen- cerebrospinal luid (CSF) poorly; rifampicin achieves CSF con-
etration. Antibacterial activity may be reduced by the persistence centrations that are only 10–20% of that in the blood. Isoniazid
of organisms within low pH environments, their long genera- has good CSF penetration in patients with inlamed meninges,
tion time, dormancy and low metabolic activity. Consequently, but achieves CSF concentrations that are only 20% of that in
treatment of TB requires combinations of several anti-TB drugs, the blood when the meninges are not inlamed. Ethambutol has
because monotherapy is liable to generate resistance, as demon- poor CSF penetration and may only be useful when the menin-
strated in the original trials of streptomycin. If untreated there is ges are inlamed.
a 5-year mortality rate of 65%. Glucocorticoids are also recommended for the treatment
of TB of the CNS because they have been demonstrated to
reduce mortality and disabling residual neurological dei-
Drug-sensitive tuberculosis
cit (Prasad and Singh, 2008). High doses of prednisolone or
Most patients with drug-sensitive TB can be treated in outpatient dexamethasone are recommended, with NICE recommending
676 settings and do not require admission to hospital. The treatment an initial dosage in adults of intravenous dexamethasone
 TUBERCULOSIS 41
Table 41.1 First-line antituberculosis drugs

Daily unsupervised dose Daily supervised dose

Drug Preparations Adults Children Adults Children

Individual drugs

Isoniazid Oral: 50 mg, 100 mg 300 mg once a day 10 mg/kg (max. 300 15 mg/kg (max. 900 15 mg/kg (max. 900
tablets Consider 5 mg/kg mg) once a day mg) three times a mg) three times a
Liquid (as a manufac- once a day if low week week
tured special) body weight
Parenteral:
50 mg/2 mL ampoules

Rifampicin Oral: 150 mg, 300 mg <50 kg: 450 mg once 15 mg/kg (max. 450 600–900 mg three 15 mg/kg (max. 900
capsules a day mg if <50 kg; 600 mg times a week mg) three times a
100 mg/5 mL syrup ≥50 kg: 600 mg once if ≥50 kg) once a day week
Parenteral: a day
600 mg powder for
reconstitution

Pyrazinamidea Oral: 500 mg tablets <50 kg: 1.5 g once 35 mg/kg (max. 1.5 g <50 kg: 2 g three 50 mg/kg (max. 2 g if
Liquid (as a manufac- a day if <50 kg; 2 g if ≥50 times a week <50 kg; 2.5 g if ≥50 kg)
tured special) ≥50 kg: 2 g once a kg) once a day ≥50 kg: 2.5 g three three times a week
day times a week

Ethambutola,b Oral: 100 mg, 400 mg 15 mg/kg once daily 20 mg/kg once daily 30 mg/kg three 30 mg/kg three times
tablets times per week per week

Fixed-dose combination drugs

Voractiv Oral: rifampicin 150 30–39 kg: 2 tablets Not recommended Not recommended Not recommended
mg, isoniazid 75 mg, daily
pyrazinamide 400 mg, 40–54 kg: 3 tablets
ethambutol hydrochlo- daily
ride 275 mg 55–69 kg: 4 tablets
daily
≥70 kg: 5 tablets daily

Rifater Oral: rifampicin 120 <40 kg: 3 tablets Not recommended Not recommendedc Not recommended
mg, isoniazid 50 mg, daily
pyrazinamide 300 mg 40–49 kg: 4 tablets
daily
50–64 kg: 5 tablets
daily
≥65 kg: 6 tablets daily

Rifinah Oral: Rifinah 300/150 <50 kg: Rifinah Not recommendedd Not recommendedc Not recommended
mg (rifampicin 150/100 mg
300 mg, isoniazid 3 tablets daily
150 mg) ≥50 kg: Rifinah
Rifinah 150/100 mg 300/150 mg
(rifampicin 150 mg, 2 tablets daily
isoniazid 100 mg)
aDose adjustment may be required in renal impairment.
bUse IBW plus 40% of the excess weight in markedly obese patients.
• Male IBW (kg) = 50 + (2.3 × height in cm above 152.4)/2.54 (i.e. IBW = 50 kg + 2.3 kg for each inch over 5 feet).
• Female IBW (kg) = 45.5 + (2.3 × height in cm above 152.4)/2.54 (i.e. IBW = 45.5 kg + 2.3 kg for each inch over 5 feet)
cThe BNF for Children advises that the use of Rifinah or Rifater in older children may be considered outside of license, provided that the respective dose of each

drug is appropriate for the weight of the child.

dRifinah is often used in supervised regimens to reduce tablet burden, but may require additional isoniazid to make up the full dose.

max., Maximum; IBW, ideal body weight.

677
 41 THERAPEUTICS

Table 41.2 Treatment regimens for mono-resistant tuberculosis (NICE, 2016)

Initial phase
Drug resistance (2 months’ duration) Continuation phase

Rifampicin Treat using multidrug-resistant tuberculosis regimen

Isoniazid Rifampicin, pyrazinamide, ethambutol Rifampicin and ethambutol for 7 months

(up to 10 months in extensive disease)

Pyrazinamide Rifampicin, isoniazid, ethambutol Rifampicin and isoniazid for 7 months

Ethambutol Rifampicin, isoniazid, pyrazinamide Rifampicin and isoniazid for 4 months

0.3–0.4 mg/kg once daily, then gradually tapered over 4–8 drug resistance can be highly variable in MDR-TB, there are
weeks (NICE, 2016). limited clinical trials to guide treatment decisions and drug
regimens need to be individualised. The treatment of MDR-TB
is signiicantly more expensive than treating drug-sensitive
Drug-resistant tuberculosis
TB, with drug costs of approximately £18,000 for a 20-month
Drug-resistant TB is most commonly caused by non-adherence course of treatment compared with £260 for standard treatment.
to the full treatment regimen, prescribing of inappropriate treat- However, the costs of prolonged admissions, outpatient clinic
ment regimens or lack of availability of high-quality drugs. In one appointments, stafing and testing will drive overall costs much
meta-analysis, the risk of development of MDR-TB in patients higher.
in whom treatment was unsuccessful after being prescribed an MDR-TB is relatively uncommon in the UK, with just 1.5%
inappropriate treatment regimen was increased 27-fold (van der cases reported in England in 2016 (Public Health England, 2017).
Werf et al., 2012). Although the number of drug-resistant cases Because there are relatively few doctors in the UK with experi-
of TB in the UK is relatively low, resistance to anti-TB drugs is ence in managing MDR-TB, it is recommended that cases are
becoming an increasing problem in many countries including registered with the British Thoracic Society MDR-TB Clinical
the UK. Advice Service to allow other registered healthcare professionals
There are varying degrees of drug resistance that are to provide advice. Guidelines for managing MDR-TB have been
encountered: produced by the WHO (2016), and drug information is available
• mono-resistance: resistance to one anti-TB drug; from the UK TB Drug Monographs (http://www.tbdrugmonogra
• MDR-TB: resistance to at least isoniazid and rifampicin; phs.co.uk).
• XDR-TB: resistance to any luoroquinolone, and at least one Treatment regimens for MDR-TB are based on known drug
injectable second-line drug (capreomycin, kanamycin or ami- sensitivity data, and it is of critical importance that just one drug
kacin), in addition to multidrug resistance. is not added to failing treatment regimens, because this could
The treatment of drug-resistant TB is complex, with a paucity result in further resistance developing to the new drug. The prin-
of randomised controlled trials to guide treatment regimen selec- ciples of treating MDR-TB with second-line drugs (Table 41.3)
tion, and second-line anti-TB drugs are generally less effective are complex, but treatment regimens usually comprise at least
than irst-line drugs and often have poor adverse effect proiles. ive effective drugs during the intensive phase (WHO, 2016):
• one group A drug: a luoroquinolone (moxiloxacin most
effective);
Mono-resistant tuberculosis
• one group B drug: a parenteral agent (amikacin or
In 2016 in England, 7.5% of cases had resistance to at least one capreomycin);
irst-line antibiotic, comprising 7.0% resistant to isoniazid, 1.7% • two group C drugs: prothionamide, cycloserine linezolid or
to rifampicin, 1.2% to ethambutol and 0.6% to pyrazinamide clofazimine;
(Public Health England, 2017). Treatment of mono-resistant TB • usually pyrazinamide (unless resistant);
requires the remaining irst-line anti-TB drugs to be used for lon- • if ive drugs cannot be selected, one drug from group D2
ger durations, as outlined in Table 41.2. (bedaquiline or delamanid) and others from group D3 (e.g.
p-aminosalicylic acid, meropenem-clavulanate) are used;
• ethambutol and/or high-dose isoniazid may be used in addition.
Multidrug-resistant tuberculosis
The intensive phase of treatment should last 8 months, at
The treatment of MDR-TB is complex and requires prolonged which time the parenteral agent is stopped and the remaining
courses of treatment. Only specialist doctors with experience in drugs continued for a total of 20 months. If the regimen appears
treating drug-resistant TB should manage these cases. Newly to be failing (often an indicator of poor adherence or increased
diagnosed patients require admission to hospital into a negative resistance), at least two new drugs should be commenced. This
pressure isolation room until they become non-infectious, to pre- is because adding a single drug is liable to result in further resis-
678 vent transmission to other people. Because the precise pattern of tance developing.
 TUBERCULOSIS 41
Table 41.3 Second-line antituberculosis drugs (WHO, 2016)

WHO
grouping Drug Route Adultsa Childrena

Group A: Levofloxacin Oral 10–15 mg/kg once daily (usually 750–1000 mg Age >5 years: 10–15 mg/kg once
fluoroquino- (not licensed once daily) daily
lones to treat Age ≤5 years: 7.5–10 mg/kg twice
TB in the UK) a day (limited experience)

Moxifloxacin Oral, intrave- Usual dose 400 mg once daily 7.5–10 mg/kg once a day
(not licensed nous WHO recommendations for MDR-TB short
to treat TB in course regimen (safety of the higher doses not
the UK) verified):
Weight <30 kg: 400 mg once a day
Weight 30–50 kg: 600 mg once a day
Weight >50 kg: 800 mg once a day

Group B: Streptomycin Intravenous Age ≤59 years 15 mg/kg daily (usual max. 1 g 20–40 mg/kg daily (max.
second- (unlicensed daily, but can be increased if necessary in large, 1 g daily)
line in the UK) muscular adults) After initial period: 20–40 mg/kg
injectable Age >59 years: 10 mg/kg daily (max. 750 mg three times per week
agents daily)
All ages: after initial period: 15 mg/kg three
times per week

Amikacin (not Intravenous or Age ≤59 years: 15 mg/kg daily (usual max. 15–22.5 mg/kg daily (usual max.
licensed to intramuscular 1 g daily, but can be increased if necessary in 1 g daily)
treat TB in injection large, muscular adults) After initial period:
the UK) Age >59 years: 10 mg/kg daily (max. 750 mg 15–30 mg/kg three times per
daily) week
All ages: after initial period: 15 mg/kg three
times per week

Capreomycin Intramuscular Age ≤59 years: 15 mg/kg daily (usual max. 15–30 mg/kg daily (usual max.
injection 1 g daily, but can be increased if necessary in 1 g daily)
There is expe- large, muscular adults) After initial period:
rience using as Age >59 years: 10 mg/kg daily (max. 750 mg 15–30 mg/kg three times per
an intravenous daily) week
infusion All ages: after initial period: 15 mg/kg three
times per week

Group C: Prothionamide Oral 15–20 mg/kg (max. 1 g) once daily 15–20 mg/kg (max. 1 g) once daily
other core (unlicensed Once-daily dosing is preferred to maximise Once-daily dosing is preferred to
second-line in the UK) peak levels, particularly for daily doses maximise peak levels, particularly
agents ≤750 mg; consider twice-daily dosing if patients for daily doses ≤750 mg; consider
are unable to tolerate once-daily regimens twice-daily dosing if patients are
unable to tolerate once-daily
regimens

Cycloserine Oral Initially 250 mg twice a day, increased to The usual target dose is 10–20
500 mg twice a day depending on serum con- mg/kg/day once or twice per day;
centrations. max. 1 g/day
The usual target dose is 10–20 mg/kg/day
once or twice per day; max. 1 g/day

Linezolid (not Oral, intrave- 600 mg once a day Age ≤11 years: 10 mg/kg three
licensed to nous Consider reducing to 300 mg once daily if times daily
treat TB in serious adverse effects develop Age >11 years: 10 mg/kg twice
the UK) daily (max. 600 mg in 24 h)

Clofazimine Oral 100–200 mg once daily Limited data, recommendation is

(unlicensed Doses of 200 mg daily for 2 months, then based on experience and expert
in the UK) 100 mg daily have been used opinion and suggests
1 mg/kg/day
679
Continued
 41 THERAPEUTICS

Table 41.3 Second-line antituberculosis drugs (WHO, 2016)—cont’d

WHO
grouping Drug Route Adultsa Childrena

Group D: Bedaquiline Oral 400 mg daily for the first 2 weeks, followed Not recommended; limited expe-
add-on by 200 mg three times per week for the remain- rience
agents ing 22 weeks

Delamanid Oral 100 mg twice a day for 24 weeks Not recommended; limited expe-
rience

p-Aminosalicylic Oral 150 mg/kg/day in two to four divided doses; 200–300 mg/kg/day
acid usual dose is 8–12 g/day p-Aminosalicylic acid is only
available in 4 g sachets; the
GranuPAS brand comes with a
dosage scoop graduated in
milligrams to aid dosing in
children

Co-amoxiclav (not Oral, intrave- Oral: 625 mg three times daily Limited data, consult the UK TB
licensed to treat TB nous Intravenous: 1.2 g three times daily Drug monographs
in the UK)

Imipenem/cilas- Intravenous Body weight >50 kg: 1 g twice a day 20–40 mg/kg (max. 2 g) three
tatin (not licensed Body weight (≤50 kg): 15 mg/kg twice a times a day
to treat TB in the day (dose is based on the imipenem
UK) component)

Meropenem (not Intravenous 1 g three times a day 1 month to 12 years: 20–40 mg/
licensed to treat TB Should be used in combination with clavulanate kg every 8 h (max. 6000 mg in
in the UK) (as co-amoxiclav) 625 mg three times a day 24 h)

Thiacetazone Oral 150 mg once daily No information

(unlicensed in the
UK)
aConsultproduct literature or the UK TB Drug monographs (http://www.tbdrugmonographs.co.uk) for dose adjustment recommendations in marked obesity, renal
impairment, or in response to serum levels.
max., Maximum; TB, tuberculosis; WHO, World Health Organization.

An alternative, shorter 9- to 12-month regimen has been should be sought from multidisciplinary teams, and cases must
proposed by WHO (2016) for patients with MDR-TB who be registered with the British Thoracic Society MDR-TB Clinical
have not previously been treated with second-line drugs and in Advice Service.
whom resistance to luoroquinolones and second-line inject- Treatment regimens are likely to comprise any or all remaining
able agents has either been excluded or is considered highly anti-TB drugs to which the isolate is likely to be sensitive, and
unlikely. In Western Europe, this regimen is likely to be suit- drug costs may exceed £70,000. Bedaquiline and delamanid are
able only for a minority of patients based on current drug- two drugs with novel modes of action that have recently been
resistance patterns. licensed in the UK for the treatment of drug-resistant TB and may
The short regimen comprises two phases of treatment: have a role when treating XDR-TB. Currently, however, there
• 4-month intensive phase (extended up to a maximum of are very limited data on the safety of combining bedaquiline and
6 months in case of lack of sputum smear conversion): gati- delamanid in treatment regimens.
loxacin (or moxiloxacin), kanamycin, prothionamide, clo-
fazimine, high-dose isoniazid, pyrazinamide and ethambutol;
HIV/tuberculosis co-infection
• 5-month continuation phase: gatiloxacin (or moxiloxacin),
clofazimine, pyrazinamide and ethambutol. Patients with TB/HIV co-infection should be managed by a mul-
tidisciplinary team that includes physicians with expertise in the
treatment of both TB and HIV infection (Pozniak et al., 2011).
Extensively drug-resistant tuberculosis
First-line anti-TB drugs are recommended, and non-interacting
There is a lack of evidence for suitable treatment regimens for antiretrovirals (ARVs) should be used where possible. TB treat-
people with XDR-TB, and very limited experience in the UK. ment should only be modiied where intolerance, severe toxicity
680 Cases should be managed only at specialist TB centres, advice or genotypic resistance limits ARV choice.
 TUBERCULOSIS 41
ARVs should ideally be commenced early during TB treat- as a paradoxical reaction or immune reconstitution inlammatory
ment, because delayed treatment may prolong or worsen syndrome, and is thought to be due to an exaggerated immune
immunosuppression. However, the treatment of HIV/TB co- response to dead bacilli. Patients may respond to treatment with
infection is complicated because of overlapping toxicities, high-dose prednisolone, such as 30 mg once daily (increased if
drug interactions, immune reconstitution disease and high on rifampicin), which is gradually reduced after 1–2 weeks. Non-
pill burdens. Potential interactions between ARVs and anti- pharmacological treatment options include recurrent needle aspi-
TB drugs must be checked before administration, using ration of lymph nodes or abscesses.
either manufacturer’s summaries of product characteris-
tics, the British HIV Association 2011 guidelines (Pozniak
Adverse drug reactions
et al., 2011) on the treatment of TB/HIV co-infection or
the University of Liverpool HIV drug interactions website Side effects from anti-TB drugs are common and patients should
(http://www.hiv-druginteractions.org). be advised of the common and serious effects, and how to man-
The British HIV Association provides recommendations for age them. This may be supplemented with patient information
commencing ARVs in patients with TB: lealets (PILs) such as those produced by TB Alert (http://www.t
• CD4 less than 100 cells/microlitre: Start as soon as practical hetruthabouttb.org/professionals/patient-support/). Common and
within 2 weeks after starting TB therapy, because there is an serious adverse drug reactions of irst- and second-line anti-TB
increased risk of further AIDS-deining events and increased drugs are listed in Table 41.4.
mortality. In drug-sensitive TB, rifampicin will cause an orange-red
• CD4 100–350 cells/microlitre: Commence as soon as practi- discolouration of urine and other body secretions throughout
cal, but can wait until after completion of 2 months of TB treatment, but is harmless. Gastro-intestinal side effects, such
treatment, especially when there are dificulties with drug as nausea and vomiting, are common, particularly with pyra-
interactions, adherence and toxicities. zinamide, but also with rifampicin and isoniazid. Whilst this is
• CD4 consistently greater than 350 cells/microlitre: Begin at often mild and transient, some patients may experience severe
physician discretion, because there is a low risk of HIV dis- symptoms that require antiemetics. Skin reactions including itch-
ease progression. ing and rashes may occur with any irst-line anti-TB drug; mild
cases may require antihistamines, but if severe may require treat-
ment interruption or systemic corticosteroid treatment.
Latent tuberculosis infection
Rifampicin, isoniazid and pyrazinamide are all potentially
Latent TB infection can be successfully eradicated with appro- hepatotoxic, and liver function tests (LFTs) should be checked
priate courses of anti-TB drugs; however, these are not without before commencing treatment. Many centres will also recheck
risks due to their side effect proile. Treatment is recommended LFTs periodically throughout treatment. If transaminases rise
for children and adults aged up to 65 years, including those with greater than ive times the upper limit of normal, or greater than
HIV infection, conirmed to have latent TB infection after active three times normal with symptomatic liver disease, all potentially
TB disease is excluded (NICE, 2016). UK treatment regimens hepatotoxic drugs (i.e. rifampicin, isoniazid and pyrazinamide)
include either 3 months of isoniazid and rifampicin or 6 months should be stopped immediately. LFTs should be closely moni-
of isoniazid alone. tored and the advice of a liver specialist sought if necessary. If
The choice of treatment depends on each individual’s circum- the patient is well and sputum smear negative (i.e. non-infec-
stances, such that 3 months of isoniazid and rifampicin is recom- tious), no treatment is required until after LFTs return to normal.
mended for people younger than 35 years, if hepatotoxicity is a However, if the patient is unwell or sputum smear positive, TB
concern after assessment of both liver function and risk factors, treatment must continue using two anti-TB drugs with low risk
whereas 6 months of isoniazid alone may be preferred where drug of hepatotoxicity, such as streptomycin and ethambutol, with or
interactions with rifamycins are a concern (e.g. with ARVs, contra- without a luoroquinolone (levoloxacin or moxiloxacin). Once
ceptives, immunosuppressants). Because the risk of hepatotoxic- liver function has returned to normal, the irst-line anti-TB drugs
ity increases with age, adults aged between 35 and 65 years should can be reintroduced sequentially at full dose over a period of no
receive treatment only if there are no concerns of hepatotoxicity. more than 10 days, usually in the order of ethambutol, isoniazid,
Treatment of latent TB infection in people who are contacts of rifampicin, then pyrazinamide. Some guidelines advise against
patients with infectious MDR-TB is currently not recommended reintroducing pyrazinamide if the hepatotoxic reaction was par-
because of the lack of data demonstrating eficacy of any poten- ticularly severe and prolonged, but continuing with ethambutol,
tial regimen. rifampicin and isoniazid initially and extending the course dura-
tion to 9 months.
Peripheral neuropathy is a rare side effect of isoniazid and
Adverse effects
is more common in patients who are malnourished, immuno-
compromised, diabetic, elderly, alcoholic or have renal impair-
Paradoxical reactions
ment. At-risk groups should be prescribed prophylactic doses
Occasionally patients treated for active TB may experience of pyridoxine 10–50 mg once a day, although some guidelines
an exacerbation of signs or symptoms of disease (e.g. worsen- recommend prescribing pyridoxine routinely for all patients. If
ing lymph node swelling), or radiological manifestations of TB symptomatic neuropathy occurs, larger pyridoxine doses may be
despite otherwise responding to anti-TB treatment. This is known required. 681
 41 THERAPEUTICS

Ethambutol can rarely cause optic neuritis, resulting in blurred red-orange colouration due to taking rifampicin, or with isoniazid
vision or red/green colour blindness, and patients should be advised urine test strips.
to report any changes in vision. The risk is increased with large dos- Anti-TB drugs are associated with a range of adverse effects
ages greater than 15 mg/kg/day and with prolonged courses. Visual that require routine monitoring. Routine tests for monitoring
acuity and colour vision should be checked using a Snellen chart adverse effects of treatment include:
and Ishihara plates at the start of treatment and during treatment. • urea and electrolytes, LFTs: repeated every 2–4 weeks for 2
months;
• baseline uric acid;
Monitoring of treatment
• baseline vitamin D level;
Adherence is possibly the most important aspect of monitoring of • baseline full blood count, clotting;
anti-TB drug treatment. It can be assessed in community settings • HIV and hepatitis screen;
simply by patient interview, tablet counts, reviewing prescription • baseline visual acuity and colour vision testing;
collection data or even by taking urine samples to assess for a • nutritional assessment.

Table 41.4 Adverse drug reactions

WHO grouping Drug Common side effects Serious side effects

First-line agents Isoniazid Neurological: peripheral neuropathy Dermatological: skin reactions, e.g. urticaria (uncom-
Hepatic: transient increases in LFTs mon)
Haematological: agranulocytosis, megaloblastic anae-
mia, thrombocytopaenia
Hepatic: hepatotoxicity (rare)
Immunological: drug-induced lupus (rare)
Musculoskeletal: arthralgia, rhabdomyolysis
Neurological: seizure, psychosis (rare)

Rifampicin Reddish discolouration of urine, sweat, Haematological: agranulocytosis (rare), haemolytic

sputum, tears anaemia (rare, usually intermittent therapy), throm-
Gastro-intestinal: anorexia, nausea, bocytopaenia (rare, usually high-dose/intermittent
vomiting, heartburn therapy)
Hepatic: transient increases in LFTs Hepatic: hepatotoxicity (rare)
Flu-like syndrome Renal: nephrotoxicity (rare)

Pyrazinamide Hyperuricaemia Haematological: sideroblastic anaemia (rare), throm-

Arthralgia bocytopaenia (rare)
Gastro-intestinal: anorexia, nausea, Hepatotoxicity
vomiting
Hepatic: transient increases in LFTs
Dermatological: rash

Ethambutol Endocrine: hyperuricaemia Ophthalmic:

Gastro-intestinal: nausea, vomiting Optic neuritis (1–6%; greatest risk at doses
>25 mg/kg/day, or >2 months of treatment)
Red/green colour blindness

Group A: fluoro- Fluoroquino- Cardiovascular: QTc prolongation (risk: Cardiovascular: QTc prolongation
quinolones lones (e.g. hypokalaemia, proarrhythmic condi- Dermatological: SJS or TEN (rare)
levofloxacin, tions, in combination QT-prolonging Haematological: (uncommon) agranulocytosis, aplastic
moxifloxacin) drugs) anaemia, haemolytic anaemia, thrombocytopaenia
Gastro-intestinal: nausea, vomiting, Hepatic: acute hepatitis (rare)
diarrhoea Immunological: anaphylaxis, immune hypersensitivity
Hepatic: transient increases in LFTs (uncommon)
Other: dizziness, headache Metabolic: hypoglycaemia (in patients receiving hypo-
glycaemic drugs, uncommon)
Musculoskeletal: tendon inflammation and rupture
Neurological: seizures
Renal: renal impairment (rare)
Respiratory: extrinsic allergic alveolitis (rare)
Other: serum sickness (rare)

682
 TUBERCULOSIS 41
Table 41.4 Adverse drug reactions—cont’d

WHO grouping Drug Common side effects Serious side effects

Group B: second-line Injectable agents Nephrotoxicity: accumulation if renal Dermatological: induration and local pain with intra-
injectable agents (e.g. amikacin, impairment muscular injection
capreomycin, Ototoxicity: irreversible vestibulo- Endocrine: hypocalcaemia, hypomagnesaemia and
streptomycin) cochlear nerve damage hypokalaemia
Drug-induced eosinophilia (capreomy- Neurological: neuromuscular blockade and respiratory
cin): usually subsides with intermittent paralysis (more common in neuromuscular disease;
dosing usually dose-related and self-limiting)
Audiological: ototoxicity: auditory > vestibular (higher
with amikacin, prolonged use and older age)
Renal: nephrotoxicity (higher with prolonged use)

Group C: other core Prothionamide Hepatic: transient increases in LFTs Hepatic: acute hepatitis (rare)
second-line agents Gastro-intestinal: nausea, vomiting, Neurological (maybe increased with cycloserine): dizzi-
diarrhoea, anorexia, excessive saliva- ness, encephalopathy, peripheral neuropathy
tion, metallic taste, stomatitis, and Ophthalmic: optic neuritis (rare)
abdominal pain Psychiatric: psychotic disturbances, depression
Metabolic: gynaecomastia, hypoglycaemia, hypothy-
roidism

Cycloserine Neurological: confusion, disorientation, Cardiovascular: sudden development of congestive

dizziness, somnolence (increased risk if heart failure (doses >1–1.5 g daily [rare])
peak serum level >35 mg/L) Dermatological: rash and photosensitivity, SJS (rare)
Haematological: vitamin B12 and/or folic acid defi-
ciency, megaloblastic anaemia or sideroblastic anaemia
(rare)
Psychiatric: depression, seizure, psychotic disturbanc-
es (increased risk if peak serum level >35 mg/L)

Linezolid Gastro-intestinal: diarrhoea (4%), nau- Metabolic: lactic acidosis

sea (3%), vomiting Dermatological: urticaria, rash; (rare) bullous disor-
Neurological: headache (2%) ders, e.g. SJS and TEN
Infections: candidiasis, particularly oral Haematological: myelosuppression
and vaginal (1%) Neurological: peripheral neuropathy, seizure, seroto-
Hepatic: transient increases in LFTs nin syndrome
Ophthalmic: optic neuropathy: risk with prolonged
treatment

Clofazimine Dermatological: pink to brownish- Gastro-intestinal (<1%): bowel obstruction, gastro-

black skin discolouration within 1–4 intestinal haemorrhage
weeks in 75–100% of patients; gradu- Ophthalmic: conjunctival pigmentation (38–57%),
ally disappears within 6–12 months subjective dimness of vision (12.3%), and dry eyes,
after stopping treatment. Ichthyosis burning and other ocular irritation (24.6%)
and dry skin (8–38%), pruritus (5%), Psychiatric: reactive depression due to skin discoloura-
rash (1–5%), photosensitivity reac- tion
tions (wear protective clothing and Other: splenic infarction, discolouration of body fluids
sunscreens)
Gastro-intestinal (up to 50% of pa-
tients): abdominal pain, nausea, vomit-
ing, diarrhoea, weight loss

p-Aminosalicylic Gastro-intestinal: nausea, vomiting, Metabolic: hypothyroidism

acid diarrhoea, abdominal pain Haematological: haemolytic anaemia (patients with
Immunological: hypersensitivity reac- G6PD deficiency), agranulocytosis, eosinophilia, leuco-
tions (5–10%) including rash and fever paenia and thrombocytopaenia
Hepatic: acute hepatitis (rare)

Continued

683
 41 THERAPEUTICS

Table 41.4 Adverse drug reactions—cont’d

WHO grouping Drug Common side effects Serious side effects

Group D: add-on Bedaquiline Arthralgia Cardiovascular: QTc prolongation (more common

agents Chest pain in hypokalaemia, proarrhythmic conditions, in
Gastro-intestinal: nausea combination with other drugs that prolong the QT
Neurological: headache interval such as clofazimine, fluoroquinolones or
Respiratory: haemoptysis macrolides)
Hepatic: increases in LFTs

Delamanid Dermatological: dermatitis and Cardiovascular: QTc prolongation; increased risk if:
urticaria hypoalbuminaemia (especially <28 g/L), known
Gastro-intestinal: nausea, vomiting, congenital prolongation of the QTc interval, any
diarrhoea condition or concomitant drug that may prolong the
Neurological: dizziness, insomnia, QTc interval
paraesthesia, tremor Haematological: anaemia, eosinophilia, thrombocyto-
Respiratory: haemoptysis paenia, leucopaenia
Hepatic: increases in LFTs
Metabolic: hypertriglyceridaemia, hypercholesterol-
aemia
Psychiatric: psychotic disorder, agitation, anxiety,
depression, restlessness

p-Aminosalicylic Gastro-intestinal: nausea, vomiting, Metabolic: hypothyroidism

acid diarrhoea, abdominal pain Haematological: haemolytic anaemia (patients with
Immunological: hypersensitivity reac- G6PD deficiency), agranulocytosis, eosinophilia, leuco-
tions (5–10%) including rash and fever paenia and thrombocytopaenia
Hepatic: acute hepatitis (rare)

G6PD, Glucose-6-phosphate dehydrogenase; LFT, liver function test; SJS, Stevens–Johnson syndrome; TB, tuberculosis; TEN, toxic epidermal necrolysis.
Adapted from the UK TB Drug Monographs.

failure, but also disease relapse, development of drug resistance

Drug interactions and transmission to other people. Factors that affect adherence
Rifampicin is a potent inducer of cytochrome P450 enzymes, to treatment include communication barriers, size and number of
and drug interactions are common, resulting in accelerated drug tablets, adverse events of treatment and cost of prescriptions.
metabolism and reduced plasma concentrations. An accurate Approximately three-quarters of new cases of TB in England
medication history must be taken, including herbal and over- are born outside the UK (Public Health England, 2017), and lan-
the-counter remedies. Common signiicant drug interactions guage barriers may exist. Communication and adherence can be
frequently encountered in clinical practice, resulting in reduced supported by the provision of PILs, such as those produced by TB
eficacy, include opiate analgesics, anticoagulants, antiepileptics, Alert, which contain photographs of the tablets that the patient
antifungals, antivirals, corticosteroids, immunosuppressants and takes, and are available in a range of foreign languages.
hormonal contraceptives. To reduce tablet burden to support adherence, FDC tablets are
The absorption of isoniazid and rifampicin is reduced in the recommended in TB treatment regimens, to prevent patients from
presence of food, and both should both be taken on an empty being selective about which drugs to take and prevent drug resis-
stomach, 30–60 minutes before food or 2 hours after food. tance from developing, which may occur with separate drugs.
Isoniazid is also associated with a possible increased risk of Although there is a lack of evidence on adherence with different
headache, sweating, palpitations, lushing and hypotension when treatment regimens in TB, studies have demonstrated that FDC
eating certain foods rich in histamine or tyramine such as cheese, tablets are easier to swallow and more convenient to take than
skipjack tuna or other tropical ish, or red wine. In practice, no taking the four drugs given separately (Bartacek et al., 2009).
dietary restrictions are usually required unless symptoms are
experienced. This reaction is thought to be due to an exagger- Supervised versus unsupervised treatment
ated histamine poisoning reaction following inhibition of hista-
mine metabolism, or to the sympathomimetic action of tyramine Most patients diagnosed with active TB in the UK do not need to
resulting from inhibition of monoamine oxidase. have their treatment supervised, but all should have a risk assess-
ment for their likely adherence, and Directly Observed Therapy
(DOT) should be considered for patients thought likely to be non-
Adherence adherent. DOT should be considered for people who:
Ensuring full adherence to treatment is critical to achieving treat- • have a history of non-adherence;
684 ment success, because non-adherence risks not only treatment • have been treated previously;
 TUBERCULOSIS 41
• have a history of homelessness, drug or alcohol misuse;
Liver disease
• are currently in prison or have been in the past 5 years;
• have a major psychiatric, memory or cognitive disorder; The incidence of active TB is increased in people with chronic
• are in denial of the diagnosis; liver disease, but is complicated by the fact that many anti-TB
• have MDR-TB. drugs are potentially hepatotoxic. The frequency of hepatotoxic-
DOT is performed by directly observed swallowing of medica- ity is also increased in the presence of liver cirrhosis, chronic
tion, and for drug-sensitive TB this is usually given three times hepatitis B and chronic hepatitis C. Such patients should be
weekly (often on Mondays, Wednesdays and Fridays) rather than closely monitored with regular and frequent checks of LFTs, and
daily (see doses in Table 41.1). Healthcare workers are usually treatment suspended if there is a rise in plasma aspartate amino-
responsible for observing medication being swallowed, although transferase or alanine aminotransferase greater than ive times the
relatives or friends may be suitable observers in some situations. upper limit of normal, or three to ive times the upper limit if also
Although in the UK TB nurses frequently provide the DOT ser- symptomatic.
vice, this can also be performed by community pharmacies as
an enhanced service subject to local funding arrangements. The
Pregnancy and breastfeeding
use of DOT (either given daily or intermittently) has been dem-
onstrated to have similar outcomes in terms of cure and cure Active TB during pregnancy poses risks to both the mother and
plus treatment completion in a systematic review (Karumbi and fetus, as well as to any close contacts. Complications of TB in
Garner, 2015). pregnancy include spontaneous abortion, preterm labour, low
birth weight and increased neonatal mortality. The irst-line anti-
TB drugs isoniazid, rifampicin, pyrazinamide and ethambutol are
Patient education
all considered compatible with use in pregnancy, and any risks of
When commencing treatment, all patients should receive harm from these drugs are outweighed by the risks of untreated
verbal and written information on their diagnosis, whether active TB. Many second-line drugs are not compatible with use
active or latent TB infection, and their treatment. Although all in pregnancy, in particular the aminoglycosides, which are asso-
patients must be issued with a PIL provided by the manufac- ciated with hearing and/or balance problems.
turer, these may be hard for some patients to read because of Pregnant women who are diagnosed with latent TB infection
the complexity of language and size of the text. Consequently, may choose to delay commencing chemoprophylaxis until after
many patients find the TB Alert PILs easier to read and delivery, provided that active TB is deinitively excluded.
understand, particularly because these are available in many Breastfeeding is considered safe whilst taking anti-TB drugs,
languages. and all mothers should take supplemental pyridoxine 10–50 mg
Patients should be advised of the benefits of treatment, daily whilst taking isoniazid given the small risk of neurotoxicity
emphasising that complete adherence to treatment will ensure to the feeding infant.
that they will be cured, but whilst they may begin to feel bet-
ter within a few weeks, the full treatment course will take
Elderly
months to prevent relapse of disease. All patients should be
advised that they may experience side effects, and whilst The use of anti-TB drugs may be complicated in elderly patients
some may be harmless or temporary, others may be more because of the presence of comorbidities, drug interactions and
serious and require the patient to contact a named healthcare increased incidence of adverse effects of treatment compared with
professional. younger people. In particular, healthcare professionals should be
alert for the presence or worsening of renal or liver disease, and
adverse effects of anti-TB drugs. Where necessary, doses may
Special circumstances
need to be adjusted and potential drug interactions managed by
altering existing treatment plans.
Renal disease
Several anti-TB drugs are eliminated by the renal route and con-
Children
sequently may require dose adjustment in moderate to severe
kidney disease (Milburn et al., 2010). Of the irst-line drugs, The treatment of TB in children is similar to that of adults,
pyrazinamide and ethambutol should have their dose interval requiring a 2-month intensive phase of four drugs followed by a
extended to three times weekly dosing in stage 4 and 5 chronic 4-month continuation phase of two drugs (extended to 12 months
kidney disease, whereas isoniazid and rifampicin may be con- for TB affecting the CNS). See Table 41.1 for recommended
tinued at the full daily dose. The dose and/or frequency of a doses. Adverse effects of treatment tend to be less frequent in
number of second-line anti-TB drugs should also be adjusted, children than in adults, and consequently LFTs do not need to
including all injectable agents, prothionamide, cycloserine and be routinely monitored unless there is clinical suspicion of hepa-
p-aminosalicylic acid. Patients with chronic kidney disease totoxicity. Furthermore, because isoniazid may cause pyridox-
should be closely monitored for adverse effects, and therapeutic ine deiciency, supplementation is recommended in children at
drug monitoring may be utilised to ensure that a safe and effec- higher risk of experiencing symptoms, particularly malnour-
tive dose is used, particularly for ethambutol, aminoglycosides ished children, HIV-infected children, breastfeeding infants and
and cycloserine. pregnant adolescents. 685
 41 THERAPEUTICS

Treatment in children is also complicated by the lack of avail- An alternative option would be to use rifabutin instead of rifampi-
ability of drug preparations suitable for use in children. Of the cin, because it appears to interact to a lesser extent.
FDCs, Rifater (rifampicin, isoniazid, pyrazinamide) may not be 3. Due to his history, Mr SD would be considered high risk of
non-adherence to TB treatment, and a DOT regimen should be
appropriate as the dose of each drug is not suitable for recom-
strongly considered. This could be provided by local TB nurses,
mended doses in children; Voractiv (rifampicin, isoniazid, pyra- or alternatively the community pharmacist who supervises Mr
zinamide, ethambutol) is not licensed for children younger than SD’s methadone treatment could be asked to provide this role.
8 years or less than 30 kg body weight; and Riinah (rifampi- Community pharmacists may provide DOT as an enhanced ser-
cin, isoniazid) is licensed only for use in adults. Consequently vice, with an agreement between the TB service and pharmacist
children diagnosed with TB frequently receive treatment with about each other’s responsibilities, including when the pharmacist
the four anti-TB drugs given separately. However, some UK spe- should refer back to the TB service, for example, because of side
effects or non-adherence.
cialist paediatric TB centres do use FDCs, but only after careful
consideration of individual doses, which may require dose sup-
plementation with individual drugs. Case 41.2
There is a lack of suitable preparations to use if children are
unable to swallow large tablets. Rifampicin syrup is the only Ms RW is a 28-year-old Lithuanian woman who has lived in England
licensed liquid preparation available for treating TB, whilst iso- for 3 years. She has been referred to the TB clinic with a 2-month
niazid, pyrazinamide and ethambutol must all be ordered as an history of weight loss, fever, night sweats and productive cough.
Chest X-ray shows upper lobe infiltrates and cavities on both
unlicensed special.
sides. A diagnosis of pulmonary TB is made.

Case studies Questions

1. Is Ms RW at low or high risk of drug-resistant TB?
Case 41.1 2. Should she be in isolation?
3. What microbiological investigations are required?
Mr SD is a 25-year-old man with a history of drug use, for which he 4. What treatment should she receive?
is prescribed daily supervised methadone. He was released from
prison 2 years ago. He has been referred to a chest physician with
a cough productive of sputum and a fever (2 months in duration). Answers
A sputum sample, obtained by his primary care doctor, is positive
for acid, alcohol-fast bacilli, and a chest radiograph shows right 1. Data collated by the WHO show that 12% of new TB cases in
upper lobe cavities. A diagnosis of TB is made. Lithuania are MDR-TB (WHO, 2017). Consequently Ms RW would
be assumed to be at high risk of having MDR-TB.
2. Because there is a high risk of MDR-TB, Ms RW should be admit-
ted to a negative pressure isolation room until she is demonstrated
Questions to be either not drug-resistant or non-infectious.
1. What risk factors does Mr SD have for TB? 3. Sputum samples should be taken and undergo smear to test for
2. What effects might TB treatment have on methadone, and how the presence of acid, alcohol-fast bacilli. If positive, they should
should this be managed? then undergo rapid diagnostic nucleic acid amplification tests for
3. How should Mr SD’s TB treatment be managed? rifampicin resistance. Tests should also be done to assess suscep-
tibility to other drugs.
4. Treatment should incorporate at least four second-line anti-
TB drugs that are likely to be effective, in addition to pyra-
Answers
zinamide. In the absence of any history of contact with other
1. Mr SD may be at risk of TB because of his lifestyle. He has the cases of drug-resistant TB, a suitable regimen is likely to ini-
potential for chronic poor health and nutrition due to drug and tially comprise pyrazinamide, a fluoroquinolone (e.g. moxiflox-
alcohol abuse, which could result in a weakened immune system. acin), an injectable agent (e.g. capreomycin), prothionamide
The risk of TB in prisoners and people who have recently and cycloserine. This should be supplemented with pyridox-
been discharged from prison in the UK is not currently clear, ine, to reduce neurological side effects from cycloserine, and
although prisoners are more likely to have other risk factors for an antiemetic.
TB (such as social exclusion and drug abuse). Recently, TB in UK
prisoners has increased.
2. Rifampicin is a potent inhibitor of cytochrome P450 enzymes and Case 41.3
will accelerate the metabolism of methadone, which can result in
withdrawal symptoms. It is likely that most patients will require Mr KP is a 40-year-old man who was born in India. Six weeks
significant increases in methadone dose (as much as twofold to ago, he was referred to the TB clinic with a productive cough
threefold dose increases) whilst being prescribed rifampicin. and fever. Chest X-ray film showed patchy upper lobe con-
Consequently, the drug addiction service that prescribes Mr SD’s solidation, and sputum smear was positive for acid, alcohol-
methadone should be advised of the TB diagnosis and asked to fast bacilli. He was commenced on Voractiv treatment as an
monitor withdrawal symptoms and adjust the methadone dose outpatient.
accordingly. An appointment with the drug addiction service Mr KP subsequently failed to turn up for his weeks 2 and 4 out-
should ideally be arranged within 24 hours of commencing TB patient appointments, and so the local TB nurses had scheduled
treatment. a home visit, but Mr KP was not at home at the appointed time.
686
 TUBERCULOSIS 41
His wife was at home, and she telephoned Mr KP on his mobile
phone so that the TB nurses could speak to him. He admitted that
Case 41.4
he had taken only a few days of treatment and did not intend to
Mr FR, a 50-year-old man being treated for pulmonary TB, is
take any more. The TB nurses advised him that if he did not take
reviewed in the outpatient clinic at week 4 of his standard anti-
his treatment, he would need to be admitted to hospital.
tuberculous treatment (isoniazid, rifampicin, pyrazinamide and
ethambutol). He reports feeling generally run-down with some
Questions increased nausea. Routine blood tests are performed and his ala-
nine transaminase (ALT) has risen from 37 to 230 U/L.
1. What form of TB does Mr KP have?
2. How can Mr KP be forced into hospital admission?
3. Which groups of healthcare staff should be involved in arrange- Questions
ments for his admission to hospital?
1. Should Mr FR’s treatment be stopped?
2. What is the likely causative medicine?
Answers 3. How should the medicines be re-introduced?

1. Mr KP has sputum-smear-positive pulmonary TB, and thus would be

considered to be and potentially pose an infection risk to others. Answers
2. In the UK legal measures are allowed for compulsory admission
1. Once the ALT has risen to five times the upper limit of normal
of people with infectious pulmonary TB under section 37 of the
(>200 U/L), then the medicines should be discontinued.
Public Health (Control of Disease) Act 1984. Two separate applica-
2. Unfortunately, all of the drugs used can cause liver toxicity. The
tions to the magistrates court are required for compulsory hospital
least likely cause is ethambutol.
admission: the first for the admission, and the second for deten-
3. Mr FR’s liver function should be monitored off treatment to ensure it
tion under section 38 of the Public Health (Control of Disease) Act
is returning to baseline. At the same time it is important to assess for
1984. This allows an infectious person to be isolated and prevent
factors that may have increased risk of liver toxicity, such as viral hep-
transmission; however, compulsory treatment of TB is not allowed.
atitis. When the ALT is less than two times the upper limit of normal
3. Because Mr KP is infectious, admission to a hospital side room is
(<80 U/L) reintroduction can take place in a sequential fashion start-
required. A multidisciplinary approach should be taken to prepare
ing with ethambutol plus either isoniazid or rifampicin. Pyrazinamide
and plan for the compulsory admission, including the ward nurs-
is reintroduced last, because it may be the most likely culprit. Latest
ing staff, doctors and public health representatives. This should be
NICE guidelines (NICE, 2016) recommend that the reintroduction
discussed with the patient, including the reasons why he will need
regimen should take place quickly over no more than 10 days.
to be kept in isolation.

References
Bartacek, A., Schütt, D., Panosch, B., et al., 2009. Comparison of a four-drug Public Health England, 2013. The ‘Green Book’ Immunisation against infec-
ixed-dose combination regimen with a single tablet regimen in smear- tious disease. Available at: https://www.gov.uk/government/collections/
positive pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 13, 760–766. immunisation-against-infectious-disease-the-green-book.
Karumbi, J., Garner, P., 2015. Directly observed therapy for treating tuberculosis. Public Health England, 2017. Tuberculosis in England 2017 report (present-
Cochrane Database Syst. Rev. 2015 (5), CD003343. Available at: http://online ing data to end of 2016). Available at: https://www.gov.uk/government/
library.wiley.com/doi/10.1002/14651858.CD003343.pub4/otherversions. uploads/system/uploads/attachment_data/ile/654152/TB_Annual_
Lawn, S.D., Zumla, A.I., 2011. Tuberculosis. Lancet 363, 1050–1058. Report_2017.pdf.
Milburn, H., Ashman, N., Davies, P., 2010. Guidelines for the prevention van der Werf, M.J., Langendam, M.W., Huitric, E., et al., 2012. Multidrug
and management of Mycobacterium tuberculosis infection and disease in resistance after inappropriate tuberculosis treatment: a meta-analysis. Eur.
adult patients with chronic kidney disease. Thorax 65, 559–570. Respir. J. 39, 1511–1519.
National Institute for Health and Care Excellence (NICE), 2016. NICE World Health Organization. 2016. WHO treatment guidelines for drug-
Guideline 33. Tuberculosis. NICE, London. Available at: https:// resistant tuberculosis. 2016 update. October 2016 revision. WHO/HTM/
www.nice.org.uk/guidance/ng33/. TB/2016.04. WHO, Geneva. Available at: http://www.who.int/
Pozniak, A.L., Coyne, K.M., Miller, R.F., et al., 2011. British HIV Association tb/areas-of-work/drug-resistant-tb/treatment/resources/en/.
guidelines for the treatment of TB/HIV coinfection 2011. HIV Med. 12, 517–524. World Health Organization, 2017. Global Tuberculosis Report 2017. WHO/
Prasad, K., Singh, M.B., 2008. Corticosteroids for managing tuberculous menin- HTM/TB/2017.23. WHO, Geneva. Available at: http://apps.who.int/iris/
gitis. Cochrane Database Syst. Rev. 2008 (1), CD002244. Available at: http:// bitstream/10665/259366/1/9789241565516-eng.pdf?ua=1.
onlinelibrary.wiley.com/doi/10.1002/14651858.CD002244.pub3/abstract.

Useful websites
TB Drug Monographs: http://www.tbdrugmonographs.co.uk/ TB Alert: http://www.tbalert.org/
Liverpool HIV Pharmacology Group. HIV Drug interactions: The Truth About TB: http://www.thetruthabouttb.org/
http://www.hiv-druginteractions.org

687
 THERAPEUTICS

42 HIV Infection Sheena Castelino, Alison Grant and Katie Conway

cellular immune response, and so the term acquired immune

Key points deiciency syndrome, or AIDS, was coined. In 1984 a new
• As a result of effective combination antiretroviral therapy (cART), human retrovirus, subsequently named human immunodei-
infection with the human immunodeficiency virus (HIV) has ciency virus (HIV), was isolated and identiied as the cause
changed from being a terminal illness to a long-term manageable of AIDS.
chronic infection, and many people living with HIV can enjoy a
Although initially described in homosexual men, it soon became
good quality of life, with essentially normal life expectancy.
apparent that other population groups were affected, including
• Untreated infection with HIV leads to a progressive dete-
intravenous drug users and individuals with haemophilia. During
rioration in the cellular immune response. After primary HIV
infection (PHI), or ‘seroconversion’, the infected individual may the irst decade, the epidemic grew and the importance of trans-
appear asymptomatic for a number of years before experienc- mission via heterosexual intercourse and from mother to child
ing development of symptomatic disease and/or acquired (vertical transmission) was increasingly recognised. There are
immune deficiency syndrome. two types of HIV: HIV-1, which is the predominant type world-
• Complications arising from untreated HIV infection can mani- wide; and HIV-2, which is less pathogenic and mainly found in
fest in a variety of ways, usually as opportunistic infections or West Africa.
malignancies that are uncommon in the immunocompetent Globally there are more than 36.9 million people living with
population.
HIV (UNAIDS, 2015), with the main burden of disease affect-
• The aim of the treatment of HIV infection is to suppress viral
ing sub-Saharan Africa. Heterosexual transmission of infection
replication to prevent further deterioration of the immune
system and allow immune reconstitution, thereby reducing is most commonly seen worldwide. In the UK there are more
morbidity and mortality associated with chronic HIV. than 100,000 people living with HIV and this number continues
• Currently available antiretroviral agents are classified by their to rise, mainly because of effective HIV treatment, an aging HIV
mechanism of actions as nucleoside or nucleotide analogue population and increased levels of testing. The number of those
reverse transcriptase inhibitors, non-nucleoside reverse tran- living with undiagnosed HIV has declined since 2010 (25% to
scriptase inhibitors, protease inhibitors, integrase inhibitors and 17% in 2014). There remain high and increasing levels of new
entry inhibitors. infections amongst men who have sex with men (MSM), and pre-
• Antiretroviral agents are given in combination, usually of at least vention strategies are more important than ever. Amongst hetero-
three agents, to improve efficacy and reduce the development
sexuals in 2014, the overall prevalence of HIV is 1 in 1000, but
of viral resistance. A high level of adherence to therapy is vital to
ensure efficacy and prevent the emergence of resistant virus.
amongst black African men and women rates are 1 in 56 and 1
in 22, respectively. There are declining levels of new infections,
• Treatment regimens have improved both in terms of efficacy
and tolerability over time, with the majority of people living in particular from those acquiring HIV abroad particularly from
with HIV experiencing virological suppression and good treat- sub-Saharan Africa. However, there is a stable number of hetero-
ment outcomes. There are some important toxicities related to sexuals acquiring HIV within the UK. Within the heterosexual
ART, and drug–drug interactions remain a challenge, particu- population, late diagnosis is still a signiicant problem. In 2014,
larly when faced with an aging HIV population and increasing 55% of cases were diagnosed late (i.e. CD4 cell count <350 cells/
poly-pharmacy.
mm3), and therefore at a 10-fold increased risk of death over
• Effective treatment and virological suppression also signifi- the next year compared with those diagnosed early. The increas-
cantly reduce the onward transmission of HIV.
ing proportion of individuals with HIV who are living into older
age leads to an increase in comorbidities, such as cardiovascular
disease, osteoporosis and osteopaenia, cancer, cognitive impair-
Epidemiology ment, and hepatic and renal dysfunction. It is postulated that HIV
directly and some antiretroviral therapies may contribute to the
In June 1981 ive cases of Pneumocystis jiroveci (formerly development of these comorbidities.
known as carinii) pneumonia (PCP) were described in homo- The impact of treatment advances on reducing the incidence
sexual men in the USA. Reports of other unusual conditions, of AIDS-related illnesses and mortality has been dramatic.
such as Kaposi’s sarcoma (KS), followed shortly. In each of However, the absolute numbers of new AIDS diagnoses and HIV-
688 these patients, there was found to be a marked impairment of related deaths in the UK have plateaued and are largely due to
 HIV INFECTION 42
late presentation, failure to diagnose HIV infection amongst the
asymptomatic population and those disengaged from care. Pathogenesis
Although the number living with HIV globally continues to rise,
there are encouraging trends which include many low- and middle- HIV, in common with other retroviruses, possesses the enzyme
income countries having declining incidence (35% decrease since reverse transcriptase and consists of a lipid bilayer membrane sur-
2000) and fewer AIDS-related deaths (42% decrease since 2004). rounding the capsid (Fig. 42.1). Its surface glycoprotein molecule
There has also been an increase in access to available antiretrovi- (gp120) has a strong afinity for the CD4 receptor protein found pre-
ral agents (ARVs; 84% increase since 2010). However, challenges dominantly on the T helper/inducer lymphocytes. Monocytes and
remain, with 17.1 million people unaware of their infection and 22 macrophages may also possess CD4 receptors in low densities and
million who still need access to treatment. In resource-poor set- can therefore also be infected. The process of HIV entry is more
tings, choice of agents and facilities for monitoring may be limited, complex than originally thought, and in addition to CD4 attachment,
and locally produced generic formulations are often used. subsequent binding to co-receptors such as C-C chemokine receptor
The virus has been isolated from a number of body luids, type 5 (CCR-5) or C-X-X chemokine receptor type 4 (CXCR-4) and
including blood, semen, vaginal secretions, saliva, breast milk, membrane fusion also occur (Fig. 42.2).
tears, urine, peritoneal luid and cerebrospinal luid (CSF). After penetrating the host cell, the virus sheds its outer coat
However, not all of these are important in the spread of infec- and releases its genetic material. Using the reverse transcriptase
tion, and the predominant routes of transmission remain: sexual enzyme, the viral RNA is converted to DNA using nucleosides.
intercourse (anal or vaginal); sharing of unsterilised needles or The viral DNA is then integrated into the host genome in the
syringes; blood or blood products in areas where supplies are not cell nucleus, where it undergoes transcription and translation,
screened or treated; and vertical transmission in utero, during enabling the production of new viral proteins. New virus par-
labour or through breastfeeding. ticles are then assembled and bud out of the host cell, inally

Trans-membrane
glycoprotein (gp41)

Capsid (major
structural protein p24)

Extracellular (envelope)
glycoprotein (gp120)

Lipid layer

Nucleocapsid (p17)

Protease
Reverse
transcriptase

Integrase RNA
Fig. 42.1 Structure of the human immunodeficiency virus. 689
 42 THERAPEUTICS

maturing into infectious virions under the inluence of the pro- new infection, an equilibrium is then reached, which brings the
tease enzyme. level of the virus down to a ‘set point’, which is a relatively stable
During primary HIV infection (PHI), there is a very high rate level of virus in the body and will vary between individuals. The
of viral turnover and a subsequent drop in CD4 count as these CD4 count stabilises and may improve, but to a lower level than
cells are depleted. As the host immune system responds to this before infection occurred. At this stage the infection may appear

Viral envelope HIV-1 RNA

Nucleocapsid

CD4
attachment

Targeted cell
Co-receptor
attachment

Co-receptor DNA copy of viral RNA

HIV-1 virion
CD4 receptor

Multiple
RNA mRNA
transcripted
Reverse
transcriptase

Integrase enables
integration of viral
DNA into cellular DNA Viral
DNA
mRNA translation
forms polypeptides
Cellular DNA and protease
Fusion

Polypeptide

Uncoating

Polypeptide
Polypeptide
Protease

RNA and structural

proteins gather at
cell surface

Protease cleaves
polypeptides
into functional
HIV-1 proteins

The HIV-1 virion buds

from the cell surface
HIV-1 virion

Fig. 42.2 Life cycle of human immunodeficiency virus (HIV) and the sites of action of currently available
690 antiretroviral agents (in bold).
 HIV INFECTION 42
to be clinically latent, but in fact, as many as 10,000 million new • direct manifestations of HIV infection, for example, HIV
virions are produced each day. encephalopathy, HIV myelopathy and HIV enteropathy;
Over time, as chronic infection ensues, cells possessing CD4 • consequences of chronic immune activation, including prema-
receptors, particularly the T helper lymphocytes, are depleted from ture cardiovascular disease, neurocognitive dysfunction and
the body. The T helper cell is often considered to be the conduc- bone mineral density loss.
tor of the ‘immune orchestra’, and thus as this cell is depleted,
the individual becomes susceptible to a myriad of infections and
tumours. The rate at which this immunosuppression progresses is Investigations and monitoring
variable, and the precise interaction of factors affecting it is still not
Current and previous infections
fully understood. It is well recognised that some individuals rapidly
develop severe immunosuppression, whereas others may have been The initial diagnosis of HIV infection is made using a fourth-
infected with HIV for many years whilst maintaining a relatively generation serological test, which tests for HIV antibodies and
intact immune system. It is likely that a combination of viral, host antigen simultaneously, and will detect the vast majority of indi-
(genetic) and environmental factors contributes to this variation. viduals who have been infected with HIV at 4 weeks after spe-
ciic exposure. A further test at 8 weeks post-exposure need only
be considered following an event assessed as carrying a high risk
Clinical manifestations of infection. Many of the rapid ‘point-of-care tests’ which test in
real time, using inger prick or saliva, test only for HIV antibodies
Approximately 80% of individuals develop a lu-like illness dur- and may miss early infection hence have a ‘window period’ and
ing PHI, and this is characterised most commonly by a combina- need to be repeated 3 months after exposure. After conirmation
tion of some or all of the symptoms, such as fever, pharyngitis, of HIV infection, the patient is usually tested for prior exposure
rash, myalgia and headache/aseptic meningitis. Rarely, the degree to a number of potential pathogens, including syphilis; hepatitis
of associated CD4 count depletion may be suficient to result in A, B and C; CMV; varicella zoster virus (VZV) and Toxoplasma
development of an opportunistic illness such as oropharyngeal/ gondii. This can enable subsequent treatment (in the case of
oesophageal candidiasis or P. jiroveci pneumonia. During this undiagnosed syphilis), vaccination (if no prior exposure to hepa-
stage testing is of great importance for the individual’s health titis A, hepatitis B or VZV), prevention (if no prior exposure to
both to avoid late diagnosis and to reduce onward transmission Toxoplasma and CMV) and prophylaxis (if previous exposure
of the virus because PHI is the most infectious phase. to Toxoplasma), and can aid subsequent diagnosis (according to
Although the clinical course of HIV disease varies with each CMV or Toxoplasma status).
individual, there is a fairly consistent and predictable pattern that
enables appropriate interventions and preventive measures to
CD4 count
be adopted. Patients can be classiied into one of three groups
according to their clinical status: asymptomatic, symptomatic or The level of immunosuppression is most easily estimated by
AIDS. This clinical progression generally relates to a decline in monitoring a patient’s CD4 count. This measures the number of
CD4 count and advancing immunosuppression. CD4+ T lymphocytes in a sample of peripheral blood. The normal
Asymptomatic disease usually follows PHI and can last for a range can vary between 500 and 1500 cells/mm3. As HIV disease
number of years. Symptomatic disease is characterised by non- progresses, the number of cells declines. Particular complications
speciic symptomatology such as fevers, night sweats, lethargy and of HIV infection usually begin to occur at similar CD4 counts
weight loss, or by complications including oral candidiasis, oral (Fig. 42.3), which can assist in differential diagnoses and enable
hairy leucoplakia, and recurrent herpes simplex or herpes zoster the use of prophylactic therapies. For example, patients with a
infections. AIDS is deined by the diagnosis of one or more spe- CD4 count less than 200 cells/mm3 should always be offered pro-
ciic conditions including P. jiroveci pneumonia, Mycobacterium phylaxis against P. jiroveci pneumonia. The CD4 count is also
tuberculosis infection and cytomegalovirus (CMV) disease. The used to monitor response to antiretroviral treatment.
World Health Organization (WHO, 2007) has produced a com-
prehensive guide to the clinical staging of HIV/AIDS and a full
Viral load
list of HIV-related and AIDS-deining conditions.
The sequelae of untreated HIV infection can be broadly con- The measurement of plasma HIV RNA (viral load) estimates the
sidered in ive categories: amount of circulating virus in the blood. This has been proven to
• infections that can occur in immunocompetent patients but correlate with prognosis, with a high viral load predicting faster
tend to occur more frequently, more severely and often atypi- disease progression (Mellors et al., 1997). Conversely, a reduc-
cally in the context of underlying HIV infection, for example, tion in viral load after commencement of antiviral therapy is asso-
Salmonella, herpes simplex and M. tuberculosis; ciated with clinical beneit. This measure, in combination with
• opportunistic infections, that is, infections that would not nor- the CD4 count, allows patients and clinicians to make informed
mally cause disease in an immunocompetent host, for exam- decisions regarding which antiretrovirals to start, because some
ple, P. jiroveci pneumonia and CMV; perform better at higher viral loads, to ensure that the medica-
• malignancies, particularly those that occur rarely in the immu- tions are working (maintaining a fully supressed viral load) and
nocompetent population, for example, KS and non-Hodgkin’s when to change antiretroviral therapies (i.e. virological failure),
lymphoma; enabling the most effective use of such agents. 691
 42 THERAPEUTICS

AIDS – defining infections

1000

ns
tio
ec
inf

s)
s

)
ria tion

itis
ail
st

fe l)
he

col
a
ng dia si cte ec

,
kin ge
lc

et

s)
Fu ndi culo t ba inf

(s yn

tis,
gu
Ca ber rren skin

al) es ns
,
ns ar

ia

ha

agi
500

tio ph

o
on
r)

op
i
ag s, ect

)
Tu cu rial

te
lla ia

um
ec (oro

oph

AC
al sis s

os
ce lak

ph ne inf
Re cte

ne

I/M
z

oes
p

br ex
ip
Ba

(v uco

MA
)
ec

(o em mpl

ted
inf

tis,
les y le

a
v

e
i
400

iro
ar

re (
i

ina
as us m es s

tini
ing air

sj
CD4 count

llula
em
sti
Sh al h

o p

(re
is
o
er
350

git
es

sis
s
oc

ina ace
Or

Ca n, m nt h

dis

ns
nin
mo
m

Ce ococ sis (

)
ctio
is
ki te

r
eu

ted
u

me

t
300

las

sem in
(s sis
Pn

is

infe
mo
idi

(dis vium
op
r

ios
l
ca
Pe

nd

sis
tox
las
250

rid

irus

ns m a
dio
p

po
al
sto

ori

lov
r
t

tos

ctio eriu
yp
reb
200

Hi

sp
Cr

ega
yp

infe act
cro
Cr

tom

cob
150

Mi
Bacterial infections

Cy

My
Protozoal infections
100 Fungal infections
Viral infections
50

Time after onset of HIV infection

Fig. 42.3 Opportunistic complications of human immunodeficiency virus (HIV) infection and the CD4
count ranges at which they commonly occur.

Resistance testing
symptom control. For the irst decade of the epidemic, most of
Certain mutations in the HIV virus confer resistance to certain the available drugs and therapeutic strategies were aimed at treat-
antiretrovirals. Due to the implications of transmitted (primary) ing or preventing opportunistic complications and alleviating
resistance, it is recommended that all patients have a genotypic HIV-related symptoms. Since the advent of effective combina-
HIV resistance test performed soon after diagnosis; this will tion antiretroviral therapy (cART) the main aim is to suppress the
ensure that appropriate initial therapy is selected. Further resis- HIV viral load, restore immune function and reduce the potential
tance tests should be performed at any subsequent virological consequences of comorbidities. Unfortunately some opportunis-
failure to direct therapy choice. tic infections are still seen, as well as malignancies, often because
of late diagnosis and because patients are from populations
which are disengaged from care. Management of comorbidities
Tropism testing
is becoming much more important because the majority of people
Viruses may enter the CD4 cell using the CCR5 co-receptor, the with HIV are living to an older age.
CXCR4 co-receptor or both co-receptors. Those that just use one The speed at which new antiretroviral agents are developed
co-receptor are known as CCR5-tropic or CXCR4-tropic viruses; means that there is often a lack of comprehensive data on drug
those that can use both receptor types are called dual-tropic. Where interactions, side effects, etc. Thus, the ability to apply general
a mixture of virus populations is present, the term mixed-tropic is pharmacological and pharmacokinetic principles, together with
used. Different methods of determining tropism are currently under common sense, is required.
evaluation. The tests must be performed in real time because viral The treatment of many of the opportunistic complications of
tropism changes as the disease progresses. If CCR5 inhibitors are HIV comprises an induction phase of high-dose therapy, fol-
to be used, it is essential to determine that the virus is CCR5 tropic; lowed by maintenance and/or secondary prophylaxis using
that is, that there is no signiicant use of the CXCR4 receptor. lower doses. This is due to the high rate of relapse or progres-
sion after a irst episode of diseases such as P. jiroveci pneumo-
nia, cerebral toxoplasmosis, systemic cryptococcosis and CMV
Drug treatment retinitis. Where a cost-effective agent with an acceptable risk/
beneit ratio exists, primary prophylaxis may be offered to indi-
The drug treatment of HIV disease can be classiied as antiretrovi- viduals who are deemed to be at high risk of development of a
ral therapy, the management of opportunistic infections or malig- particular opportunistic infection, for example, PCP prophylaxis.
692 nancies, the management of ‘non-HIV-related’ comorbidities and Discontinuation of prophylaxis, both primary and secondary, is
 HIV INFECTION 42
possible in individuals who demonstrate immunological restora- in morbidity and mortality associated with triple therapy has
tion on cART. been conirmed in routine clinical practice, as well as in other
Paradoxically, this immunological restoration may result in trials (e.g. Palella et al., 1998; Smit et al., 2006). Subsequent
apparent clinical deterioration with opportunistic infections dur- clinical trials have largely been for licensing purposes and/or
ing the irst few weeks after initiation of highly active antiretrovi- have served to reine therapeutic choices rather than to change
ral therapy. This is known as immune reconstitution inlammatory the paradigm of treatment. The concept of intermittent rather
syndrome and usually occurs in those with a low baseline CD4 than continuous therapy was evaluated in the SMART study but
count. shown to be linked with an increased risk of comorbidities not
The goals of therapy in people living with HIV are to: previously thought to be associated with HIV (such as cardio-
• improve the quality and duration of life, vascular disease, hepatic failure and renal failure), as well as
• prevent deterioration of immune function and/or restore HIV disease progression (El-Sadr et al., 2006).
immune status, There are studies which have evaluated novel strategies, such
• treat and/or prevent opportunistic infections, as monotherapy/dual-therapy approaches to reduce drug expo-
• relieve symptoms. sure and cost. The current BHIVA guidelines (BHIVA, 2015)
advise triple therapy in those initiating cART and advise against
boosted protease inhibitor (PI) monotherapy because of lower
Antiretroviral therapy
rates of virological eficacy (Delfraissy et al., 2008). Speciic
Antiretroviral therapy is one of the fastest evolving areas of medi- dual therapy can be used (darunavir [boosted with ritonavir] plus
cine. The speciic details of treatment will therefore continue to raltegravir) if there is a need to avoid certain nucleoside/nucleo-
change as new drugs emerge, although it is likely that the follow- tide reverse transcriptase inhibitors (NRTIs), but with speciic
ing general principles will remain: CD4 and viral load boundaries. Switching those patients who
• A combination of three antiretroviral agents, selected on the have achieved virological suppression because of toxicity, inter-
basis of treatment history and resistance tests, should usually actions or personal preference usually ensures patient adherence
be prescribed to increase eficacy and reduce the development and subsequent maintenance on triple therapy. However, there
of drug-resistant virus. are dual-therapy strategies should drug toxicities become prob-
• Treatment strategies should be adopted that sequence drug lematic with a boosted PI plus lamivudine as the recommended
combinations, being mindful of potential cross-resistance and alternative to triple therapy.
future therapy options.
• Given the crucial importance of a high level of adherence to
When to start therapy
these therapies, the regimen adopted for a particular individ-
ual should, wherever possible, be tailored to suit his or her Current UK guidelines (BHIVA, 2015) recommend starting
daily lifestyle. antiretrovirals in all patients living with HIV regardless of their
Many organisations, such as the British HIV Association CD4 count. This is a change from previous guidelines, which
(BHIVA), the European AIDS Clinical Society, the International recommended starting therapy when the CD4 count declined to
AIDS Society and the WHO, produce regularly updated guide- ≤350 cells/mm3. This change was based on a large global study
lines on the use of antiretroviral therapy. These guidelines include (INSIGHT START Study Group, 2015) which showed the risk
the most up-to-date considerations of: of development of AIDS, serious non-AIDS events or death
• when to start therapy; (combined as the primary endpoint) after 3 years was reduced by
• what to start with; 57% in those who started at a higher CD4 count compared with
• how to monitor, including use of therapeutic drug monitoring patients who waited until their CD4 declined to ≤350 cells/mm3.
(TDM) and resistance testing; In the UK, current funding is lagging behind guideline advice;
• when to switch therapy; therefore, patients are offered treatment with a CD4 ≤350 cells/
• what therapy to switch to; mm3, hepatitis B/C co-infection and speciic conditions (e.g.
• treating individuals who have been highly exposed to multiple HIV-associated nephropathy, malignancy, pregnancy) and treat-
agents; ment as prevention. Treatment as prevention is the use of ARVs
• managing individuals with signiicant comorbidities, for to suppress viral load to undetectable levels, to reduce the likeli-
example, tuberculosis (TB) or hepatitis B/C. hood of onward transmission. This has been demonstrated to be
Most studies that evaluate triple combinations of antiret- highly effective in a number of large randomised control trials
rovirals have been designed with so-called surrogate marker (Cohen et al., 2011; Rodger et al., 2014).
endpoints, measuring the effect on laboratory parameters such
as CD4 count and HIV viral load. These trials are generally
Choosing and monitoring therapy
smaller and shorter in duration than clinical endpoint studies
that are powered to measure the impact on survival and dis- The majority of individuals are currently commenced on a com-
ease progression. Hammer et al. (1997) undertook the irst large bination of two NRTIs and a third agent: either a boosted PI, an
clinical endpoint trial that demonstrated the superiority of a tri- integrase inhibitor (INI) or a non-nucleoside reverse transcriptase
ple combination over dual therapy. Following the results of this inhibitor (NNRTI). The term ‘boosted PI’ refers to a combina-
trial, the standard approach, where treatment is indicated, has tion of one PI combined with a low dosage (usually 100–200
been to use a combination of at least three agents. The reduction mg once or twice daily) of ritonavir, another PI. The ritonavir 693
 42 THERAPEUTICS

does not directly add to the antiretroviral activity of the regimen;

Box 42.1 General prescribing and monitoring information for
it is used purely as a pharmacokinetic enhancer of the other PI,
antiretroviral agents
by increasing the maximum plasma concentration, Cmax, due to
inhibition of cytochrome P450 enzymes and P-glycoprotein in • The Liverpool University HIV Drug interaction website is an
the gut wall and/or extending the half-life (t½) by inhibition of invaluable tool and should be consulted, and other clinicians
hepatic cytochrome P450 enzymes. Triple NRTI therapy is no managing people living with HIV should be informed of this
longer recommended because it is associated with unacceptable resource (http://www.hiv-druginteractions.org).
rates of virological failure. • The Summary of Product Characteristics, current British National
Formulary and national guidelines should be consulted when
The aim of initial therapy is to achieve viral load suppression
managing the treatment of an HIV-positive patient.
in the plasma to levels less than the detection limits of available • Adverse events should be reported. With greater exposure
assays (50 copies/mL). Such virological suppression is almost and long-term use, it is likely that more adverse events will
invariably accompanied by an elevation in CD4 count and clini- be recognised. Some of these may be class effects associated
cal evidence of immune reconstitution. Whilst sustained suppres- with particular groups of antiretrovirals and should therefore
sion over many years is usually possible, viral rebound may occur be monitored even in new agents within a class. Examples
and is often accompanied by the development of resistance to one include dyslipidaemia and diabetes mellitus with PIs, mito-
chondrial myopathy and lipoatrophy with NRTIs, and rash with
or more agents in the combination. Upon conirmed virological
NNRTIs.
failure, a resistance test is performed which will help to identify • There are limited data on the safety of many antiretroviral
to which agents the virus may have adapted and the extent to drugs when taken during pregnancy and their long-term
which any such resistance mutations may confer cross-resistance effects on babies/children. Updated safety information from
to other available drugs. A second-line regimen is then con- the Antiretroviral Pregnancy Register is published twice
structed, wherever possible, utilising a new class of drug to which yearly. Caution should therefore be exercised with all agents.
the individual has not previously been exposed. Upon virological Treatment of women who are planning conception or who
are pregnant must be discussed with the relevant experts and
failure of subsequent regimens, the available therapeutic options guidelines consulted (BHIVA, 2014). All pregnant women who
become increasingly complex, but with the availability of more are treated with antiretrovirals should be reported prospec-
agents targeting different parts of the virus life cycle, virological tively to the Antiretroviral Pregnancy Register.
suppression is still usually possible and should remain the goal
of treatment.
General prescribing guidelines for antiretrovirals are pre- Adherence aids such as pillboxes, medication record cards and
sented in Box 42.1, whereas details of common side effects and alarms (e.g. on mobile phone) can also help to support adherence.
interactions of the currently available agents are summarised in However, practical issues are not the only barriers to adherence,
Table 42.1. and the individual’s health beliefs and motivation, particularly
The routine use of TDM is not recommended, but blood levels around HIV and antiretroviral therapy, should also be addressed
of PIs and NNRTIs should be measured in selected patients, for before treatment is commenced, because these are likely to have
example, where there is liver impairment, suspected non-adher- a signiicant impact on outcome (Horne et al., 2004). Although
ence, in pregnancy and children, or where there are concerns there is little evidence to demonstrate what the optimal interven-
regarding potentially interacting drugs. tions to improve adherence are, multidisciplinary and multia-
HIV mutates readily, and resistance to some antiretrovirals gency approaches appear to be most useful (Poppa et al., 2004).
develops rapidly in the face of suboptimal treatment, for exam-
ple, monotherapy or subtherapeutic blood levels. A high level of
Treatment interruptions
adherence to treatment is crucial to the sustained, successful out-
come of antiretroviral regimens. In view of this, patients should For many reasons, including toxicity, cost and adherence, patients
be advised to take cART as close as possible to the same time and clinicians have been interested in considering ‘drug holidays’
every day and ideally within 2 hours of the agreed time each day. or treatment interruptions. However, this strategy is no longer
If they forget a dose, it should be taken as soon as they remem- recommended in routine practice (El-Sadr et al., 2006). It is now
ber and then return to the original schedule. There are variations recognised that there are dangers associated with this approach
in the genetic barrier to resistance of different antiretrovirals. because of CD4 decline, disease progression, mortality related
Many are fragile in terms of development of drug resistance in to comorbidities, for example, cardiovascular disease, and viral
that a single point mutation will confer drug resistance, which load rebound associated with increased transmission risk and a
can cross the drug class (NRTIs, NNRTIs and some INIs). cART seroconversion-like syndrome. Further, because different anti-
with boosted PIs (particularly darunavir) and dolutegravir (INI) HIV medications have different half-lives, there may be a risk
allow more latitude because it takes a number of mutations to of functional monotherapy, particularly with NNRTIs, and the
reduce their eficacy and as such will be more appropriate for development of resistance if combinations are stopped abruptly
patients who struggle with adherence or who have historical drug in an unplanned fashion.
resistance.
There has been signiicant progress over the years in reducing
Post-exposure prophylaxis
some of the physical burden of therapy, through the development
of combination tablets and the use of strategies such as ritona- Post-exposure prophylaxis (PEP) involves the use of anti-
694 vir boosting to reduce dietary restrictions and dosing frequency. retroviral drugs to prevent infection with HIV after possible
 Table 42.1 Commonly used antiretroviral drugs: adult dosing information and general prescribing points

Drug and formulation Dosage Side effects Main interactions/caution

NRTIs

abacavir (ABC) 300 mg twice a day/600 mg Nausea, vomiting, diarrhoea Caution with drugs inhibiting or metabolised by alcohol dehy-
300 mg tablets once a day Rash (without systemic symptoms) drogenase or UDP transferase (i.e. disulfiram, chlorpromazine,
isoniazid, chloral hydrate, alcohol, retinoids)
300 mg/15 mL oral solution Fatigue, fever, headache
Caution with potent enzyme inducers of UDP transferase (e.g.
Ziagen HSR: in clinical studies and post-marketing
rifampicin, phenobarbitone, phenytoin) – may reduce levels of
surveillance ∼6–8% of patients developed this
abacavir
usually within the first 6 weeks (but may occur
anytime) with symptoms indicating multi-organ Monitor for evidence of withdrawal if given with methadone
system involvement – fever with or without a rash Abacavir and ribavirin share the same phosphorylation pathway
(maculopapular or urticarial), respiratory symp- and may compete for phosphorylation which could lead to a
toms, gastro-intestinal symptoms, malaise, fever, reduction in intracellular phosphorylated metabolite of ribavirin
myalgia, elevated LFTs; symptoms worsen with and reduced sustained virological response to hepatitis C treat-
continued therapy and resolve on stopping; once ment
suspected, the patient must not be rechallenged
– a second reaction can be life threatening.
The risk of HSR is high in patients who test
positive for the HLAB*5701 allele; therefore, it
should not be used in these patients
Take with or without food

emtricitabine (FTC) 200 mg once a day Headache, nausea and vomiting, diarrhoea, Do not give concurrently with other cytidine analogues like
200 mg capsule Adjust dose in renal impairment ↑ creatine kinase lamivudine
10 mg/mL oral solution CrCl < 50 mL/min Insomnia, dizziness, neutropenia and anaemia, In patients co-infected with hepatitis B, discontinuation of em-
↑ amylase, rash, ↑ LFTs tricitabine may result in a rebound hepatitis – monitor LFTs and
200 mg capsule = 240 mg
Skin hyperpigmentation has been reported markers of HBV replication
solution
Emtriva Take with or without food

lamivudine (3TC) 150 mg twice a day/300 mg Headache, insomnia, nausea and vomiting, Avoid high-dose co-trimoxazole (trimethoprim increases
150 mg tablets once a day gastro-intestinal disorders, cough and na- lamivudine levels by 40%, dosage adjustment needed in renal
Adjust dose in renal impairment sal symptoms, neutropenia and anaemia (in impairment)
300 mg tablets
combination with zidovudine), ↑ amylase, rash, In patients co-infected with hepatitis B, discontinuation of
150 mg/15 mL oral solution CrCl < 50 mL/min
alopecia, arthralgia lamivudine may result in a rebound hepatitis – monitor LFTs and
Epivir Take with or without food markers of HBV replication

HIV INFECTION
zidovudine (AZT) 250 mg twice a day/200 mg Anaemia, neutropenia, leucopenia, myalgia, ↑ Risk of myelotoxicity with ganciclovir, high-dose co-trimoxazole,
100 mg and 250 mg three times a day (up to 250 mg nausea and vomiting, anorexia, rash, headache, pyrimethamine, dapsone, flucytosine, vinblastine, doxorubicin,
capsules four times a day) insomnia, nail and skin pigmentation interferon-α
Syrup 50 mg/5 mL Adjust dose in renal impairment Take with or without food Caution with potentially nephrotoxic drugs – pentamidine,
CrCl ≤ 10 mL/min amphotericin, aminoglycosides, ribavirin
Retrovir
Monitor if receiving phenytoin (reports of changes in phenytoin
levels)
Do not use with ribavirin (increased risk of anaemia)

42
Clarithromycin reduces the absorption of zidovudine (give 2 h apart)
Reports of lactic acidosis and mitochondrial toxicity

Continued
695
696

42
Table 42.1 Commonly used antiretroviral drugs: adult dosing information and general prescribing points—cont’d

Drug and formulation Dosage Side effects Main interactions/caution

NTRTIs

THERAPEUTICS
tenofovir disoproxil (TDF) 245 mg once a day Gastro-intestinal upset (diarrhoea, flatulence, Monitoring renal function recommended before starting and
245 mg (tenofovir disoproxil Adjust dose in renal impairment nausea and vomiting), renal impairment, hypo- 2–4 weeks of treatment, at 3 months, and thereafter every 3–6
fumarate 300 mg) phosphatemia, proximal tubulopathy (includ- months; more frequent monitoring required in patients with renal
CrCl <50 mL/min
ing Fanconi syndrome) have been reported, impairment
Viread Take with or after food decrease in bone mineral density Avoid giving with potentially nephrotoxic drugs (e.g. pentami-
dine, amphotericin, aminoglycosides)
Avoid concomitant use of cidofovir which is secreted by the
same renal pathway as tenofovir
In patients co-infected with hepatitis B, discontinuation of teno-
fovir disoproxil may result in a rebound hepatitis – monitor LFTs
and markers of HBV replication

tenofovir alafenamide (TAF) F/TAF 200 mg/10 mg recom- Better safety profile on bone and kidneys relative In patients co-infected with hepatitis B, discontinuation of TAF
Available only in combina- mended with boosted PIs (e.g. to tenofovir disoproxil fumarate may result in a rebound hepatitis – monitor LFT and markers of
tion products atazanavir/ritonavir HBV replication
or darunavir/ritonavir or
F/TAF 200 mg/10 mg
Kaletra)
emtricitabine 200 mg/teno-
F/TAF 200 mg/25 mg recom-
fovir alafenamide 10 mg
mended with unboosted third
Descovy 200 mg/10 mg agents (e.g. dolutegravir,
F/TAF 200 mg/25 mg raltegravir, rilpivirine, efavirenz,
emtricitabine 200 mg/teno- nevirapine)
fovir alafenamide 25 mg F/TAF can be taken with or
Descovy 200 mg/25 mg without food
R/F/TAF 25 mg/200 mg/ E/C/F/TAF should be taken
25 mg with or after food
rilpivirine/emtricitabine/te- R/F/TAF must be taken with a
nofovir alafenamide meal (390 kcal)
Odefsey TAF is not recommended if
emtricitabine 200 mg, elvite- eGFR < 30 mL/min
gravir 150 mg/cobicistat 150
mg/tenofovir alafenamide
10 mg
Genvoya

NNRTIsa

etravirine (ETR) 200 mg twice a day or 400 mg Skin rash, diarrhoea, nausea, headache Significantly reduces plasma concentrations of dolutegravir
100 mg once a day Can only be used with dolutegravir when co-administered with
200 mg Take with or after food atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir
Tablets The 100 mg tablets may be Clarithromycin levels reduced, but concentration of its active
dispersed in water metabolite increased (which has reduced activity against Myco-
Intelence
bacterium avium complex, so alternatives e.g. azithromycin, are
recommended)
 Reduces levels of anticonvulsants carbamazepine, phenobarbital,
phenytoin
Rifampicin decreases levels of etravirine
Rifabutin decreases levels of etravirine and increases levels of rifabutin
Reduces levels of antiarrhythmics
Increases levels of warfarin
Reduces levels of tacrolimus and ciclosporin
Reduces the effect of hormonal contraceptives

efavirenz (EFV) 600 mg once a day Skin rash, CNS effects (e.g. dizziness, light-head- Do not give with terfenadine, astemizole, cisapride, triazolam,
200 mg capsules Take at bedtime to minimise edness, insomnia, abnormal dreaming) – gener- midazolam
CNS side effects ally resolves after the first 2–4 weeks Efavirenz is an inducer of CYP3A4 and an inhibitor of other cyto-
600 mg tablets
Take on an empty stomach to Depression chrome P450 isoenzymes
efavirenz oral solution
30 mg/mL minimise the risk of CNS side Psychiatric adverse reactions With clarithromycin ↑ risk of rash and 39% ↓ in clarithromycin con-
effects centration, whereas 34% ↑ in concentration of active metabolite
600 mg tablet or capsule
of clarithromycin; therefore, use alternatives (e.g. azithromycin)
= 720 mg in 24 mL oral
solution Potential for increase or decrease in levels of phenytoin, phe-
nobarbitone, carbamazepine, methadone – monitor for signs of
Sustiva
withdrawal
With rifampicin, 26% ↓ in efavirenz concentration; therefore,
increase dosage of efavirenz to 800 mg once a day
With rifabutin, decrease in rifabutin concentration – increase
rifabutin dose by 50%
Reduces levels of tacrolimus and ciclosporin
Reduces the effect of hormonal contraceptives

rilpivirine (RPV) 25 mg once a day Skin rash, headache, dizziness, insomnia, depres- Antacids (aluminium, magnesium, calcium) should be taken
25 mg tablets Must be taken with a meal sion, abdominal pain 2 h before or 4 h after rilpivirine
Edurant (390 kcal) Causes mild decrease in creatinine clearance Do not use with proton pump inhibitors (loss of therapeutic
effect of rilpivirine); can use with H2 antagonists if dosed once a
day and given 12 h before or 4 h after rilpivirine

nevirapine (NVP) 200 mg once a day for 2 weeks Skin rash (skin reactions including Stevens–Johnson Not recommended with rifampicin; with rifabutin, monitor for
200 mg tablets (lead-in period to lessen the syndrome and toxic epidermal necrolysis have toxicity – some patients may experience large increases in rifabu-
frequency of rash), then 200 been reported – discontinue immediately if severe tin levels because of high interpatient variability
400 mg prolonged-release
mg twice a day or 400 mg pro- or accompanied by constitutional Nevirapine is a hepatic enzyme inducer; careful monitoring of
tablets

HIV INFECTION
longed release once a day symptoms [fever, blistering, oral lesions]), the effectiveness of other drugs that are metabolised by the
Suspension 10 mg/mL
Note: Dose escalation should nausea, headache and abnormal LFTs cytochrome P450 enzyme system is recommended when taken
Viramune not occur if rash observed dur- Patients should be intensively monitored dur- in combination
ing the lead-in period, until rash ing the first 18 weeks to disclose the potential Methadone levels may be reduced
resolves appearance of severe skin or hepatic reactions With warfarin has the potential to ↑ or ↓ coagulation time
Adjust dose in renal impairment Do not initiate nevirapine in female adults if CD4 Reduces the effect of hormonal contraceptives
CrCl < 20 mL/min > 250 cells/mm3 and in male adults if CD4 count
> 400 cells/mm3 and detectable HIV viral load
With or without food
because of the risk of serious and life-threatening

42
hepatotoxicity

Continued
697
Table 42.1 Commonly used antiretroviral drugs: adult dosing information and general prescribing points—cont’d

42
Drug and formulation Dosage Side effects Main interactions/caution

PIsb

atazanavir (ATV) 300 mg once a day + ritonavir Nausea, vomiting, headache, diarrhoea, rash, Do not give with rifampicin; with rifabutin, reduce dosage by
150 mg capsules 100 mg once a day scleral icterus and jaundice, fatigue 75% (if rifabutin dosage is 300 mg once a day, then reduce it to

THERAPEUTICS
Take with or after food Asymptomatic QTc prolongation 150 mg three times a week)
200 mg capsules
Reyataz Nephrolithiasis Do not give with terfenadine, astemizole, pimozide, ergot de-
rivatives, cisapride, quinidine, bepridil, quetiapine, alfuzosin
Caution with amiodarone, lidocaine (↑ levels of these drugs)
Caution with drugs known to induce PR prolongation on ECG
Not recommended with simvastatin or lovastatin (↑ risk of myopa-
thy including rhabdomyolysis); caution with atorvastatin
Caution with sildenafil (↑ in sildenafil levels)
With warfarin, monitor anticoagulation parameters
Not recommended with apixaban, dabigatran and rivaroxaban
(increase in concentration of anticoagulant)
With diltiazem, ↓ initial dose of diltiazem by 50% and titrate;
caution with verapamil (↑ verapamil levels)
Levels of ketoconazole and itraconazole, ciclosporin, tacrolimus
may be ↑
With tenofovir ↓ in atazanavir levels; must be used boosted (i.e.
atazanavir 300 mg once a day with ritonavir 100 mg once a day)
With efavirenz ↓ in atazanavir levels; use 400 mg atazanavir
boosted with ritonavir 100 mg once a day
Not recommended with nevirapine (↓ atazanavir levels)
With antacids or products containing buffers, administer atazanavir
+ ritonavir 2 h before or 1 h after the buffered product
(atazanavir levels reduced because of ↑ gastric pH)
Do not give with proton pump inhibitors (e.g. with omeprazole 76%
decrease in atazanavir levels due to increase in gastric pH); caution
with H2 receptor antagonists; give atazanavir 2 h before or 10 h
after ranitidine (which should be dosed as 300 mg once a day)

fosamprenavir (FPV) fosamprenavir Nausea, vomiting, diarrhoea, headache, dizzi- Do not give with rifampicin; with rifabutin, reduce dosage by
700 mg tablets 700 mg twice a day ness, rash 75% (if rifabutin dosage is 300 mg once a day, then reduce it to
Contains sulfonamide moiety – caution in 150 mg three times a week)
50 mg/mL suspension +
sulfonamide allergy Do not give with terfenadine, astemizole, pimozide, ergot derivatives,
Telzir ritonavir 100 mg twice a day
cisapride, quinidine, bepridil, quetiapine, alfuzosin, lidocaine
Take with or after food
Caution with amiodarone and other antiarrhythmics (darunavir ↑
levels of these)
Not recommended with simvastatin or lovastatin (↑ risk of myopa-
thy including rhabdomyolysis); caution with atorvastatin
Caution with sildenafil (↑ in sildenafil levels)
With warfarin, monitor anticoagulation parameters
Not recommended with apixaban, dabigatran and rivaroxaban
(increase in concentration of anticoagulant)
Levels of ketoconazole and itraconazole, ciclosporin
closporin, tacrolimus may be ↑
 darunavir (DRV) darunavir 800 mg once a day Rash, nausea, vomiting, headache, dizziness, Do not give with rifampicin; with rifabutin, reduce dosage by
800 mg + insomnia 75% (if rifabutin dosage is 300 mg once a day, then reduce it to
Contains sulfonamide moiety – caution in 150 mg three times a week)
600 mg ritonavir 100 mg once a day
sulfonamide allergy Do not give with terfenadine, astemizole, pimozide, ergot
Tablet darunavir 600 mg twice a day
derivatives, cisapride, quinidine, bepridil, quetiapine, alfuzosin
100 mg/mL suspension +
Caution with amiodarone, lidocaine (↑ levels of these drugs)
Prezista ritonavir 100 mg twice a day
Not recommended with simvastatin or lovastatin (↑ risk of myopa-
(in patients with drug resistance) thy including rhabdomyolysis); use lowest dose of atorvastatin
Take with or after food Caution with sildenafil, dose of sildenafil should not exceed 25
mg in 48 h
Levels of ketoconazole and itraconazole, ciclosporin, tacrolimus
may be ↑
With warfarin, monitor anticoagulation parameters
Not recommended with apixaban, dabigatran and rivaroxaban
(increase in concentration of anticoagulant)
Do not give with ticagrelor (increased levels of ticagrelor)

lopinavir/ritonavir (LPV/RTV) 2 tablets twice a day/4 tablets Nausea, vomiting, diarrhoea; increase in LFTs, Do not give with rifampicin; with rifabutin, reduce dosage by
200 mg/50 mg once a day/5 mL twice a day triglycerides and cholesterol 75% (if rifabutin dosage is 300 mg once a day, then reduce it to
Take with or after food 150 mg three times a week)
Tablets
Do not give with terfenadine, astemizole, midazolam, triazolam,
Liquid lopinavir 400 mg/
pimozide, ergot derivatives, flecainide, propafenone, cisapride
ritonavir 100 mg in 5 mL
Not recommended with simvastatin or lovastatin (↑ risk of myopa-
Kaletra
thy including rhabdomyolysis); caution with atorvastatin
Caution with sildenafil, dose of sildenafil should not exceed
25 mg in 48 h
With warfarin, monitor anticoagulation parameters
Not recommended with apixaban, dabigatran and rivaroxaban
(increase in concentration of anticoagulant)
Levels of calcium channel blocking agents may be ↑
Levels of ketoconazole and itraconazole, ciclosporin, tacrolimus
may be ↑
Dexamethasone, phenobarbitone, phenytoin, carbamazepine
may ↓ lopinavir levels
With methadone, methadone levels may be ↓
With clarithromycin, consider ↓ dose of clarithromycin if renal or

HIV INFECTION
hepatic impairment
Because it contains ritonavir there is the risk of Cushing’s syn-
drome with potent corticosteroids metabolised by cytochrome
P450 pathways (e.g. triamcinolone, fluticasone, budesonide) and
subsequent risk of iatrogenic adrenal suppression when cortico-
steroid is discontinued

Continued

42
699
700

42
Table 42.1 Commonly used antiretroviral drugs: adult dosing information and general prescribing points—cont’d

Drug and formulation Dosage Side effects Main interactions/caution

ritonavir (RTV) Used as a pharmacokinetic Nausea and vomiting, diarrhoea, asthenia, taste Do not give with rifampicin and rifabutin
enhancer at a dosage of 100 perversion, circumoral (around the mouth) and

THERAPEUTICS
100 mg tablets Do not give with terfenadine, astemizole, cisapride, some seda-
mg once a day when taken in peripheral paraesthesia, fatigue and vasodilata- tives (alprazolam, clorazepate, diazepam, flurazepam, triazolam,
Solution 400 mg/5 mL
combination with atazanavir 300 tion midazolam, zolpidem), some analgesics (piroxicam, dextropropoxy-
Norvir mg once a day or darunavir 800 phene [contained in co-proxamol], pethidine), some antiarrhyth-
mg once a day mics (flecainide, amiodarone, quinidine, propafenone), clozapine,
100 mg twice a day when taken pimozide, bupropion, meperidine, ergot derivatives
with darunavir 600 mg twice Caution with sildenafil, dose of sildenafil should not exceed
a day 25 mg in 48 h
Take with or after food Levels of ketoconazole and itraconazole, ciclosporin, tacrolimus may be ↑
With methadone or morphine, ↑ in methadone or morphine dose
may be needed
Do not give the oral solution with metronidazole (oral solution con-
tains 40% alcohol), avoid with the capsules (12% alcohol)
With theophylline, ↑ dose of theophylline may be required
With warfarin, monitor anticoagulation parameters
With clarithromycin, adjust dose of clarithromycin if renal impairment
Not recommended with apixaban, dabigatran and rivaroxaban
(increase in concentration of anticoagulant)
Not recommended with salmeterol
Risk of Cushing’s syndrome with potent corticosteroids metabolised
by cytochrome P450 pathways (e.g. triamcinolone, fluticasone,
budesonide) and subsequent risk of iatrogenic adrenal suppression
when corticosteroid is discontinued

Other pharmacokinetic enhancers

cobicistat (COBI) 150 mg once a day Nausea, diarrhoea, fatigue Do not give with rifampicin; with rifabutin, reduce dosage by
150 mg In combination with atazanavir 75% (if rifabutin dosage is 300 mg once a day, then reduce it to
300 mg once a day or darunavir 150 mg three times a week)
Tablet
800 mg once a day Do not give with amiodarone, quinidine, carbamazepine, phenobar-
Tybost
Take with or after food bitone, phenytoin, ergot derivatives, cisapride, pimozide, midazol-
am, triazolam, lovastatin, simvastatin, alfuzosin, St. John’s wort
Not recommended with salmeterol, rivaroxaban
With warfarin and dabigatran, monitor anticoagulation parameters
Caution with sildenafil, dose of sildenafil should not exceed
25 mg in 48 h
 Reduces eGFR due to inhibition of tubular secretion of creatinine
Contains azo colouring agent sunset yellow which may cause
allergic reactions
Risk of adrenal suppression and Cushing’s syndrome with
corticosteroids metabolised by cytochrome P450 pathways (e.g.
fluticasone, budesonide)
Reduces the effect of hormonal contraceptives
Concentration of immunosuppressants (e.g. ciclosporin and
tacrolimus) may be increased
Do not use with the herbal remedy St. John’s wort
Risk of Cushing’s syndrome with potent corticosteroids
metabolised by P450 pathways (e.g. triamcinolone, fluticasone,
budesonide) and subsequent risk of iatrogenic adrenal suppres-
sion when corticosteroid is discontinued

Entry inhibitor

enfuvirtide injection (T-20) 90 mg twice a day by subcu- Injection-site reactions (discomfort/pain at the No clinically significant interactions expected with products
90 mg/mL taneous injection (upper arm, injection site, induration, erythema, nodules and metabolised by cytochrome P450 enzymes
anterior thigh or abdomen) cysts, pruritus), diarrhoea, nausea,
Fuzeon
Alternate sites peripheral neuropathy
Use immediately after reconsti-
tution; if not used immediately,
store in the fridge
(2–8 °C) for a maximum of 24 h
and protect from light

maraviroc (MVC) Confirm that virus is CCR5 Rash, abdominal pain, flatulence, nausea, With potent CYP3A inhibitors (e.g. cobicistat, rifabutin + PI, clar-
150 mg tablets tropic before starting maraviroc depression, insomnia ithromycin, itraconazole, ketoconazole), other PIs reduce dosage
300 mg twice a day Delayed HSRs to 150 mg twice a day
300 mg tablets
Reduce dosage to 150 mg once Cases of syncope caused by postural hypoten- Not recommended with fosamprenavir/ritonavir
Celcentri
a day if CrCl < 80 mL/min and sion; caution in patients with severe renal Not recommended with St. John’s wort
on a potent CYP3A4 inhibitor impairment and in patients who have risk
With efavirenz and rifampicin, factors for or history of postural hypotension
increase dosage to 600 mg
twice a day
Take with or without food

HIV INFECTION
Integrase inhibitors

raltegravir (RAL) 400 mg twice a day Dizziness, headache, nausea and vomiting, Rifampicin reduces levels of raltegravir; if co-administration is
400 mg tablets Take with or without food insomnia, abnormal dreams, depression unavoidable, double the dose of raltegravir
Isentress Aluminium and magnesium hydroxide antacids reduce raltegravir
levels – give 6 h apart

Continued

42
701
702

42
Table 42.1 Commonly used antiretroviral drugs: adult dosing information and general prescribing points—cont’d

Drug and formulation Dosage Side effects Main interactions/caution

dolutegravir (DTG) 50 mg once a day Headache, nausea and diarrhoea, rash, ↑ Efavirenz, etravirine, nevirapine and rifampicin decrease dolute-

THERAPEUTICS
50 mg tablets Take with or without food creatinine kinase, insomnia, abnormal dreams, gravir levels – increase dolutegravir dosage to 50 mg twice a day
depression Magnesium, aluminium, calcium, iron and multivitamins should
Tivicay
10–14% decrease in creatinine clearance be taken 2 h after or 6 h before dolutegravir
Metformin levels increase (area under the curve increased by
79% with dolutegravir 50 mg once a day) – adjust metformin
dose when starting and stopping dolutegravir

elvitegravir (EVG) 85 mg once a day (in combina- Diarrhoea, nausea, headache, rash, fatigue Do not give with rifampicin; with rifabutin, reduce dosage by
85 mg tablets tion with atazanavir 300 mg 75% (if rifabutin dosage is 300 mg once a day, then reduce it to
once a day/ritonavir 100 mg 150 mg three times a week)
150 mg tablets
once a day or lopinavir 400 mg/ Do not give with carbamazepine, phenobarbitone, phenytoin,
Vitekta ritonavir 100 mg twice a day) St. John’s wort
150 mg once a day (in combina- Magnesium- and aluminium-containing antacids and multivita-
tion with darunavir 600 mg mins should be separated 4 h apart from elvitegravir
twice a day + ritonavir 100 mg With warfarin, monitor anticoagulation parameters
twice a day or fosamprenavir
700 mg twice a day + ritonavir
100 mg twice a day)
Take with or without food

This information is not exhaustive – refer to the Summary of Product characteristics for further information. For combination products, see the individual drugs.
aNon-nucleoside reverse transcriptase inhibitors (NNRTIs) have a long half-life: Patients should be warned that if they discontinue them for whatever reason they should do so in consultation with their clinic which

may recommend continuing the other drugs, e.g. the nucleotide analogue reverse transcriptase inhibitor (NRTI), for 2 weeks, or switching the NNRTI to a protease inhibitor (PI) for 2 weeks to prevent drug
resistance. Do not use the herbal remedy St. John’s wort.
bProtease inhibitors (PIs) reports of new or exacerbated diabetes mellitus and hyperglycaemia. There are reports of lipodystrophy with PIs. There are reports of increased bleeding in patients with haemophilia

with PIs. Do not use the herbal remedy St. John’s wort with PIs. PIs reduce the effect of hormonal contraceptives.
CNS, Central nervous system; CrCL, creatinine clearance; ECG, electrocardiogram; eGFR, estimate of glomerular filtration rate; HBV, hepatitis B virus; HSR, hypersensitivity reaction; LFT, liver function test; PI,
protease inhibitor; UDP, uridine diphosphate.
 HIV INFECTION 42
exposure, which may be recommended after occupational inju- • A barrier method of contraception should also be recom-
ries (Department of Health, 2008) or sexual exposure (Cresswell mended in addition to hormonal contraception, to prevent
et al., 2016). Whilst PEP is a largely unproven and unlicensed transmission of HIV and other sexually transmitted infections.
indication for the drugs used, it is supported by animal model • Because women living with HIV are living longer, menopause
data and case–control studies. Where recommended in guide- and hormone replacement therapy (HRT) will become more
lines, PEP is usually commenced as a 3- to 5-day starter regi- of a prominent issue. There is currently a lack of data; there-
men of two NRTIs and an INI (tenofovir disoproxil fumarate, fore, potential drug interactions between HRT and ARVs need
emtricitabine and raltegravir), followed by an ongoing course for to be considered.
a total of 4 weeks post-exposure. It is believed this will reduce the Mother-to-child transmission. The introduction of routine
likelihood of infection by at least 80%. The decision to prescribe antenatal testing in the UK for HIV has made mother-to-child
or take PEP must relect a careful risk–beneit evaluation. transmission a rare occurrence. Guidelines set out the manage-
ment of HIV infection in pregnant women and the prevention of
mother-to-child transmission (de Ruiter et al., 2014). In general,
Pre-exposure prophylaxis
intervention relects a risk–beneit evaluation between the efi-
Pre-exposure prophylaxis (PrEP) uses one or two antiretroviral cacy of reducing transmission and the potential harmful effects to
drugs (tenofovir disoproxil fumarate +/– emtricitabine) to pre- both mother and fetus.
vent acquisition of HIV in high-risk populations. Many stud- The BHIVA pregnancy guidelines (2014) identify that women
ies (Grant et al., 2010; McCormack et al., 2015) have shown who require ART for their own health should commence treatment
a reduction in those at risk of acquiring HIV; those with less as soon as possible. Women who need ART solely to reduce trans-
eficacious results are generally attributable to lower levels of mission should start two NRTIs and a boosted PI by week 24 of
adherence. The PROUD study (Dolling et al., 2016) found that pregnancy. Consideration should be given to starting ART at the
PrEP conferred higher protection than in placebo-controlled tri- beginning of the second trimester (viral load >30,000 copies/mL)
als, reducing HIV incidence by 86% in a population with sev- or even earlier (viral load >100,000 copies/mL). Zidovudine mono-
enfold higher HIV incidence than expected. Although available therapy can be used in women planning a caesarean section who
in many countries, PrEP is not currently funded by the National have a baseline viral load less than 10,000 copies/mL and a CD4
Health Service. count greater than 350 cells/mm3. However, because the BHIVA
(2015) guidelines for the treatment of HIV-1+ adults with antiret-
roviral therapy recommend starting ART at any CD4 count once
Women with HIV
they are ready to commit to taking therapy, this is likely to change.
In addition to the general points covered elsewhere in this chap- Decisions regarding type of birth should be made after review
ter, there are speciic issues for women with HIV. These include: of plasma viral loads at 36 weeks. Vaginal delivery is recom-
• Cervical screening should be carried out at least annually, mended if the plasma viral load is less than 50 copies/mL. A pre-
to check for gynaecological manifestations of HIV because labour caesarian section is recommended if plasma viral load is
cervical intraepithelial neoplasia/cervical cancer has a higher greater than 400 copies/mL. This should also be considered if
incidence in women living with HIV. plasma viral load is between 50 and 399, taking into account the
• Drug interactions between antiretrovirals and some oral con- decline of the HIV viral load trajectory time of ART, adherence
traceptives and contraceptive implants are important and issues, obstetric factors and the woman’s views.
should be discussed with women. Infant post-exposure prophylaxis. Four weeks of zidovudine
• Guidelines are available from the Faculty of Sexual and monotherapy is recommended if the maternal viral load is less
Reproductive Healthcare Clinical Guidance (http://www.fsrh. than 50 copies/mL at 36 weeks’ gestation and thereafter before
org) on drugs that reduce contraceptive eficacy and from delivery. Triple-drug therapy is recommended for all other cir-
the University of Liverpool HIV drug interactions website cumstances. All infants should be exclusively formula fed from
(http://www.hiv-druginteractions.org). birth. Where a mother who is receiving effective ART and has
• All ritonavir boosted PIs and the NNRTIs nevirapine and efa- repeated undetectable viral load chooses to breastfeed, this should
virenz may reduce the eficacy of hormonal contraception by be exclusive (except during the weaning period) and should be
enzyme induction. completed by the end of 6 months. This is because foods and lu-
• There is a potential reduction in eficacy of the progesterone- ids introduced to the gut of mixed-fed babies damage the bowel
only subdermal implant etonogestrel (Nexplanon). The long- and may facilitate the entry into the body tissues of the HIV pres-
acting injectable progesterones, depot medroxyprogesterone ent in these mothers’ breast milk. Maternal ART should be closely
acetate (DMPA; Depo-Provera) and depot norethisterone monitored up to 1 week after breastfeeding has ended.
enanthate (NET-EN; Noristerat), are not affected and can be
used.
Ethnicity
• There are no interactions with the intrauterine device (IUD)
(copper coil) or the levonorgestrel-releasing intrauterine sys- It is now recognised that ethnicity, as well as gender, can affect
tem (Mirena). drug handling and response to treatment. This is due, in part, to
• The NRTIs etravirine, rilpivirine, raltegravir, dolutegravir and epidemiological differences in gene expression. For example,
maraviroc do not have clinically signiicant interactions with reduced activity of cytochrome P450 2B6, one of the key enzymes
hormonal contraceptives. involved in the metabolism of the NNRTI efavirenz, appears to 703
 42 THERAPEUTICS

be more common amongst African than Caucasian individuals. PIs. Cross-resistance between nevirapine and efavirenz is high.
These drugs, therefore, have a signiicantly longer plasma half- Second-generation NNRTIs, like etravirine and rilpivirine, are
life in those affected, which may impact on eficacy, toxicity and active against some viruses resistant to nevirapine and efavirenz.
treatment interruptions. The prevalence of the HLA*B5701 gene, The NNRTIs have much longer plasma half-lives than PIs
associated with abacavir hypersensitivity, also varies in different and NRTIs, so when stopping an NNRTI-containing combina-
ethnic groups, although the clinical implications of this have yet tion, consideration should be given to either continuing the other
to be fully researched. agents for a period (e.g. 2 weeks after cessation of the NNRTI) or
As pharmacogenomics becomes more widely incorporated into switching to a boosted PI before discontinuation.
clinical trials and routine patient care, it is hoped that a greater
understanding will be gained of differences in response to treat-
Protease inhibitors
ment, enabling treatment strategies to be individualised and
optimised. PIs bind to the active site of the HIV-1 protease enzyme, prevent-
ing the maturation of the newly produced virions so that they
remain non-infectious. Commonly used PIs include:
Nucleoside and nucleotide analogue reverse
• atazanavir (ATV; Reyataz),
transcriptase inhibitors
• darunavir (DRV; Prezista),
NRTIs must be phosphorylated within host cells to be activated. • low-dose ritonavir (RTV; Norvir) as a booster (1100 mg)
The active form resembles the host nucleotides and is used in together with other PIs.
reverse transcriptase chain elongation. This false substrate termi- Less commonly used PIs include:
nates the chain and viral replication ceases. • fosamprenavir (FPV; Telzir),
The NRTIs commonly used are: • lopinavir co-formulated with ritonavir (LPV/RTV; Kaletra),
• abacavir (ABC; Ziagen), • saquinavir (SQV; Invirase).
• emtricitabine (FTC; Emtriva), Other PIs are no longer available, but patients may have been
• lamivudine (3TC; Epivir), exposed to them in the past. These include:
• tenofovir disoproxil fumarate (TDF; Viread). • indinavir (IDV; Crixivan),
Combination formulations of NRTIs are also available: • nelinavir (NFV; Viracept),
• abacavir + lamivudine (Kivexa), • tipranavir (TPV; Aptivus).
• tenofovir disoproxil fumarate + emtricitabine (Truvada). Second-generation PIs, like darunavir, are effective against
Older NRTIs are rarely used, but patients may have been many viruses resistant to the earlier PIs. Darunavir is used in irst-
exposed to these in the past. These include: line PI therapy as a once-daily boosted regimen (800 mg with
• didanosine (ddI; Videx), 100 mg ritonavir); for patients with signiicant PI resistance, a
• stavudine (d4T; Zerit), higher dosage of 600 mg twice daily, boosted with ritonavir 100
• zalcitabine (ddC; Hivid), mg twice a day is used. An alternative booster to ritonavir is cobi-
• zidovudine (AZT; Retrovir), cistat, which has no activity against HIV but is used as a booster
• zidovudine + lamivudine (Combivir), at a dose of 150 mg once a day. Cobicistat is co-formulated with
• zidovudine + lamivudine + abacavir (Trizivir). some PIs (e.g. darunavir [Rezolsta] and atazanavir [Evotaz]) and
There are two mechanisms by which resistance to NRTIs can with an INI (e.g. elvitegravir [Genvoya and Stribild]).
occur. The irst involves mutations (e.g. M184V, K65R, Q151M)
which occur at or near the drug-binding site of the reverse tran-
Integrase inhibitors
scriptase gene conferring drug resistance. The second, known
as pyrophosphorolysis, is when the chain-terminating residue is INIs bind to the integrase enzyme, thus blocking the integration
removed, enabling viral replication to resume. of viral DNA into host DNA. Raltegravir and elvitegravir have a
lower genetic barrier to resistance than dolutegravir. In general,
INIs must be used within a fully suppressive regimen to minimise
Non-nucleoside reverse transcriptase inhibitors
the risk of drug resistance. INIs include:
NNRTIs inhibit the reverse transcriptase enzyme by binding to • dolutegravir (DTG; Tivicay),
its active site. They do not require prior phosphorylation and can • raltegravir (RAL; Isentress),
act on cell-free virions, as well as infected cells. The NNRTIs • dolutegravir co-formulated with abacavir + lamivudine
available include: (Triumeq),
• efavirenz (EFV; Sustiva), • elvitegravir (EVG) co-formulated with cobicistat + tenofovir
• etravirine (ETR; Intelence), disoproxil fumarate + emtricitabine (Stribild).
• nevirapine (NVP; Viramune),
• rilpivirine (RPV; Edurant),
Entry inhibitors
• Delavirdine (DLV; Rescriptor) is no longer available, but
patients may have been exposed to this in the past. There are currently two types of entry inhibitors: fusion inhibitors
Resistance to NNRTIs occurs rapidly in incompletely sup- and CCR5 inhibitors. Fusion inhibitors block the structural rear-
pressive regimens, and it is therefore essential that they are pre- rangement of HIV-1 gp41, and thus stop the fusion of the viral
704 scribed with at least two NRTIs or a combination of NRTIs and cell membrane with the target cell membrane, preventing viral
 HIV INFECTION 42
RNA from entering the cell. CCR5 inhibitors selectively bind to Whilst there are many individual drug toxicities, there are also
the human chemokine receptor CCR5, preventing CCR5-tropic a number of class-speciic or drug-related toxicities (Carr and
HIV-1 from entering cells. Cooper, 2000).
Enfuvirtide (T-20; Fuzeon), a fusion inhibitor, is adminis- Non-nucleoside reverse transcriptase inhibitors. Abacavir
tered subcutaneously and is primarily used in heavily treatment- can cause a hypersensitivity reaction in 6–8% of individuals.
experienced patients. The main side effect is injection-site The use of pharmacogenomics testing for HLA B*5701 status
reactions. The need to administer enfuvirtide by injection and and only using abacavir in patients who are B*5701-negative has
the availability of other groups of drugs means it is rarely used. dramatically reduced the incidence of this hypersensitivity reac-
Maraviroc (MVC; Celsentri), a CCR5 inhibitor, is indicated for tion (Mallal et al., 2008).
use in patients with only CCR5-tropic virus, which is determined Tenofovir disoproxil fumarate can rarely cause proximal renal
by a tropism test just before commencing treatment. It is usually tubular dysfunction (Fanconi syndrome). This is characterised by
used in patients with resistance to one or more other antiretroviral glycosuria, hypophosphatemia and renal tubular acidosis from
classes. reduced bicarbonate reabsorption. Tenofovir disoproxil fuma-
The different groups of drugs are co-formulated as ixed-dose rate has also been shown to potentially reduce the estimate of
combinations, and this helps reduce pill burden and may make glomerular iltration rate in certain patients. Caution should be
them more acceptable to patients and also support adherence. observed when using tenofovir disoproxil fumarate in patients
Fixed-dose combinations are not suitable for patients with renal with pre-existing renal dysfunction or when patients are also tak-
dysfunction who require dose modiication. Currently available ing other nephrotoxic drugs. Regular monitoring of renal func-
combinations include: tion and checking for proteinuria is recommended for all patients
• Atripla (emtricitabine/tenofovir disoproxil fumarate/ receiving tenofovir disoproxil fumarate. Clinical observations
efavirenz), have revealed a correlation between tenofovir disoproxil fuma-
• Eviplera (emtricitabine/tenofovir disoproxil fumarate/ rate use and a reduction in bone mineral density, especially in
rilpivirine), young children and adolescents. This risk should be considered
• Triumeq (abacavir/lamivudine/dolutegravir), with patients who have risk factors for osteoporosis.
• Stribild (emtricitabine/tenofovir disoproxil fumarate/ Tenofovir alafenamide is a novel targeted prodrug of tenofovir.
elvitegravir/cobicistat), It enters the cells, including HIV-infected cells, more eficiently
• Descovy (F/TAF; emtricitabine/tenofovir alafenamide), and produces higher intracellular levels with lower doses. There
• Odefsey (R/F/TAF; rilpivirine/emtricitabine/tenofovir are lower concentrations in the bloodstream and less exposure for
alafenamide), the kidneys, bone and other organs and tissues. While the long-
• Genvoya (E/C/F/TAF; elvitegravir/cobicistat/emtricitabine/ term clinical effects will be known by post-marketing surveil-
tenofovir alafenamide), lance, there is currently a strong suggestion that it is safer for the
• Rezolsta (darunavir/cobicistat), kidneys and bone than is tenofovir disoproxil fumarate.
• Evotaz (atazanavir/cobicistat), The older NRTIs like didanosine, stavudine and zidovudine
• Dutrebis (raltegravir/lamivudine). caused mitochondrial toxicity which may manifest as peripheral
A combination not currently licensed in the UK is: neuropathy, myopathy, lipoatrophy (fat loss particularly from the
D/C/F/TAF: darunavir/cobicistat/emtricitabine/tenofovir alafen- face, upper limbs and buttocks), hepatic steatosis, pancreatitis
amide and lactic acidosis (McComsey and Lonergan, 2004). This is less
As HIV drug patents expire many of these drugs are now common with the NRTIs which are now routinely prescribed (e.g.
available as cheaper generics with potential savings for drug lamivudine, emtricitabine and tenofovir disoproxil fumarate).
budgets. Non-nucleoside reverse transcriptase inhibitors. NNRTIs
cause rash, which frequently resolves early in therapy. In rare
cases, Stevens–Johnson syndrome and toxic epidermal necrolysis
Toxicity of antiretroviral therapies
have occurred. For patients who are taking nevirapine, the risk of
The availability and use of the different groups of antiretroviral rash is highest with a higher CD4 count; therefore, it should not
drugs have led to decreased morbidity and mortality from HIV be initiated if the CD4 count is greater than 250 cells/mm3 for
infection due to immune reconstitution and HIV viral suppres- women and greater than 400 cells/mm3 for men. There is also the
sion. However, there is also recognition of side effects and tox- small risk of serious hepatic toxicity. These factors make nevirap-
icities associated with ART. Patients who experience signiicant ine a less favourable choice as irst-line therapy.
side effects may become non-adherent or refuse to take ART. A Efavirenz is associated with central nervous system (CNS) tox-
proactive approach to discussion with patients on how to recog- icity including insomnia and mood problems. Caution is advised
nise and manage side effects will support successful treatment when considering initiating efavirenz in patients who have pre-
(Max and Sherer, 2000). With all people living longer, managing existing depression or other mood problems. Patients with the
ageing people living with HIV who have comorbidities requires homozygous G516T genotype of the enzyme CYP2B6 may metab-
healthcare staff to be mindful of the toxicities of ART and the olise it more slowly and have greater efavirenz exposure leading
impact of this on an ageing patient. Bone mineral density loss, to higher rates of neuropsychiatric adverse reactions. The G516T
kidney dysfunction, cardiovascular disease and neurocognitive genotype is more common in African individuals. Exposure to efa-
disorders are more frequent in older patients, and these must be virenz is also signiicantly higher in women than in men and in non-
considered when choosing an HIV drug regimen. Caucasian patients (Burger et al., 2006). This increased exposure is 705
 42 THERAPEUTICS

independent of body composition, use of hormonal contraceptives eficacy, potential side effects and toxicities, patient preference
that may inhibit the metabolism of efavirenz and genetic polymor- and cost should be considered. Choosing the appropriate drug
phism, and further research is needed to identify other factors. combination, monitoring patient parameters and switching to
Protease inhibitors. All PIs are associated with metabolic drugs that have a more favourable proile based on patient factors
abnormalities including dyslipidaemias, insulin resistance, diabe- will ensure safety and success of treatment. Therefore, based on
tes, lipodystrophy (abnormal fat distribution particularly affect- current evidence:
ing the abdomen and neck) and are well reported in HIV studies • Abacavir or abacavir-containing combinations (e.g. Kivexa)
(Smith et al., 2010). These abnormalities may result in risk of should be used with caution in patients whose baseline HIV
coronary and/or cerebral vascular morbidity and mortality which viral load is greater than 100,000 copies/mL (except when
is increased because people living with HIV have chronic inlam- used in combination with dolutegravir) because of the risk of
mation as a result of long-term exposure to the virus. virological failure. Abacavir-containing regimens should not
be used in patients with high risk of CVD (≥20%) and if they
are HLA*B5701-positive.
Cardiovascular risk associations of antiretroviral agents
• Rilpivirine should not be used in patients whose baseline HIV
Observational studies have reported an increased risk of myo- viral load is greater than 100,000 copies/mL because of the
cardial infarct with abacavir (Worm et al., 2010). A US Food risk of virological failure.
and Drug Administration (FDA) meta-analysis of 26 randomised • Tenofovir disoproxil fumarate should not be used in patients
controlled trials, however, showed no association between aba- with stage 3–5 chronic kidney disease (CKD) or they have a
cavir and myocardial infarct (Ding et al., 2012). In spite of this high risk of progression to CKD. It should also be avoided in
conlicting evidence and uncertainty, in clinical practice abaca- individuals older than 40 years with osteoporosis, a history of
vir tends to be avoided in patients with high cardiovascular risk fragility fracture or a FRAX score greater than 20% (major
(≥20% risk over 10 years). osteoporotic fracture).
Cumulative exposure to the older PIs, Kaletra and indina- • There is a theoretical advantage of using emtricitabine
vir, has also been associated with increasing risk of myocardial rather than lamivudine because of its longer half-life and
infarct. A similar association exists for fosamprenavir (Worm in vitro potency. It is also incorporated more eficiently into
et al., 2010). No association has been reported between the use of proviral DNA.
atazanavir/ritonavir and the risk of myocardial infarct, and there • Zidovudine/lamivudine is considered for use only in speciic
was insuficient evidence to include darunavir/ritonavir in the circumstances (e.g. short-term use in pregnancy) because of
analysis (Monforte et al., 2013). its association with mitochondrial toxicity.
Maraviroc can cause postural hypotension. Therefore, care Third agent choice. As similar critical treatment outcomes
should be taken in patients with a history of postural hypoten- are obtained, atazanavir/ritonavir, darunavir/ritonavir, raltegravir,
sion, renal impairment or those taking antihypertensives. In view dolutegravir, rilpivirine and elvitegravir/cobicistat are all recom-
of limited data, maraviroc should be used with caution in patients mended in current guidelines. Rilpivirine is recommended only
with high cardiovascular risk. in patients whose baseline HIV viral load is less than 100,000
Identifying and managing cardiovascular risk is an essen- copies/mL. In patients who tend to be non-adherent to their HIV
tial part of HIV care. National Institute for Health and Care medicines and have treatment interruptions, a PI/ritonavir-based
Excellence (NICE) recommends the QRISK2 calculator for the regimen is recommended because it may be associated with less
English population (NICE, 2014). There is no HIV-speciic car- frequent selection for drug resistance (BHIVA, 2015).
diovascular risk calculator for those of non-white ethnicity. The availability and use of effective ARV combinations has
One approach suggested is to use the QRISK2 equation with resulted in a decline in the incidence of severe HIV-associated
a correction for HIV status of 1.6 (Islam et al., 2012). As in the cerebral disease. However, subtle forms of brain disorders, known
general population, encouraging patients to adopt modiiable life- as HIV-associated neurocognitive disorders, remain prevalent.
styles including smoking cessation, healthy diets and exercise will Attempts have been made to correlate the pharmacokinetics of
reduce the risk. Baseline cardiovascular risk assessment is recom- ARVs with respect to CNS penetration (clinical effectiveness pen-
mended by BHIVA, and an annual cardiovascular risk assessment etration scores) and CSF HIV-RNA with change in neurocognitive
is recommended if the patient is a smoker, is diabetic and or has function. However, results have been conlicting. Table 42.2 shows
a body mass index greater than 30 and age greater than 40 years. the clinical effectiveness scores that have been assigned to the
People who are living with HIV are at higher risk of non-alco- various HIV drugs. Based on limited evidence, switching to ARV
holic fatty liver disease. Factors associated with this include older combinations that have higher clinical effectiveness penetration
age, overweight and waist circumference, lipodystrophy, insulin scores may be considered in clinical practice in patients who have
resistance, previous use of the older NRTIs (e.g. ddI, d4T, AZT) neurocognitive disorders (Letendre et al., 2010).
or PI use (e.g. indinavir and ritonavir) (Capeau et al., 2012). Local guidance may recommend the rationale for choosing
third agents which would include patient acceptability to a par-
ticular regimen. Interventions to address adherence and potential
Specific HIV drug choice
barriers should be embedded in the roles of all members of the
HIV treatment usually involves a three-drug regimen that con- HIV multidisciplinary team. This should include being mindful
tains either an NNRTI or a PI plus a ‘backbone’ consisting of of patient’s beliefs that may affect adherence, patient preferences
706 two NRTIs. When selecting an NRTI backbone, factors such as with regard to practical barriers (e.g. pill burden and tablet size) and
 HIV INFECTION 42
Table 42.2 Central nervous system penetration effectiveness of human immunodeficiency virus drugs

CNS penetration effectiveness scoresa

HIV drug group 4 3 2 1

NRTIs Zidovudine Abacavir, emtricitabine Lamivudine Tenofovir

NNRTIs Nevirapine Efavirenz Etravirine

PIs Darunavir/ritonavir Atazanavir/ritonavir Saquinavir/ritonavir

Fosamprenavir/ritonavir
Lopinavir/ritonavir

Entry inhibitors Maraviroc Enfuvirtide

Integrase inhibitors Raltegravir

aA score of 4 is the highest and 1 is the lowest.
CNS, Central nervous system; HIV, human immunodeficiency virus; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleotide analogue reverse
transcriptase inhibitors; PI, protease inhibitor.
Adapted from Letendre et al., (2010).

the requirement to take some medicines with food which can be

Table 42.3 HIV drugs that are major CYP450 enzyme inducers,
restrictive to those with busy lifestyles. Accommodating medicine
inhibitors and substrates
taking into account a patient’s individual lifestyle and use of appro-
priate adherence aids should be considered. This would include the CYP enzyme
use of multi-compartment compliance aids (e.g. Dossette boxes).
Peer support, use of buddies and outreach services into the commu- Type of
action 1A2 2C19 2D6 3A4
nity can also augment strategies to support adherence.
Inducers Ritonavir Ritonavir Nevirapine
HIV drug–drug interactions Efavirenz Efavirenz
Etravirine
Absorption Ritonavir

The absorption of some HIV drugs may be altered by the presence Inhibitors Atazanavir Etravirine Ritonavir Protease
or absence of food. For example, rilpivirine needs 390 kcal for opti- Cobicistat inhibitors
mal absorption. Increase in pH by antacids (aluminium, magnesium Cobicistat
hydroxide, calcium carbonate), H2 antagonists or proton pump inhibi-
tors can reduce some HIV drug levels (e.g. atazanavir and rilpivirine). Substrates Etravirine Nevirapine
Chelation caused by polyvalent ions like calcium, magnesium or iron Efavirenz
can reduce levels of some HIV drugs (e.g. dolutegravir and elvitegra- Elvitegravir
vir). It is therefore important that patients who are prescribed these Etravirine
medicines understand how to manage these drug–drug interactions, Rilpivirine
for example, timing separation when taking multivitamins containing Maraviroc
iron and magnesium (4 hours apart from dolutegravir) or completely Protease
avoiding proton pump inhibitors like omeprazole with rilpivirine. inhibitors
Cobicistat

Metabolism
Some HIV drugs, especially NNRTIs and PIs, are metabolised by it to act as a pharmacokinetic booster. Drugs that inhibit CYP450
the cytochrome P450 enzyme system. The enzyme responsible for enzymes decrease the metabolism of other drugs metabolised by the
the majority of drug metabolism is CYP3A4, although CYP2C19 same enzyme. This can result in higher drug levels and an increase
and CYP2D6 are also common. Table 42.3 shows the HIV drugs in the potential for drug toxicities. Inhibition usually occurs quickly.
that are major CYP450 enzyme inducers, inhibitor and substrates. Induction of CYP450 enzymes causes increased clearance
Drugs may interact with the CYP450 enzymes through induction, of drugs metabolised by the same enzyme, with the maximum
inhibition or acting as a substrate. Some drugs act as inducers and effect taking 1–2 weeks. Some drugs, like nevirapine, induce
inhibitors of different CYP450 enzymes. CYP450 enzymes are in their own metabolism, and the starting dose (200 mg once a day
the liver and in the small intestine. Ritonavir inhibits CYP3A4 in for 2 weeks) is increased after this period (400 mg once a day).
the liver and the intestine. This is one of the mechanisms that allows The herbal remedy St. John’s wort is a strong inducer of CYP3A 707
 42 THERAPEUTICS

and will reduce levels of NNRTIs, PIs and cobicistat. Therefore, tubule cells, and this plays a role in the aetiology of nephrotoxic-
co-administration is not recommended. ity. Tenofovir alafenamide is not a substrate for organic anionic
The most important antiretroviral drugs to consider when transporters and is likely to be associated with reduced tenofovir
evaluating drug–drug interactions are the pharmacoenhancers levels in the proximal renal tubule cells.
ritonavir and cobicistat. These agents can increase levels of many The NRTIs in general tend to be renally cleared and require
commonly used medicines including some statins, antidepres- dose modiication in renal impairment.
sants, anticonvulsants, corticosteroids and cardiac drugs. One
signiicant drug–drug interaction is between PIs and steroids
Hepatitis B co-infection
metabolised by CYP3A enzymes (e.g. budesonide, luticasone,
methylprednisolone and triamcinolone). This interaction can Hepatitis B virus (HBV) co-infection is less likely to be cleared
result in adrenal insuficiency and iatrogenic Cushing’s syndrome spontaneously and more likely to become chronic in the HIV-
(Saberi et al., 2013). Despite well-documented case reports, positive population. It is likely to be associated with higher hepa-
patients continue to inadvertently receive these combinations. titis B DNA levels and faster ibrosis progression rate, end-stage
Therefore, HIV healthcare staff should obtain a complete medi- liver disease and hepatocellular carcinoma (Wilkins et al., 2013).
cation history for any patient exhibiting signs and symptoms of People who are co-infected with HBV should be treated with
Cushing’s syndrome. Inhaled corticosteroids are used extensively tenofovir-, disoproxil-, fumarate-, and emtricitabine- or lamivu-
in asthma and allergic rhinitis, and injectable corticosteroids in dine-based cART, because these are effective against both HBV
rheumatology and surgical patients. and HIV.
Conducting a thorough medication history at each visit, includ- Response to hepatitis B vaccination is less with the standard
ing asking direct questions about prescribed medicines in other dose; therefore, a higher dose (HBVAXPRO and Engerix B
healthcare settings (e.g. by primary care doctors, other special- dose 40 micrograms, Fendrix 20 micrograms) is recommended
ist hospital departments) and use of over-the-counter, herbal and (Geretti et al., 2015).
recreational drugs is an important strategy in preventing signii-
cant drug–drug interactions which may result in virological fail-
Hepatitis C co-infection
ure or drug toxicity. Patients need to be counselled to explain that
they are taking HIV medicines when in other healthcare settings Hepatitis C virus (HCV) co-infection is cleared spontaneously
to minimise this risk. Patient should also be advised to check in an estimated 10–25% of people, and chronic infection of
drug–drug interactions before commencing new medicines. HCV will develop in the majority. Patients with HCV/HIV co-
Mycobacterium treatment results in complex drug–drug infection have higher hepatitis C RNA levels and an accelerated
interactions. Rifampicin is a potent CYP3A4 inducer, although liver ibrosis progression rate. It increases the risk of hepato-
rifabutin has less effect. Therefore, rifabutin is the drug of cellular carcinoma, which tends to occur at a younger age and
choice in patients who require treatment for M. tuberculosis within a shorter period since infection. A global epidemic of
or Mycobacterium avium complex, to avoid signiicant reduc- acute hepatitis in HIV-infected MSM has been observed in the
tion in HIV drug levels of, for example, nevirapine and the PIs. past decade. Transmission appears to be associated with high-
Rifampicin is also a strong inducer of the metabolising enzyme risk traumatic sexual practices, presence of sexually transmitted
of the glucuronidation pathway UGT-1A1. Raltegravir is metab- infections and recreational drug use.
olised by UGT-1A1-mediated glucuronidation. Rifampicin will Early ART initiation is recommended to slow the ibrosis pro-
therefore reduce raltegravir levels, and co-administration is not gression rate. The ART regimen should be selected to suit the
recommended. planned hepatitis C treatment. Eficacy, side-effect proile and
Tenofovir alafenamide (TAF) is a substrate for intestinal the duration of treatment have signiicantly improved since the
P-glycoprotein. Ritonavir and cobicistat both inhibit intestinal introduction of HCV direct-acting antiviral agents, with sus-
P-glycoprotein, thereby increasing tenofovir alafenamide expo- tained virological response rates of more than 90%. The choice
sure. For this reason a lower dose of tenofovir alafenamide (10 of regimen and duration of HCV treatment are based on HCV
mg) is recommended when used with ritonavir- or cobicistat- genotype, HCV RNA, liver ibrosis stage, prior treatment history
boosted PIs. The standard dose of tenofovir alafenamide (25 mg) and drug–drug interaction (NICE, 2015).
is recommended when administered with efavirenz, nevirapine,
raltegravir, dolutegravir and maraviroc.

Excretion Opportunistic infections

Rilpivirine, dolutegravir and cobicistat inhibit renal transporters Treatment guidelines are produced by many different countries
of creatinine, causing mild-to-moderate increase in serum creati- and may differ slightly; one example of UK guidelines are those
nine and reduction in estimated creatinine clearance. Healthcare produced by the BHIVA. Examples of guidelines available from
staff must correctly interpret these changes on initiating these BHIVA are for the management of opportunistic infections (Nelson
drugs and differentiate this from clinically signiicant renal et al., 2011), HIV-associated malignancies (Bower et al., 2014),
toxicities. hepatitis viruses (Wilkins et al., 2013) and TB (Pozniak et al.,
Tenofovir disoproxil fumarate undergoes active renal tubular 2011). Such guidance should be consulted for further detailed
708 secretion via organic anionic transporters in the renal proximal information on the management of people living with HIV.
 HIV INFECTION 42
Fungal infections as erythematous patches or as angular cheilitis. If swallowing
is dificult (dysphagia) or painful (odynophagia), oesophageal
Pneumocystis jirovecii pneumonia
involvement may be suspected. Oesophageal candidiasis with-
P. jirovecii is an atypical fungus causing pneumonia in immuno- out oral plaques is not common; therefore, any patient present-
compromised individuals. It remains a major pathogen in those ing with oesophageal symptoms without oral candidiasis should
unaware of their HIV status, in people not seeking medical care be considered for alternative diagnoses (Nelson et al., 2011).
for HIV and in those non-adherent to antiretroviral medication Diagnoses of oral and oesophageal candidiasis are made clini-
and/or prevention therapy (Miller and Huang, 2004; Morris and cally because microbiological conirmation is likely to give a
Gingo, 2015). It is thought to mainly cause clinical disease by positive result in the absence of clinical disease. Cultures should
exposure to an exogenous source, with likely transmission being be requested only in patients who are not responding to standard
via inhalation of airborne spores. In people living with HIV, PCP treatment (Nelson et al., 2011).
most commonly occurs in those with a CD4 T-cell count less than Treatment regimens are described in Table 42.5. Systemic
200 cells/microlitre (or CD4 T-cell percentage <14%) (Nelson azole antifungals are irst-line therapy for oral and oesophageal
et al., 2011). Presentation is typically a gradual progression over candidiasis with higher doses and longer treatment courses gen-
several weeks, with principal symptoms being fatigue, fever, erally used in oesophageal candidiasis. Topical treatment with
chills, sweats, non-productive cough and dyspnoea. Physical nystatin is effective for oropharyngeal candidiasis; however, it
examination indings are non-speciic and include fever, tachy- is associated with a slower clearance of yeast from the mouth
pnoea and tachycardia. Signs of pulmonary consolidation or and a higher relapse rate. First-line azole therapy is luconazole
changes in pulmonary signs are uncommon (Morris and Gingo, with other azoles or antifungal classes being reserved in cases
2015; Nelson et al., 2011). of drug resistance. Routine prophylaxis is not recommended
Presence of oxygen desaturation supports the diagnosis of PCP and is associated with the emergence of resistance (Nelson
along with a typical chest radiographic appearance of bilateral et al., 2011).
interstitial shadowing; however, radiological imaging is not spe-
ciic for PCP and can, in some cases, appear normal. Therefore,
Cryptococcus neoformans
for a deinitive diagnosis of PCP, this requires either an induced
sputum for visualisation of the fungi (if routinely available) or Cryptococcus is an encapsulated yeast present in the environment.
bronchoscopic examination with bronchoalveolar lavage (BAL) People become exposed to the yeast after inhalation of fungal
(Morris and Gingo, 2015). spores, although this rarely causes infection in immunocompe-
Treatment is instigated in patients with a proven diagnosis, or tent individuals (Centers for Disease Control and Prevention,
empirically where there is suspicion before conirmation (Table 2015). In patients with a compromised immune system, the yeast
42.4). Oxygen is essential for patients with compromised respi- can localise to the lungs and cause infection. This can rapidly dis-
ratory function. First-line therapy is high-dose trimethoprim- seminate to the blood and develop into cryptococcal meningitis
sulfamethoxazole (co-trimoxazole) for 21 days. In cases of (Nelson et al., 2011).
co-trimoxazole intolerance, several alternative treatment choices Symptoms are dependent on site of infection. Meningitis is the
are available. most common presentation in people who are living with HIV.
Adjunctive corticosteroids should be given where PaO2 <9.3 Symptoms include fever and headache, often without the char-
kPa or SpO2 <92% to prevent further deterioration. Oral pred- acteristic symptoms of meningism such as photophobia and neck
nisolone is given at high doses for 21 days. Alternatively, intra- stiffness. Raised intracranial pressure may be associated with
venous methylprednisolone can be substituted if the patient is nausea, vomiting, confusion and coma. Other symptoms may be
unable to take oral medication. respiratory secondary to pulmonary disease or dermatological
PCP can be prevented in people living with HIV by initiating lesions resembling molluscum in skin disease.
ART, with the aim of restoring and preserving immunological The principal test is serum cryptococcal antigen which, if neg-
function (Morris and Gingo, 2015). In patients with a CD4 T-cell ative, generally excludes disseminated disease. In the presence
count less than 200 cells/microlitre, CD4 T-cell percentage less of a positive result, all patients should have a lumbar puncture
than 14%, oral candidiasis or previous AIDS-deining illness, PCP for CSF culture after cerebral imaging with computed tomog-
prophylaxis should be started. First-line therapy is co-trimoxazole, raphy (CT) or magnetic resonance imaging (MRI). Manometry
which also provides prevention against toxoplasmosis; however, via lumbar puncture should be performed to exclude raised intra-
other regimens are available if this is contraindicated or not toler- cranial pressure. Blood cultures should also be performed and if
ated (see Table 42.4). Prophylaxis can be discontinued when CD4 positive for Cryptococcus, sensitivity testing may be performed
T-cell count is sustained at greater than 200 cells/microlitre and if available (Nelson et al., 2011).
suppression of HIV replication for more than 3 months on ART. Treatment consists of an induction phase and a maintenance
phase (Table 42.6). First-line treatment in the induction phase is
intravenous liposomal formulation of amphotericin 4 mg/kg/day
Oropharyngeal/oesophageal candidiasis
(once daily dosing) plus intravenous lucytosine 100 mg/kg/day
Candida species are common commensals in the general pop- (four times daily dosing). This is continued for at least 2 weeks
ulation, and candidiasis is a frequent manifestation of HIV or until CSF culture is negative for Cryptococcus. Liposomal
infection, which may occur in early disease. It is usually char- amphotericin is the preferred formulation to reduce drug toxicity
acterised by white plaques on the oral mucosa, but may present (Nelson et al., 2011). 709
710

42
Table 42.4 Treatment and prophylaxis of Pneumocystis jirovecii pneumonia

Dosage: route, frequency,

Drug duration Common or significant side effects Significant interactions Monitoring Comments

Atovaquone Treatment (mild to moderate): Anaemia, neutropenia, hyponatraemia, Drugs known to reduce LFTs, renal function, Absorption improved by

THERAPEUTICS
750 mg PO twice daily (with insomnia, headache, nausea, diarrhoea, atovaquone: rifampicin, FBC taking with food
food) for 21 days vomiting, elevated liver enzyme levels, hy- rifabutin, metoclopramide, (especially high-fat food);
persensitivity reactions including angioede- efavirenz, boosted protease reduced by diarrhoea
Prophylaxis (unlicensed indica-
ma, bronchospasm and throat tightness, inhibitors, tetracycline
tion): 750 mg PO twice daily
rash, pruritus, urticaria, fever Drugs known to be increased
(with food)
by atovaquone: zidovudine

Clindamycin Treatment (severe): 600 mg IV/ Clindamycin: abdominal pain, diarrhoea, Neuromuscular block- LFTs, renal function, Change in bowel habit
PO four times daily or 900 mg pseudomembranous colitis, abnormal LFTs, ing agents, erythromycin, FBC, diarrhoea should be investigated
IV/PO three times daily for 21 nausea, vomiting, rash, urticaria, blood dys- neostigmine, pyridostigmine, for Clostridium difficile
days (given with primaquine crasias, dysgeusia (IV), thrombophlebitis (IV) oestrogens (risk of interaction Check G6PD status
15–30 mg PO once daily) Primaquine: nausea, vomiting, methaemo- is small) before use of
globinaemia, haemolytic anaemia (espe- primaquine
cially in G6PD deficiency), bone marrow
suppression

Co-trimoxazole Treatment: Moderate to Hyperkalaemia, headache, nausea, diar- Ciclosporin (deterioration LFTs, renal function, Caution in G6PD
(trimethoprim- severe: 120 mg/kg/day IV/PO rhoea, skin rash (rare: blood dyscrasias, in renal function); rifampicin FBC, monitoring for deficiency
sulfamethoxa- for 3 days, then reduced to 90 drug fever, serious skin reactions, e.g. (can reduce plasma half-life rash
zole) mg/kg/day for 18 days in three Stevens–Johnson syndrome and toxic epi- of trimethoprim, although not
or four divided doses dermal necrolysis) thought to be significant); di-
Mild to moderate: 1920 mg uretics, in particular thiazide
three times a day or 90 mg/kg/ (increased risk of thrombocy-
day in 3 divided doses for 21 topenia); pyrimethamine (risk
days of megaloblastic anaemia);
Prophylaxis: 480 mg (preferred) warfarin (potentiates antico-
or 960 mg once daily or 960 mg agulant activity); phenytoin
three times a week (prolongs phenytoin half-life);
methotrexate (increases
plasma levels of methotrex-
ate); lamivudine (increases
plasma levels of lamivudine
in doses >960 mg); sulpho-
nylureas (could potentiate
hypoglycaemic effect)
 Dapsone Treatment (mild to moderate): Rash, photosensitivity, pruritus, haemolysis Probenecid, rifampicin LFTs, FBC Check G6PD status
100 mg PO once daily (given and methaemoglobinaemia are rare in before use
with trimethoprim 20 mg/kg/day dosages >100 mg daily or in individuals not
PO for 21 days G6PD deficient, ‘dapsone syndrome’ may
Prophylaxis: 50–200 mg PO occur 3–6 weeks after therapy, anorexia,
once daily (100 mg preferred) headache, hepatitis, jaundice, abnormal
LFTs, insomnia, nausea, psychosis, tachycar-
dia and vomiting are infrequent

Pentamidine Treatment: 4 mg/kg IV once IV: leucopenia, thrombocytopenia, anaemia, Foscarnet, drugs that prolong Renal function, Nebulised: pretreat with
daily for 21 days azotaemia, hypoglycaemia, hyperglycae- QT interval blood glucose, a bronchodilator and use
Prophylaxis: 300 mg nebulised mia, hypocalcaemia, hypomagnesaemia, blood pressure, LFTs, an appropriate nebuliser
every 4 weeks dizziness, hypotension, flushing, nausea, FBC, blood urea
vomiting, taste disturbance, abnormal nitrogen, calcium
LFTs, rash, renal impairment, macroscopic and magnesium,
haematuria; rare: pancreatitis, QT interval ECG for QT interval
prolongation prolongation
Nebulised: local respiratory reactions (in-
cluding bronchospasm), taste disturbance,
nausea

ECG, Electrocardiogram; FBC, full blood count; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; LFT, liver function test; PO, oral.

HIV INFECTION
42
711
712

42
Table 42.5 Treatment of oropharyngeal/oesophageal candidiasis

Dosage: route, frequency, Significant

Drug duration Common or significant side effects interactions Monitoring Comments

Azole antifungals

THERAPEUTICS
Fluconazole 50–100 mg PO once daily Headache, abdominal pain, vomiting, diarrhoea, Inducers and LFTs Duration of treatment will be less for
for 7–14 days nausea, elevated LFTs, rash inhibitors of oropharyngeal candidiasis
CYP3A4 Use with caution with medicines known
to prolong QTc interval because some
azole antifungals have been associated
with prolongation of the QTc interval

Itraconazole 200 mg PO once daily for Headache, dyspnoea, abdominal pain, vomiting, Inducers and LFTs, FBC, renal Oral solution has higher bioavailability
7–14 days (or twice daily nausea, diarrhoea, dysgeusia, elevated LFTs, rash, inhibitors of function than capsule formulation
in fluconazole refractory pyrexia CYP3A4
candidiasis)

Voriconazole Loading dose: Sinusitis, deranged FBC, peripheral oedema, Inducers, inhibitors LFTS, FBC, Only for use in fluconazole resistance,
IV: 6 mg/kg twice daily hypoglycaemia, hypokalaemia, hyponatraemia, and substrates of renal where fluconazole has been shown to be
psychiatric disorders, headache, convulsion, CYP3A4, CY- function ineffective or the patient is intolerant to
PO: 400 mg twice daily (if
syncope, tremor, hypertonia, paraesthesia, P2C19, CYP2C9 fluconazole
>40 kg) for 1 day
somnolence, dizziness, visual impairment, retinal Use with caution with medicines known
Maintenance dosage: haemorrhage, cardiac arrhythmias, hypotension, to prolong QTc interval because some
IV: 4 mg/kg twice daily respiratory distress, diarrhoea, vomiting, azole antifungals have been associated
PO: 200 mg twice daily (if abdominal pain, nausea, deranged LFTs, rash, alope- with prolongation of the QTc interval
>40 kg) for 7–14 days in cia, back pain, renal dysfunction, pyrexia
total

Posaconazole Loading dose: 300 mg twice Neutropenia, anorexia, decreased appetite, Substrates of LFTs, FBC, renal Only for use in fluconazole resistance,
daily PO for 1 day hypokalaemia, hypomagnesaemia, paraesthesia, CYP3A4, function where fluconazole has been shown to be
Maintenance dosage: 300 dizziness, somnolence, headache, dysgeusia, rifabutin, efavi- ineffective or the patient is intolerant to
mg once daily for 7–14 days hypertension, nausea, vomiting, abdominal renz, fosampre- fluconazole
in total pain, diarrhoea, dyspepsia, dry mouth, flatulence, navir, phenytoin, Use with caution with medicines known
constipation, anorectal discomfort, deranged LFTs, digoxin, to prolong QTc interval because some
rash, pruritus, pyrexia sulfonylureas azole antifungals have been associated
with prolongation of the QTc interval

Echinocandins

Anidulafungin Loading dose: 200 mg once Hypokalaemia, hyperglycaemia, convulsions, head- Nil LFTs, renal Only for use in fluconazole resistance,
daily IV for 1 day ache, hypo/hypertension, bronchospasm, dyspnoea, function, blood where fluconazole has been shown to be
Maintenance dose: 100 mg diarrhoea, nausea, vomiting, abnormal liver function, sugar ineffective or the patient is intolerant to
once daily IV for 7–14 days rash, pruritus, increased creatinine fluconazole
in total
 Caspofungin Loading dose: 70 mg once Local injection-site reactions including phlebitis, Ciclosporin, tacro- LFTs, renal func- Only for use in fluconazole resistance,
daily IV for 1 day reduced haemoglobin, reduced white cell count, limus, rifampicin tion, FBC where fluconazole has been shown to be
Maintenance dosage: hypokalaemia, headache, dyspnoea, nausea, ineffective or the patient is intolerant to
diarrhoea, vomiting, elevated LFTs, rash, pruritus, fluconazole
>80 kg: 70 mg once daily IV
erythema, hyperhidrosis,
<80 kg: 50 mg once daily IV arthralgia, pyrexia, chills
for 7–14 days in total

Micafungin 150 mg once daily IV (if >40 Leukopenia, neutropenia, anaemia, hypokalaemia, Itraconazole, siro- FBC, renal func- Only for use in fluconazole resistance,
kg) for 7–14 days hypomagnesaemia, hypocalcaemia, headache, limus, nifedipine, tion, magne- where fluconazole has been shown to be
phlebitis, nausea, vomiting, diarrhoea, abdominal amphotericin sium, calcium, ineffective or the patient is intolerant to
pain, elevated LFTs, rash, pyrexia, rigors LFTs fluconazole

Others

Liposomal 1–3 mg/kg once daily IV for Hypokalaemia, hyponatraemia, hypocalcaemia, Nephrotoxic Renal function, Only for use in fluconazole resistance,
amphotericin 7–14 days hypomagnesaemia, hyperglycaemia, headache, medication, drugs magnesium, where fluconazole has been shown to be
tachycardia, hypotension, vasodilation, flushing, that may potenti- LFTs, FBC ineffective or the patient is intolerant to
dyspnoea, nausea, vomiting, abnormal LFTs, rash, ate hypokalaemia, fluconazole
back pain, renal impairment, rigors, antineoplastic
pyrexia, chest pain agents

FBC, Full blood count; IV, intravenous; LFT, liver function test; PO, oral.

HIV INFECTION
42
713
 42 THERAPEUTICS

Table 42.6 Treatment and maintenance of Cryptococcal neoformans meningitis

Dosage: route, Common or significant side Significant

Drug frequency, duration effects interactions Monitoring Comments

Treatment

Liposomal Liposomal ampho- Amphotericin: hypokalaemia, Amphotericin: Renal function, Amphotericin: a

amphotericin tericin: 4 mg/kg IV hyponatraemia, hypocalcaemia, nephrotoxic medica- magnesium, test dose of 1 mg
+ flucytosine once daily hypomagnesaemia, hypergly- tion, drugs that may LFTs, FBC is required before
Flucytosine: 100 mg/ caemia, headache, tachycardia, potentiate hypoka- Therapeutic drug the first dose and if
kg/day PO/IV in 4 hypotension, vasodilation, flush- laemia, antineoplastic monitoring may no hypersensitivity
divided doses for at ing, dyspnoea, nausea, vomiting, agents be considered reaction after
least 2 weeks (until abnormal LFTs, rash, back pain, Flucytosine: cyta- with flucytosine 30 min, the remain-
negative CSF culture) renal impairment, rigors, pyrexia, rabine, brivudine, der of the dose can
chest pain sorivudine and ana- be given
Flucytosine: nausea, vomiting, logues, phenytoin Pre-hydration with
diarrhoea, rash, haematologi- 0.9% sodium chlo-
cal changes are more common ride may decrease
when co-administered with nephrotoxicity
amphotericin

Fluconazole + Fluconazole: 400 mg Fluconazole: headache, abdomi- Fluconazole: induc- Fluconazole: LFTs Considered as
flucytosine PO/IV once daily (or nal pain, vomiting, diarrhoea, ers and inhibitors of Flucytosine: renal an alternative to
twice daily in severe, nausea, elevated LFTs, rash CYP3A4 function, magne- amphotericin and
life-threatening infec- Flucytosine: nausea, vomiting, Flucytosine: cyta- sium, LFTs, FBC flucytosine if this
tions) diarrhoea, rash, haematologi- rabine, brivudine, fails or is not toler-
Therapeutic drug
Flucytosine: 100–150 cal changes are more common sorivudine and ana- ated
monitoring may
mg/kg/day PO/IV in when co-administered with logues, phenytoin be considered
4 divided doses for amphotericin with flucytosine
at least 2 weeks (until
negative CSF culture)

Voriconazole Loading dose: Sinusitis, deranged FBC, pe- Inducers, inhibitors LFTS, FBC, renal Only considered
IV: 6 mg/kg twice ripheral oedema, hypoglycae- and substrates function as an alternative
daily mia, hypokalaemia, hypona- of CYP3A4, to amphotericin
traemia, psychiatric disorders, CYP2C19, CYP2C9 and flucytosine if
PO: 400 mg twice
headache, convulsion, syncope, this fails or is not
daily (if >40 kg) for
tremor, hypertonia, paraes- tolerated
1 day
thesia, somnolence, dizziness,
Maintenance dose: visual impairment, retinal
IV: 4 mg/kg twice haemorrhage, cardiac arrhyth-
daily mias, hypotension, respiratory
PO: 200 mg twice distress, diarrhoea, vomit-
daily (if >40 kg) for at ing, abdominal pain, nausea,
least 2 weeks (until deranged LFTs, rash, alopecia,
negative CSF culture) back pain, renal dysfunction,
pyrexia

Posaconazole Loading dose: 300 Neutropenia, electrolyte imbal- Substrates of CY- LFTs, FBC, renal Only considered
mg twice daily PO for ance, anorexia, decreased ap- P3A4, rifabutin, efavi- function as an alternative
1 day petite, hypokalaemia, renz, fosamprenavir, to amphotericin
Maintenance dose: hypomagnesaemia, paraes- phenytoin, digoxin, and flucytosine if
300 mg once daily for thesia, dizziness, somnolence, sulphonylureas this fails or is not
at least 2 weeks (until headache, dysgeusia, hyperten- tolerated
negative CSF culture) sion, nausea, vomiting, abdomi-
nal pain, diarrhoea, dyspepsia,
dry mouth, flatulence, constipa-
tion, anorectal discomfort, raised
LFTs, rash, pruritus, pyrexia,
asthenia, fatigue

714
 HIV INFECTION 42
Table 42.6 Treatment and maintenance of Cryptococcal neoformans meningitis—cont’d

Dosage: route, Common or significant side Significant

Drug frequency, duration effects interactions Monitoring Comments

Maintenance

Fluconazole 400mg PO once daily Headache, abdominal pain, Inducers and inhibi- LFTs In some cases it
for 8–10 weeks, then vomiting, diarrhoea, nausea, tors of CYP3A4 may be considered
reduced to 200 mg elevated LFTs, rash to continue 400 mg
PO once daily and once daily regimen
continued until CD4 for duration of
T-cell count >100 maintenance phase
cells/microlitre and
an undetectable HIV
viral load for at least
3 months

Liposomal 4mg/kg IV ONCE Hypokalaemia, hyponatraemia, Nephrotoxic medica- Renal function, Fluconazole is
amphotericin weekly continued hypocalcaemia, hypomagnesae- tion, drugs that may magnesium, considered first
until CD4 T-cell count mia, hyperglycaemia, headache, potentiate hypoka- LFTs, FBC line for mainte-
>100 cells/microlitre tachycardia, hypotension, laemia, antineoplastic nance because
and an undetectable vasodilation, flushing, dyspnoea, agents has been shown
HIV viral load for at nausea, vomiting, abnormal to be superior to
least 3 months LFTs, rash, back pain, renal amphotericin with
impairment, rigors, pyrexia, less drug-related
chest pain toxicities and lower
relapse rates
Pre-hydration with
0.9% sodium chlo-
ride may decrease
nephrotoxicity

CSF, Cerebrospinal fluid; FBC, full blood count; IV, intravenous; LFT, liver function test; PO, oral.

First-line treatment in the maintenance phase is luconazole during periods of immunodeiciency. Cerebral abscesses develop
400 mg once daily for 8–10 weeks, then reduced to 200 mg once over a number of days to weeks, and the patient will commonly
daily. In some cases the decision to continue 400 mg once daily present with neurological symptoms and sometimes seizures. An
therapy may be considered and has been associated with a lower increase in intracranial pressure can cause headaches and vomit-
rate of relapse (Nelson et al., 2011). Maintenance therapy has ing (Nelson et al., 2011).
been shown to reduce the incidence of disease relapse and should Radiological imaging of the brain performed by MRI is a more
be continued until immune function has been restored second- sensitive test and, therefore, the preferred method over CT scan-
ary to HIV treatment and CD4 T-cell count is greater than 100 ning. However, if MRI is unavailable, then a CT scan should
cells/microlitre with an undetectable HIV viral load for at least be performed. Abscesses are typically multiple, ring-enhancing
3 months. lesions that may be associated with cerebral oedema and mass
effect. A positive serum toxoplasma IgG represents prior infec-
tion, which may be a useful additional diagnostic tool because
Protozoal infections
toxoplasmosis in people living with HIV is usually the result of
reactivation.
Toxoplasmosis
First-line treatment is sulfadiazine and pyrimethamine, with
Toxoplasma gondii is an obligate intracellular protozoan and calcium folinate to prevent pyrimethamine-induced myelosup-
the most common cause of space-occupying lesions or cerebral pression. Acute treatment is continued for 6 weeks followed by
abscesses in the brain in people who are living with HIV with a maintenance therapy with lower doses of the same agents until
CD4 T-cell count less than 200 cells/microlitre. Humans acquire CD4 T-cell count remains greater than 200 cells/microlitre for 6
infection by eating animals with disseminated infection or by months and suppression of HIV replication (Table 42.7). There is
ingestion of oocytes shed in cat faeces that have contaminated limited experience to guide therapy if irst- and second-line agents
soil, fruit, vegetables and water. Toxoplasmosis is then usually cannot be tolerated; however, possible alternatives can be found in
caused by reactivation of chronic infection acquired earlier in life BHIVA guidelines. Corticosteroids are not routinely used but may

715
716

42
Table 42.7 Treatment and maintenance of toxoplasmosis

Drug Dosage: route, frequency, duration Common or significant side effects Significant interactions Monitoring Comments

Treatment

THERAPEUTICS
Sulfadiazine + Sulfadiazine: 1.5 g PO four times Sulfadiazine: blood disorders, hypersensitiv- Sulfadiazine: thiopentone anaesthetics, LFTs, renal Ensure fluid intake of 2
pyrimethamine daily (≤60 kg) or 2 g PO four times ity reactions, hypoglycaemia, hypothyroid- warfarin, sulfphonylureas, clozapine, function, FBC L/day to reduce the risk
(+ calcium daily (>60 kg) ism, depression, psychosis, hallucinations, aspirin, ciclosporin, diuretics, metho- of crystalluria
folinate) Pyrimethamine: 200 mg PO load- neurological reactions, tinnitus, cough, trexate, oestrogen-containing oral Caution in G6PD defi-
ing dose followed by 50 mg PO dyspnoea, GI symptoms, hepatitis, jaundice, contraceptives, probenecid ciency
once daily (≤60 kg) or 75 mg PO purpura, rash, crystalluria Pyrimethamine: agents that depress Calcium folinate to
once daily (>60 kg) Pyrimethamine: anaemia, leucopenia, folate metabolism, agents that cause counteract myelosup-
Calcium folinate: 15 mg PO once thrombocytopenia, headache, giddiness, myelosuppression, antacids, highly pressive effects of
daily for 6 weeks vomiting, nausea, diarrhoea, rash, abnormal protein-bound drugs, methotrexate pyrimethamine
skin pigmentation, fever

Clindamycin Clindamycin: 600 mg PO/IV four Clindamycin: abdominal pain, diarrhoea, Clindamycin: neuromuscular blocking LFTs, renal Change in bowel habit
+ times daily Pseudomembranous colitis, abnormal LFTs, agents, erythromycin, neostigmine, function, should be investigated
pyrimethamine Pyrimethamine: 200 mg PO load- nausea, vomiting, rash, urticaria, blood dys- pyridostigmine, oestrogens (risk of FBC, diar- for Clostridium difficile
ing dose followed by 50 mg PO crasias, dysgeusia (IV), thrombophlebitis (IV) interaction is small) rhoea Caution in G6PD defi-
(+ calcium
once daily (≤60 kg) or 75 mg PO Pyrimethamine: anaemia, leucopenia, Pyrimethamine: agents that depress ciency
folinate)
once daily (>60 kg) thrombocytopenia, headache, giddiness, folate metabolism, agents that cause Calcium folinate to
Calcium folinate: 15 mg PO once vomiting, nausea, diarrhoea, rash, abnormal myelosuppression, antacids, highly counteract myelosup-
daily for 6 weeks skin pigmentation, fever protein-bound drugs, methotrexate pressive effects of
pyrimethamine

Maintenance

Sulfadiazine Sulfadiazine: 500 mg PO four Sulfadiazine: blood disorders, hypersensitiv- Sulfadiazine: thiopentone anaesthetics, LFTs, renal Ensure fluid intake of 2
+ times daily (preferred) or 1 g twice ity reactions, hypoglycaemia, hypothyroid- warfarin, sulphonylureas, clozapine, function, FBC L/day to reduce the risk
daily (if reduced adherence is ism, depression, psychosis, hallucinations, aspirin, ciclosporin, diuretics, metho- of crystalluria
pyrimethamine
suspected) neurological reactions, tinnitus, cough, trexate, oestrogen-containing oral Caution in G6PD defi-
(+ calcium
Pyrimethamine: 25 mg PO once daily dyspnoea, GI symptoms, hepatitis, jaundice, contraceptives, probenecid ciency
folinate) purpura, rash, crystalluria Pyrimethamine: agents that depress
Calcium folinate: 15 mg PO once Calcium folinate to
daily continued until CD4 T-cell Pyrimethamine: anaemia, leucopenia, folate metabolism, agents that cause counteract myelosup-
count >200 cells/microlitre for 6 thrombocytopenia, headache, giddiness, myelosuppression, antacids, highly pressive effects of
months and suppression of HIV vomiting, nausea, diarrhoea, rash, abnormal protein-bound drugs, methotrexate pyrimethamine
replication skin pigmentation, fever

Clindamycin Clindamycin: 300 mg PO four Clindamycin: abdominal pain, diarrhoea, Clindamycin: neuromuscular blocking LFTs, renal Change in bowel habit
+ times daily (preferred) or 600 mg Pseudomembranous colitis, abnormal LFTs, agents, erythromycin, neostigmine, function, should be investigated
three times daily (if reduced adher- nausea, vomiting, rash, urticaria, blood dys- pyridostigmine, oestrogens (risk of FBC, diar- for Clostridium difficile
pyrimethamine
ence is suspected) crasias, dysgeusia (IV), thrombophlebitis (IV) interaction is small) rhoea Caution in G6PD defi-
(+ calcium
Pyrimethamine: 25 mg PO once daily Pyrimethamine: anaemia, leucopenia, Pyrimethamine: agents that depress ciency
folinate)
Calcium folinate: 15 mg PO once thrombocytopenia, headache, giddiness, folate metabolism, agents that cause Calcium folinate to
daily continued until CD4 T-cell vomiting, nausea, diarrhoea, rash, abnormal myelosuppression, antacids, highly counteract myelosup-
count >200 cells/microlitre for 6 skin pigmentation, fever protein-bound drugs, methotrexate pressive effects of
months and suppression of HIV pyrimethamine
replication

FBC, Full blood count; G6PD, glucose-6-phosphate dehydrogenase; GI; gastro-intestinal; IV, intravenous; LFT, liver function test; PO, oral.
 HIV INFECTION 42
be considered in patients where there is evidence of raised intra- sputum-smear-negative result with positive culture. Deinitive
cranial pressure. Adjunctive anticonvulsants may be indicated if diagnosis is reliant on culture of the organism from biological
a patient presents with or develops seizures; however, there is no specimens but may be complicated by atypical clinical features
evidence to support routine prescribing (Nelson et al., 2011). and reduced response to tuberculin testing. It is often necessary
to initiate treatment empirically. Molecular diagnostics can rap-
idly conirm if acid-fast bacilli from a body luid smear test are
Cryptosporidiosis
not TB, which may avoid unnecessary treatment and infection-
Cryptosporidium is a protozoan parasite, which is ubiquitous control measures. The increased incidence of multidrug-resistant
in the environment. Transmission is via ingestion of cryptospo- TB and the emergence of extremely drug-resistant disease are a
ridium oocysts from contaminated water supplies, which leads cause for concern and raise many infection-control issues. They
to transmission of the parasite. Transmission may also occur also highlight the need for antibiotic therapy driven by bacterio-
during sexual intercourse, particularly via the faecal-oral route. logical sensitivities (Nelson et al., 2011).
Symptoms are profuse, non-bloody watery diarrhoea. This may Recommendations for the treatment of M. tuberculosis are simi-
be accompanied by nausea, abdominal cramps and pyrexia. lar to those in HIV-negative adults, and the appropriate guidelines
Diagnosis is via detection of cryptosporidium oocysts in a stool should be consulted, for example, NICE (2016). The potential for
sample. Several samples may need to be checked because oocyst drug–drug interactions and overlapping toxicities are greater in
excretion can be intermittent, especially in less severe infections those receiving ART, and this should be considered when initiat-
(Nelson et al., 2011). ing M. tuberculosis treatment (Table 42.9). Further information
Treatment options are described in Table 42.8. No speciic can be obtained from the University of Liverpool HIV drug inter-
treatments are available that target cryptosporidium. Optimal action website (http://www.hiv-druginteractions.org).
management is to restore immune function via initiation of
ART. Several therapeutic options have been investigated for
M. avium intracellulare/M. avium complex
treatment; however, low study numbers and lack of promising
results in immunocompromised individuals make ART the irst M. avium intracellulare (MAI) or M. avium complex (MAC) are
choice of management. If treatment is considered worth using, commonly found in the environment and are thought to enter
nitazoxanide is the preferred agent; however, it should be rec- individuals via the respiratory route and gastro-intestinal tract.
ognised that eficacy is limited in patients with compromised With the increasing use of ART, the incidence of MAI/MAC has
immune function. Patients should also be offered symptomatic decreased signiicantly in people who are living with HIV because
and supportive therapy with luid replacement, adequate hydra- it typically occurs in severe immunosuppression with CD4 T-cell
tion and anti-motility agents. count less than 50 cells/microlitre. Infection usually presents as
a systemic febrile illness with sweating, fatigue, abdominal pain,
weight loss and diarrhoea. Lymphadenopathy, hepatosplenomeg-
Bacterial infections
aly and/or splenomegaly may be present. Clinical presentation
may vary with site of infection, for example, pulmonary MAI/
Mycobacterium tuberculosis
MAC may present with respiratory symptoms (Temesgen, 2015).
In individuals who are living with HIV, M. tuberculosis (TB) is Diagnosis should be made based on culture of the organism from
characterised by increased likelihood of reactivation of latent dis- blood and sputum samples. In speciic cases, it may be neces-
ease, more rapid progression to clinical disease following acqui- sary for further investigations such as lung or lymph node tissue
sition, more frequent extrapulmonary manifestations of TB and biopsy or bone marrow aspirate.
more rapid progression of HIV disease if the individual is not First-line treatment should be with a macrolide antibiotic
receiving ART. The management of co-infection with TB and (azithromycin is preferred secondary to less drug–drug interaction
HIV requires specialist knowledge, and it is therefore mandatory potential than other macrolide antibiotics), ethambutol and, ide-
to involve specialists in both HIV and respiratory and/or infec- ally, rifabutin as a third agent. Treatment should be continued for
tious diseases (Nelson et al., 2011). at least 12 months and until individuals remain culture-negative,
Both clinical and radiographic presentation of TB may be asymptomatic and have a sustained CD4 T-cell count greater than
atypical. Patients may have a normal chest radiograph and a 100 cells/microlitre for at least 3 months (Nelson et al., 2011).

Table 42.8 Treatment of cryptosporidium

Dosage: route, Common or significant Significant

Drug frequency, duration side effects interactions Monitoring Comments

Nitazoxanide 500 mg orally twice Abdominal pain, diar- Nil known Full blood count, Take with food
daily for 3 days; rhoea, nausea, vomit- liver function tests,
course duration may ing, headache renal function
be required for up to
12 weeks
717
 42 THERAPEUTICS

Table 42.9 Drug–drug interactions between antiretroviral therapy and rifampicin/rifabutin

Antiretroviral Rifampicin Rifabutin

NRTIs/NTRTIs

There are no interaction Use standard doses Use standard doses

with any NRTIs/NTRTIs
and rifamycins

NNRTIs

Efavirenz Efavirenz levels decreased: Rifabutin levels decreased:

Consider increasing efavirenz dosage Increase daily dose of rifabutin by 50%
to 800 mg once daily in patients >50
kg (may also consider TDM)

Nevirapine Nevirapine levels decreased: Rifabutin levels increased:

Do not co-administer Use standard doses
Caution: High intersubject variability means some patients may
experience larger increases and may be at risk of rifabutin toxicity

Etravirine No data available: Limited data:

Do not co-administer Use standard doses
Caution: Etravirine and rifabutin levels both decreased

Rilpivirine Rilpivirine levels decreased: Rilpivirine levels decreased:

Do not co-administer Increase rilpivirine dose by 100%

Protease inhibitors

Atazanavir/ritonavir Atazanavir levels decreased: Rifabutin levels increased:

Do not co-administer Reduce rifabutin dosage to 150 mg three times weekly (TDM
advised because this dosage may be too low in some patients)

Darunavir/ritonavir Darunavir levels decreased: Rifabutin levels increased:

Do not co-administer Reduce rifabutin dosage to 150 mg three times weekly (TDM
advised because this dose may be too low in some patients)

Fosamprenavir/ritonavir Fosamprenavir levels decreased: Rifabutin levels increased:

Do not co-administer Reduce rifabutin dosage to 150 mg three times weekly (TDM
advised because this dose may be too low in some patients)

Lopinavir/ritonavir Lopinavir levels decreased: Rifabutin levels increased:

Do not co-administer Reduce rifabutin dosage to 150 mg three times weekly (TDM
advised because this dose may be too low in some patients)

Saquinavir/ritonavir Saquinavir levels decreased: Rifabutin levels increased:

Do not co-administer Reduce rifabutin dosage to 150 mg three times weekly (TDM
advised because this dose may be too low in some patients)

Integrase inhibitors and entry inhibitors

Dolutegravir Dolutegravir levels decreased: Use standard doses

Increase dolutegravir dosage to 50 mg
twice daily

Elvitegravir/cobicistat Elvitegravir and cobicistat levels de- Elvitegravir and cobicistat levels decreased and rifabutin levels
creased: increased:
Do not co-administer Use not recommended; however, no alternative; reduce rifabutin
to 150 mg three times weekly

Raltegravir Raltegravir levels decreased: Use standard doses

Increase raltegravir dosage to 800 mg
twice daily
Caution: Cmin still reduced at increased
718 dosage
 HIV INFECTION 42
Table 42.9 Drug–drug interactions between antiretroviral therapy and rifampicin/rifabutin—cont’d

Antiretroviral Rifampicin Rifabutin

Maraviroc Maraviroc levels decreased: Use standard doses

Increase maraviroc dosage to 600 mg
twice daily

Enfuvirtide Use standard doses Use standard doses

TDM, Therapeutic drug monitoring.

In patients with a CD4 T-cell count less than 50 cells/microlitre,

Cytomegalovirus
prophylaxis azithromycin 1250 mg once weekly should be con-
sidered. The addition of ART is considered essential to the man- CMV is a member of the β-herpes viruses which infects greater
agement to restore a weakened immune function. than 50% of the human population. After infection the virus has the
ability to establish lifelong, latent infection (Bronke et al., 2005).
In individuals with advanced immunodeiciency, typically with a
Viral infections
CD4 T-cell count less than 50 cells/microlitre, this can result in
reactivation of the virus (viraemia) and clinical end-organ disease
Herpes simplex and varicella zoster
in a proportion of patients. Major sites of CMV disease are the ret-
The herpes viruses are a large family with three phases of infec- ina (75%), gastro-intestinal tract, lung, liver and biliary tract, heart,
tion: primary infection, latency and reactivation. Herpes simplex adrenal glands and the nervous system (<1%) (Nelson et al., 2011).
viruses 1 and 2 (HSV) and VZV are classiied as α herpes viruses. Symptoms are dependent on the site of infection. Viral infec-
VZV is usually transmitted via the respiratory route and causes tion of the retina may be asymptomatic or present with loaters,
both varicella (chickenpox) and zoster (shingles). HSV is trans- scotomata, peripheral or central visual ield defects and decreased
mitted via contact with infectious secretions and causes genital or visual acuity. In the gastro-intestinal tract symptoms are likely
orolabial ulcers. VZV cutaneous presents as localised, erythema- to be colitis, weight loss, anorexia, abdominal pain, diarrhoea,
tous, maculopapular eruptions usually along a single dermatome, malaise and perforation. Oesophagitis presents with odynopha-
but may be multi-dermatomal. They then crust over a few days gia, nausea and epigastric/retrosternal discomfort. Presentation
and typically last for 2–3 weeks. VZV eye disease causes visual in lung infection is similar to many other respiratory conditions:
loss, keratitis, anterior uveitis, severe post-herpetic neuralgia and non-productive cough, exertional dyspnoea, fever and marked
necrotising retinopathy. Herpes zoster can disseminate and cause hypoxaemia. However, pneumonitis is uncommon. When the
CNS disease and present with neurological disease. CNS is involved symptoms are dementia, ventriculoencephalitis,
Orolabial HSV is most commonly caused by HSV-1 and pres- polyradiculomyelitis, lethargy, confusion and fever (Centers for
ents with sensory prodromal symptoms (usually a tingling), Disease Control and Prevention, 2015).
which typically precede development of vesicles that ulcerate CMV viraemia, as detected by polymerase chain reaction,
and crust. Left untreated, they will usually resolve within 7–10 may be positive in the absence of end-organ disease and, there-
days. Genital HSV is caused by both HSV-1 and -2. Anogenital fore, may be of negligible diagnostic use. If a positive result is
lesions develop and usually resolve untreated within 5–10 days; obtained, evidence of end-organ disease should be considered
however, they may not resolve spontaneously and require treat- depending on the patient’s clinical symptoms.
ment. Systemic HSV infection can result in pneumonia, hepatitis, For retina infections, diagnosis is usually based on clinical
oesophagitis and CNS disease. symptoms and visualisation of the retina. Endoscopy can reveal
VZV is usually diagnosed based on appearance of lesions, ulceration of the gut mucosa, and a biopsy can identify character-
especially cutaneous disease. Swabs of infected lesions can also istic inclusions to aid diagnosis. Pneumonitis is hard to differenti-
be checked for detection of expression viral antigens. CSF analy- ate from CMV shedding in respiratory secretions. Therefore, BAL
sis can be performed; a positive result for VZV DNA supports the may reasonably exclude CMV pneumonia with a negative result;
diagnosis of CNS disease. Swabs of infected lesions can be tested however, a positive result should be interpreted alongside clinical
for identiication of HSV-1 or -2, and in systemic disease appro- symptoms. Radiological imaging of the brain performed by MRI
priate samples should be obtained for analysis to identify HSV. is a more sensitive test and, therefore, the preferred method over
First-line treatment should be with aciclovir. Alternative treat- CT scanning. A lumbar puncture, if not contraindicated, can be
ment options which may be considered are valaciclovir and performed for CSF examination to assess CNS infection.
famciclovir. Oral aciclovir can be used for the treatment of local Treatment of CMV is outlined in Table 42.10. For gastro-
VZV (zoster), orolabial HSV and genital HSV if severe or recur- intestinal infection, treatment should be given with IV therapy
rent disease. Systemic aciclovir is required for VZV (varicella), because oral drugs may not be fully absorbed. Maintenance treat-
systemic VZV (zoster) and systemic HSV. Regular suppressive ment is not recommended. However, for retinitis both induction
use of oral aciclovir at lower doses can be used in cases of recur- and maintenance treatment should be given with either oral or
rent disease (Nelson et al., 2011). IV therapy. A ganciclovir implant may be considered if systemic 719
720

42
Table 42.10 Treatment and maintenance of cytomegalovirus

Dosage: route,
Drug frequency, duration Common or significant side effects Significant interactions Monitoring Comments

Treatment

THERAPEUTICS
Ganciclovir 5 mg/kg IV twice daily Sepsis, cellulitis, urinary tract infection, oral candidiasis, Imipenem-cilastin, pro- FBC, LFTs, renal Caution when handling; women of
GI: 2–4 weeks neutropenia, anaemia, thrombocytopenia, leucopenia, benecid, zidovudine, function childbearing potential must be
pancytopenia, appetite decreased, anorexia, depression, didanosine, mycophe- advised to use effective contra-
Retinitis: 2–4 weeks
anxiety, confusion, abnormal thinking, headache, insom- nolate, nephrotoxic ception during treatment; male
Lung: 3 weeks nia, dysgeusia, hypoaesthesia, paraesthesia, peripheral drugs, bone marrow– patients should be advised to
neuropathy, convulsions, dizziness, macular oedema, suppressive agents practise barrier contraception
retinal detachment, vitreous floaters, eye pain, ear pain, during and for at least 90 days
dyspnoea, cough, diarrhoea, nausea, vomiting, abdomi- following treatment
nal pain, constipation, flatulence, dysphagia, dyspepsia,
elevated LFTs, dermatitis, night sweats, pruritus, back
pain, myalgia, arthralgia, muscle cramps, renal impair-
ment, fatigue, pyrexia, rigors, pain, chest pain, malaise,
asthenia, injection-site reactions, decreased weight

Valganciclovir 900 mg PO twice daily See ganciclovir, similar potential side effects (except Imipenem-cilastin, pro- FBC, LFTs, renal Caution when handling; women of
Retinitis: 2–4 weeks those associated with IV administration) benecid, zidovudine, function childbearing potential must be
didanosine, mycophe- advised to use effective contra-
Lung: 3 weeks
nolate, nephrotoxic ception during treatment; male
drugs, bone marrow– patients should be advised to
suppressive agents practise barrier contraception
during and for at least 90 days
following treatment

Foscarnet 90mg/kg IV twice daily Granulocytopenia, anaemia, leucopenia, thrombocytope- Nephrotoxic drugs, Renal function, Good hydration, prompt correc-
GI: 2–4 weeks nia, neutropenia, sepsis, decreased appetite, hypokalae- drugs that inhibit renal magnesium, tion of electrolyte abnormalities
mia, hypomagnesaemia, hypocalcaemia, hyperphospha- tubular secretion, IV bone profile, and dose adjustment for renal
Lung: 3 weeks
taemia, hyponatraemia, hypophosphataemia, increased pentamidine, ritonavir FBC, blood function are vital
ALP, increased LDH, aggression, agitation, anxiety, pressure, LFTs Wash genital area after micturition
confusional state, depression, nervousness, dizziness, to reduce risk of ulceration
headache, paraesthesia, abnormal coordination, convul- Reduce infusion rate if infusion-
sion, hypoaesthesia, involuntary muscle contractions, related side effects
peripheral neuropathy, tremor, hypertension, hypotension,
thrombophlebitis, diarrhoea, nausea, vomiting, abdomi-
nal pain, constipation, dyspepsia, pancreatitis, elevated
LFTs, rash, pruritus, myalgia, renal impairment, genital
discomfort and ulceration, asthenia, chills, fatigue, pyrexia,
malaise, oedema

Cidofovir 5 mg/kg IV once weekly Renal impairment, neutropenia, ocular hypotony, iritis/ Nephrotoxic drugs, Renal function Must be co-administered with
Retinitis: 2 weeks uveitis, nausea, vomiting, alopecia, rash, asthenia, fever, drugs contraindicated (including urine probenecid and IV fluids to mini-
chills, headache with probenecid, te- protein), FBC mise nephrotoxicity; caution with
Lung: 3 weeks
nofovir handling (potential carcinogen)
 Maintenance

Ganciclovir 5 mg/kg IV once Sepsis, cellulitis, urinary tract infection, oral candidiasis, Imipenem-cilastin, pro- FBC, LFTs, renal Caution when handling; women of
daily for 5 days of neutropenia, anaemia, thrombocytopenia, leucopenia, benecid, zidovudine, function childbearing potential must be
the week pancytopenia, appetite decreased, anorexia, depression, didanosine, mycophe- advised to use effective contra-
GI: no maintenance anxiety, confusion, abnormal thinking, headache, insom- nolate, nephrotoxic ception during treatment; male
recommended nia, dysgeusia, hypoaesthesia, paraesthesia, peripheral drugs, bone marrow– patients should be advised to
neuropathy, convulsions, dizziness, macular oedema, suppressive agents practise barrier contraception
Retinitis: continue until
retinal detachment, vitreous floaters, eye pain, ear pain, during and for at least 90 days
CD4 T-cell count >100
dyspnoea, cough, diarrhoea, nausea, vomiting, abdomi- following treatment
cells/microlitre and
nal pain, constipation, flatulence, dysphagia, dyspepsia,
suppressed HIV
elevated LFTs, dermatitis, night sweats, pruritus, back pain,
viral load
myalgia, arthralgia, muscle cramps, renal impairment,
fatigue, pyrexia, rigors, pain, chest pain, malaise, asthenia,
injection-site reactions, decreased weight

Valganciclovir 900 mg PO once daily See ganciclovir, similar potential side effects (except Imipenem-cilastin, pro- FBC, LFTs, renal Caution when handling; women
GI: no maintenance rec- those associated with IV administration) benecid, zidovudine, function of childbearing potential must be
ommended didanosine, mycophe- advised to use effective contra-
nolate, nephrotoxic ception during treatment; male
Retinitis: continue
drugs, bone marrow– patients should be advised to
until CD4 T-cell count
suppressive agents practise barrier contraception
>100 cells/microlitre and
during and for at least 90 days
suppressed HIV
following treatment
viral load

Foscarnet 90 or 120 mg/kg IV once Granulocytopenia, anaemia, leucopenia, thrombocytope- Nephrotoxic drugs, Renal function, Good hydration, prompt correc-
daily for 5 days of the nia, neutropenia, sepsis, decreased appetite, hypokalae- drugs that inhibit renal magnesium, tion of electrolyte abnormalities
week mia, hypomagnesaemia, hypocalcaemia, hyperphospha- tubular secretion, IV bone profile, and dose adjustment for renal
GI: no maintenance rec- taemia, hyponatraemia, hypophosphataemia, increased pentamidine, ritonavir FBC, blood function are vital
ommended ALP, increased LDH, aggression, agitation, anxiety, pressure, LFTs Wash genital area after micturition
confusional state, depression, nervousness, dizziness, to reduce risk of ulceration
Retinitis: continue
headache, paraesthesia, abnormal coordination, convul-
until CD4 T-cell count Reduce infusion rate if infusion-
sion, hypoaesthesia, involuntary muscle contractions,
>100 cells/microlitre and related side effects
peripheral neuropathy, tremor, hypertension, hypotension,
suppressed HIV
thrombophlebitis, diarrhoea, nausea, vomiting, abdomi-
viral load
nal pain, constipation, dyspepsia, pancreatitis, elevated
LFTs, rash, pruritus, myalgia, renal impairment, genital
discomfort and ulceration, asthenia, chills, fatigue, pyrexia,
malaise, oedema

HIV INFECTION
Cidofovir 5 mg/kg IV every 2 weeks Renal impairment, neutropenia, ocular hypotony, iritis/ Nephrotoxic drugs, Renal function Must be co-administered with pro-
GI: no maintenance rec- uveitis, nausea, vomiting, alopecia, rash, asthenia, fever, drugs contraindicated (including urine benecid and IV fluids to minimise
ommended chills, headache with probenecid, te- protein), FBC nephrotoxicity
nofovir Caution with handling (potential
Retinitis: continue until CD4
T-cell count >100 cells/mi- carcinogen)
crolitre and suppressed HIV
viral load

42
ALP, Alkaline phosphatase; FBC, full blood count; GI, gastro-intestinal; IV, intravenous; LDH, lactate dehydrogenase; LFT, liver function test; PO, oral.
721
 42 THERAPEUTICS

treatment is contraindicated. Evidence for treatment for CNS biopsy. Treatment should be according to conventional chemo-
infection is limited; however, ganciclovir with or without addi- therapy regimens; however, potential drug–drug interactions
tion of foscarnet may be considered. In the cases of CNS infec- with ART should be considered because this can increase the
tion, correcting immunodeiciency with ART is critical. toxicity of some chemotherapy combinations (e.g. PIs), increase
Most individuals with a lung infection will not require treat- the levels of some chemotherapy agents and increase the risk of
ment, and the decision to treat should be based on positive neutropenia.
BAL results, as well as clinical symptoms with no alternative
cause.
Invasive cervical cancer
Worldwide, cervical cancer is the second most common cancer
in women overall and is associated with infection with human
Impact of antiretroviral therapy and papillomavirus (HPV). Women who are living with HIV are more
clinical infections likely to have HPV infection, and therefore a higher prevalence
of cervical cancer is seen in women living with HIV. Diagnosis
The widespread use of ART has had a dramatic effect on the inci- is based on histopathological examination of cervical biopsies,
dence, prognosis and clinical aspects of opportunistic infections, and women with HIV should have an annual cervical cytology.
with a major reduction in the vast majority of opportunistic infec- Management should be the same as HIV-negative women accord-
tions. As a consequence, there has been a reduction in mortality ing to national guidelines.
rates and hospital admissions. ART, although vital in the overall
management of opportunistic infections, can be associated with
Neurological manifestations
some complications, for example, overlapping toxicities, drug–
drug interactions and occasionally a severe immune reconstitu- Neurological symptoms may be caused by opportunistic infec-
tion inlammatory syndrome. tions, tumours or the primary neurological effects of the dis-
ease. HIV encephalopathy or HIV-associated cerebral disease is
believed to result from direct infection of the CNS by HIV. This
Cancers
has dramatically declined with the effective use of ART; however,
HIV increases the risk of many malignancies but is associated more subtle forms of brain disease, known as HIV-associated
with three AIDS-deining malignancies: KS, high-grade B-cell neurocognitive disorders, are reported. Initiation of ART should
non-Hodgkin’s lymphoma and invasive cervical cancer. be immediate in individuals demonstrating any signs of neuro-
cognitive disorders. Patients with any level of neurocognitive
deicit should start standard ART; the level of CNS drug penetra-
Kaposi’s sarcoma
tion should not inluence therapeutic choice of ART because data
KS is the most common malignancy in people who are living of improvement in neurocognitive function are not conclusive
with HIV and is caused by the KS herpes virus. Individuals pres- (Churchill et al., 2015).
ent with cutaneous or mucosal lesions, and visceral disease is
uncommon. Lesions appear as raised purple papules and may
Progressive multifocal leucoencephalopathy
be single or multiple, and in severe cases may result in oedema,
ulceration and infection. These lesions are often characteristic Progressive multifocal leucoencephalopathy is associated with
in appearance, but diagnosis should be conirmed by histology. the presence of JC virus. Transmission of the virus is not well
Plasma level of KS herpes virus DNA can also be used as a sur- understood, but it is thought to spread via respiratory secretions
rogate marker of tumour burden. Local therapy can be used for and tonsillar tissue, probably in childhood (Nelson et al., 2011).
troublesome or local disease; however, this is limited to treating The virus disseminates after primary transmission and becomes
only small areas. Radiotherapy, intralesional vinblastine and topi- latent. Following immune suppression, the virus replicates and
cal retinoids have all demonstrated some treatment success. In is transported to the brain via B lymphocytes, where it infects
more widespread disease, systemic treatment is required. permissive oligodendrocytes via the serotonin receptor (Nelson
Initiation of ART can result in an improvement and in some et al., 2011). Patients present with severe immunodeiciency over
cases resolution of KS. However, in patients with advanced, a period of weeks to months. Focal neurology, motor deicit,
symptomatic or rapidly progressive disease, administration altered mood or mental status, ataxia and cortical visual symp-
of systemic cytotoxic chemotherapy is required, and liposo- toms may be present. Seizures occur rarely. The presence of focal
mal anthracyclines and taxanes are the established standard features helps to distinguish progressive multifocal leucoenceph-
treatment. alopathy from HIV encephalopathy. Radiological brain imaging
using MRI combined with JC virus detection in a CSF sample are
suficient to conirm a diagnosis, rather than having to consider
High-grade B-cell non-Hodgkin’s lymphoma
a brain biopsy. In many cases, introduction of ART prevents pro-
High-grade B-cell non-Hodgkin’s lymphoma is the second most gression of disease, but it is unlikely to reverse the functional def-
common malignancy in people who are living with HIV, although icit. Adjunctive cidofovir or cytarabine, although active in vitro
incidence has declined since the introduction of ART. Diagnosis against JC virus, has not been shown to provide any additional
722 should be based on histological conirmation from a tissue beneit over ART alone (Nelson et al., 2011).
 HIV INFECTION 42
to be altered. The best option would be switching to a boosted PI.
Case studies As a class, the PIs are much more robust and require multiple muta-
tions to confer resistance; this strategy is recommended in the BHIVA
(2015) guidelines. Atazanavir should be avoided because it also
Case 42.1 interacts with proton pump inhibitors. Therefore, ritonavir-boosted
darunavir would be the third agent of choice, particularly if there were
Miss F is a 32-year-old legal secretary, originally from Zimbabwe, any adherence concerns. Other third agent choices would include an
and has lived in the UK for 10 years. She was diagnosed with HIV-1 INI (raltegravir, elvitegravir or dolutegravir) or maraviroc if the patient
2 years ago during a routine sexual health screen. Her baseline was CCR5 tropic. These agents would not be recommended if there
CD4 count was 320 cells/mm3 and her viral load was 37,000 cop- was any evidence of concurrent NRTI resistance.
ies/mL. She had no baseline resistance and was hepatitis B immune 3. Her contraception needs are important to consider because she is tak-
and hepatitis C-negative. She was otherwise fit and well, taking ing the combined oral contraceptive pill. Rilpivirine did not interact;
only the combined oral contraceptive pill and had no allergies. however, darunavir/ritonavir will reduce its efficacy. Therefore, if she
She had a male partner who tested HIV-negative and they used switches to this as a third agent, then she would have to be counselled
condoms. She declines primary care doctor disclosure around her and offered alternative contraception options. Medroxyprogesterone
HIV status, as she is worried about confidentiality. intramuscularly and the IUD/IUS are viable options, but the combined
In view of her CD4 count less than 350 cells/mm3 she was oestrogen/progesterone and other progesterone-based methods
offered treatment. She was keen on a single-tablet regimen and are less efficacious. If she switched to either raltegravir, dolutegravir
Eviplera (tenofovir disoproxil fumarate, emtricitabine and rilpi- or maraviroc, she could continue with the combined oral contracep-
virine) was started as a 1-pill once-a-day combination. This was tive pill because there are no significant drug–drug interactions.
chosen because there are no significant interactions with the com-
bined oral contraceptive pill and it suited her lifestyle. In addi-
tion her viral load was less than 100,000 copies/mL, above which Case 42.2
rilpivirine is not recommended in people starting cART because
of higher rates of virological failure. She tolerated this well and In 1997, Mr B, a 27-year-old man, presented with PCP. He had a
achieved an undetectable viral load after 3 months, her CD4 count CD4 count of 123 cells/mm3, and plasma HIV RNA was unknown
increased to greater than 600 cell/mm3 and she remained stable. because viral load testing was not routinely available in clinics at
She is recalled to clinic due to her viral load rising to 5697 cop- the time. He had a good response to treatment with high-dose co-
ies/mL. A repeat sample confirms virological failure (viral load trimoxazole and was subsequently commenced on triple-combina-
7812 copies/mL), and a resistance test confirms an E138K muta- tion therapy with stavudine, didanosine and indinavir. He continued
tion which confers resistance to rilpivirine. receiving this regimen for 2 years, until HIV RNA testing became
available and he was found to have a suppressed viral load and CD4
count of 412 cells/mm3. His full antiretroviral therapy history, with
Questions reasons for switching, is detailed as follows (Table 42.11).
In April 2017 (now aged 47 years) his viral load remained <40 cop-
1. What are the possible reasons for the rise in her viral load? ies/mL, with CD4 count 670 cells/mm3. However, his creatinine clear-
2. What ARV therapy change would you recommend? ance (calculated using Cockcroft–Gault equation) was 41 mL/min
3. What would you advise her to do regarding the combined oral and urine protein/creatinine ratio (UPCR) was significantly raised, at
contraceptive pill? 86 mg/mmol (normal <30 mg/mmol). Both were normal when last
monitored 4 months previously. On questioning, he revealed that
he had been taking regular ibuprofen (400 mg three times a day)
for the past month, following a wrist fracture. His QRISK2 score was
Answers
calculated at 3.5%, and he is HLA-B*5701-negative.
1. There are three main reasons for virological failure. Firstly, the patient Two weeks after stopping the ibuprofen, Mr B’s creatinine clear-
has shown poor adherence to therapy, which should be explored ance is now 52 mL/min and he is restarted on Atripla 1 tablet daily.
in detail at this patient’s appointment and support given around His repeat UPCR, 1 week after stopping ibuprofen was 42 mg/
adherence if this has been the main issue. Secondly, rilpivirine has a mmol (improving), with normal urine albumin/creatinine ratio. His
significant food requirement of 390 calories to aid absorption and serum phosphate was low and fractional excretion of phosphate
ensure adequate drug levels, so if she has been taking her Eviplera was 35% (normal <25%). Although his renal function was improv-
without food, this could put her at risk of virological failure. Thirdly, ing, it was decided to recommend changing his antiretroviral ther-
a full drug history needs to be taken. On discussion she reports that apy to Kivexa 1 tablet daily and efavirenz 600 mg daily.
her primary care doctor prescribed her omeprazole 20 mg daily for
the last 3 months due to new onset of dyspepsia. Omeprazole sig-
nificantly decreases the rilpivirine plasma concentrations caused by Questions
an increase in gastric pH; therefore, co-administration in not recom-
1. What are the possible drug-related causes of Mr B’s renal dysfunc-
mended. This is the likely cause of virological failure in this patient.
tion and what alterations, if any, to his drug therapy would you
It is important that patients are supported to disclose to their pri-
recommend?
mary care doctors/other clinicians and if they do not, that they seek
2. What information should Mr B be given about the proposed
advice from the specialist HIV pharmacy team if they are prescribed
change of his regimen to Kivexa plus efavirenz?
a new drug or buy over-the-counter medication.
2. She needs to switch her antiretroviral therapy because she is no lon-
ger receiving an effective combination. If she remains taking Eviplera, Answers
she is at risk of acquiring further drug resistance. The E138K muta-
tion compromises rilpivirine and also has cross-class resistance, so the 1. Tenofovir disoproxil fumarate use has been associated with
other NNRTIs are no longer an option. Tenofovir disoproxil fumarate renal dysfunction; the first sign of which may be a raised UPCR,
and emtricitabine are still active; therefore, only the third agent needs although there are other causes. Mr B has a raised UPCR and
723
 42 THERAPEUTICS

Table 42.11 Mr B’s antiretroviral therapy treatment history (Case 42.2)

Reason for
Start date Drug name, dose and frequency Stop date Viral load and CD4 at switch changing

May 1997 Stavudine 40 mg twice a day Apr 1999 Viral load <200 copies/mL (lower Renal stones
Didanosine 200 mg twice a day limit of detection at that time) (indinavir)
Indinavir 800 mg three times a day CD4 count 412 cells/mm3

Apr 1999 Stavudine 40 mg twice a day Jan 2002 Viral load <50 copies/mL (lower Lactic acidosis
Didanosine 200 mg twice a day limit of detection at that time) (stavudine and
Efavirenz 600 mg once a day CD4 count 503 cells/mm3 didanosine)

Jan 2002 Tenofovir disoproxil fumarate 300 mg once a day Mar 2008 Viral load <40 copies/mL Simplification
Lamivudine 300 mg once a day CD4 count 633 cells/mm3 (reducing pill
Efavirenz 600 mg once a day burden)

Mar 2008 Atripla 1 tablet once a day

reduced creatinine clearance, suggesting moderate renal dysfunc- gastro-intestinal discomfort, respiratory symptoms, lethargy,
tion, which may be tenofovir disoproxil fumarate related. However, malaise, headache, elevated liver function tests and myalgia.
regular concomitant non-steroidal anti-inflammatory drugs may Symptoms usually appear within the first 6 weeks of initiation
increase the risk of renal dysfunction. It is possible that the addi- with abacavir, although they can occur anytime. General side
tion of regular ibuprofen has precipitated the renal dysfunction. effects such as nausea, vomiting, diarrhoea, fever, lethargy
Therefore, he would be advised to change to an alternative anal- and rash are also present. Therefore, if Mr B has any of these
gesic, if one is still required, starting with regular paracetamol. symptoms he should be carefully evaluated for the presence
Tenofovir disoproxil fumarate has also been associated with hypo- of a hypersensitivity reaction. If Mr B experiences any worrying
phosphataemia, a decrease in bone mineral density and other bone adverse effects, he should present for review.
abnormalities (infrequently contributing to fractures). With Mr B’s d. Monitoring and follow-up: Because Mr B is switching medication,
recent fracture, this should be investigated via annual DEXA scan- he will need to return within 2 weeks to be monitored for toler-
ning. Atripla is not recommended for patients with creatinine clear- ance to the new medication. This is in the form of a consultation,
ance less than 50 mL/min, because the doses of emtricitabine and ideally with a pharmacist, to check whether he is experiencing
tenofovir disoproxil fumarate need to be adjusted. For creatinine any side effects. He will also have a safety blood test (usually
clearance 30–49 mL/min, a dosage of 200 mg emtricitabine and liver function tests) at this stage to check for further potential
300 mg tenofovir disoproxil fumarate (245 mg tenofovir disoproxil) adverse effects to new medication and subsequently (usually at
every 48 hours is required. The efavirenz dosage remains 600 mg 4 weeks) more safety bloods tests (usually liver and renal func-
daily. However, Mr B’s renal function must be closely monitored, tion tests) for viral suppression. At every review, patients should
for example, twice a week, to ensure that the dosages are adjusted be made aware of the ongoing plan for their care and ensure
promptly to reflect any change. This is to avoid over-dosing or they have enough medication to avoid any breaks in treatment.
under-dosing, and the associated risks of toxicity and antiretrovi-
ral therapy failure. If the renal dysfunction continued or worsened,
despite stopping the ibuprofen and dose-adjusting his antiretroviral Case 42.3
therapy, then a change of antiretroviral therapy might be warranted.
2. Mr B is being switched from Atripla 1 tablet daily to Kivexa 1 tab- Mr C is a 58-year-old MSM who was recently diagnosed HIV through
let daily and efavirenz 600 mg daily. The efavirenz component of routine sexual health testing at his local genitourinary clinic. He
his new regimen is also contained in Atripla, and therefore is not is a smoker of 12 cigarettes a day and has hypertension which is
new in terms of drug exposure, merely as form of drug delivery. under control (blood pressure120/95 mmHg) on ramipril and ben-
However, Kivexa is new for this patient. Points to include when droflumethiazide and is also taking pravastatin 40 mg once a day
counselling Mr B on this new drug regimen are: for high lipids. His fasting lipids were total cholesterol 5.9 mmol/L,
a. Why this change is being made: Mr B is demonstrating some low-density lipoprotein cholesterol 4.5 mmol/L, high-density lipo-
toxicities of tenofovir disoproxil fumarate, and it has been protein 1.0 mmol/L, triglycerides 3.3 mmol/L. His height is 175 cm
decided to stop treatment with this drug to prevent any further and his weight is 82 kg.
renal deterioration. He also has a low phosphate level with a His CD4 count is 320 cells/mm3 and his viral load is 70,000 cop-
recent bone fracture which may have been contributed to by ies/mL. He has agreed to start ART, and baseline blood samples
tenofovir disoproxil fumarate. for renal function and liver function tests, HIV drug resistance and
b. How to take this combination: It is best to take efavirenz at HLAB5701 status have been done. His calculated creatinine clear-
night to avoid any disturbance in daily activities if Mr B has any ance (Cockcroft–Gault equation) was 73 mL/min. He has no drug
CNS effects after taking his dose. He is used to taking Atripla; resistance.
therefore, both new drugs should be taken at the same time as
he has been used to taking his medication.
c. Adverse effects: Mr B is HLA-B*5701-negative and is therefore Questions
very unlikely to develop a hypersensitivity reaction to abaca-
1. What assessments would you do to decide which NRTI backbone
vir (a component of Kivexa); however, he should still be aware
(Kivexa or Truvada) Mr C should be prescribed?
of this reaction. Hypersensitivity reaction is characterised by
724 fever and/or rash. Other symptoms associated may include
2. What are the limitations of using the QRISK2 calculator? Is the
calculated risk likely to be an overestimate or underestimate?
 HIV INFECTION 42
3. Mr C is concerned about the implications of his cardiovascular risk
review. What information and advice should he be given?
Case 42.4
4. Having considered all the issues, which backbone would you
Ms D is a 50-year-old social worker who was referred to the hos-
recommend?
pital accident and emergency department by her primary care
5. What aspects need to be considered when determining the most
doctor following a 4-week history of worsening respiratory symp-
suitable third agent to prescribe for Mr C?
toms, despite empirical treatment with amoxicillin, followed by
clarithromycin. She has lost 3 kg in the last 2 months, has had a
Answers non-productive cough for 6 weeks and gets breathless climbing
the stairs at home. Pulse oximetry showed desaturation to 91% on
1. To determine the most appropriate medicine, Mr C’s HIV viral load exercise, and her arterial blood gas sample had a PaO2 of 8.1 kPa.
should first be reviewed. Because it is less than 100,000 copies/ Chest radiograph showed bilateral interstitial infiltrates. Her medi-
mL, both backbones would be appropriate. If it was more than cal history includes irritable bowel syndrome (diagnosed 5 years
100,000 copies/mL, Kivexa would be excluded. This would be ago), recurrent vaginal candidiasis for the past 7 years and allergic
followed by a cardiovascular risk assessment using the QRISK2- rhinitis, for which she uses fluticasone nasal spray. She works in an
2016 calculator (http://qrisk.org) to determine whether he would inner-city area and has no history of foreign travel outside mainland
be suitable for Kivexa (abacavir, one of the drugs in Kivexa, may Europe. The hospital has recently introduced routine (opt out) HIV
be associated with an increased risk of cardiovascular disease testing for all acute medical admissions, as a result of which Ms D
and would be best avoided if the cardiovascular risk is >20%). was found to be HIV-positive, with a CD4 count of 47 cells/mm3.
His HLAB*5701 status would be reviewed and Kivexa would only
be considered if it was HLA-negative. Mr C would be assessed
for any renal or osteoporosis risks to establish whether Truvada Questions
would be suitable. His renal function would be determined using
1. What are the most likely HIV-related differential diagnoses for her
the Cockcroft–Gault equation to ascertain whether the combina-
respiratory symptoms?
tion Truvada was appropriate. His drug resistance results would be
2. How should her respiratory symptoms be managed?
reviewed to ascertain that whatever combination was prescribed
3. When should she start antiretroviral therapy?
would result in viral suppression.
4. What drug interactions would you need to consider when manag-
2. The main limitation of using the QRISK2 is that the population
ing Ms D both in the first few weeks and also in the longer-term?
data underpinning the calculator come from individuals whose
HIV status was not recorded. HIV infection itself is thought likely
to increase the risk of cardiovascular disease, and therefore the
Answers
cardiovascular risk may need to be increased by a factor of, for
example, 1.6. Mr C’s calculated 10-year risk rate is 25.3%, and this 1. The history, signs and symptoms (gradual onset, failure to
is likely to be an underestimate. Because abacavir may be associ- respond to treatment for community-acquired pneumonia,
ated with an increased risk of cardiovascular disease and is best weight loss, non-productive cough, breathlessness on exertion,
avoided if the cardiovascular risk is greater than 20%, Kivexa may oxygen desaturation, low PaO2 and chest radiograph appear-
not be an appropriate choice. ance) are all suggestive of PCP. However, some of these could
3. Mr C should be given general lifestyle advice, especially to give also be consistent with TB which she may have been exposed
up smoking, follow a healthy, balanced diet and regular exercise. to as a result of the nature of her job. TB would need to be
Specific lipid-lowering dietary advice could be given. It would be excluded. Because Ms D has a significant degree of immunosup-
useful to establish whether Mr C has changed his lifestyle in the pression, the possibility of more than one pathogen/diagnosis
last 4–6 months, for example, change in adherence to lipid-lower- must always be considered.
ing therapy and/or change in diet. He should be encouraged to 2. Until TB has been excluded, Ms D should be nursed in a nega-
see his primary care doctor for review of his lipid-lowering agent tive pressure room. A bronchoscopy should ideally be performed
to optimise his lipids. to assist diagnosis. She should be started on treatment for PCP
4. Given Mr C’s high cardiovascular risk, Kivexa would not be ideal, immediately with high-dose co-trimoxazole and systemic corti-
but Truvada could be considered as a backbone. costeroid (see text and Table 42.4 for doses and administration
5. Aspects to consider with respect to a third agent are Mr C’s con- details). Following induction treatment (usually 3 weeks in dura-
cerns about pill burden, how medicine taking would fit into his tion), she should receive secondary prophylaxis until her CD4
lifestyle, whether he would be able to take raltegravir because count on fully suppressive antiretroviral therapy is maintained
this needs to be taken twice a day. If efavirenz is being consid- above 200 cells/mm3 for 3–6 months.
ered, then its potential to cause CNS side effects would need to If she responds well to PCP treatment and bronchial washings
be reviewed with respect to Mr C’s work and whether this could are negative for acid-fast bacilli, then it would be reasonable for
compromise safety in the workplace. In addition, if Mr C has had her to be managed expectantly with regard to the possibility of
any mood problems they should be explored because they can be TB, that is, not kept in isolation and not started on TB treatment
exacerbated by efavirenz. Resistance to drugs like efavirenz occurs unless relevant symptoms persist or worsen, or new ones develop.
if doses are missed. Therefore, if there was any likelihood that Mr C If TB treatment were required, the standard four-drug (rifampicin,
is going to miss doses, which would result in drug resistance, isoniazid, pyrazinamide, ethambutol) 2-month induction regimen,
it would be better if Mr C was changed to a more robust regi- followed by 4 months of rifampicin and isoniazid plus pyridoxine
men, for example, a PI-containing regimen – darunavir/ritonavir would be recommended.
or atazanavir/ritonavir. If Mr C was taking any other concomitant 3. With a CD4 count of 47 cells/mm3, treatment with antiretroviral
medicines (e.g. stomach ulcer medicines like proton pump inhibi- therapy would be recommended as soon as possible. Depending
tors) then atazanavir/ritonavir would not be an appropriate choice on how well she tolerated and responded to the PCP treatment,
because of the drug–drug interactions. Therefore, the patient’s and whether TB treatment was also needed, antiretroviral therapy
wishes, concerns, lifestyle, as well as additional information (e.g. would usually be started within 2–4 weeks of diagnosis. For more
drug interactions), would be considered when determining a suit- information, refer to BHIVA guidelines for management of oppor-
able third agent in line with local policy for the most cost-effective tunistic infections (Nelson et al., 2011) and TB/HIV co-infection 725
ARV therapy. (Pozniak et al., 2011).
 42 THERAPEUTICS

4. If Ms D did require TB treatment, the hepatic enzyme induction If PI-based antiretroviral therapy were initiated, either because of
effect of rifampicin would need to be considered and a thorough the presence of resistance mutations or whilst awaiting the HIV
review of drug–drug interactions would be advised. resistance test result, then TB therapy (if required) would need to
The choice and dose of antiretroviral therapy would also be be altered. Rifabutin (150 mg three times a week e.g. Monday,
affected if treatment was started after the HIV genotypic resis- Wednesday and Friday) would be used instead of rifampicin. PIs
tance test result was known; if no resistance had been found, also interact with intranasal and inhaled fluticasone and budesonide,
then efavirenz-containing antiretroviral therapy would be possi- resulting in increased levels of these steroids, due to inhibition of
ble. If co-administered with rifampicin, the efavirenz dose should cytochrome 4503A4 in the gut wall and the liver and risk of increased
be increased to 800 mg once daily if her weight was greater than steroid side effects and Cushing’s syndrome. Beclometasone nasal
60 kg; if less than 60 kg, standard dosage of 600 mg should be spray would be a suitable alternative preparation for Ms D’s allergic
used. If she is experiencing side effects from efavirenz, TDM of rhinitis and should be substituted.
efavirenz is recommended.

Acknowledgements
The authors acknowledge the contribution of H. Leake-Date and M. Fisher to versions of this chapter which appeared in previous editions.

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Further reading
Adler, M.W., Edwards, S.G., Miller, R.F., et al., 2012. ABC of HIV and Saag, M.S., Chambers, H.F., Eliopoulos, G.M., et al., 2016. The Sanford
AIDS. Wiley-Blackwell, Hoboken, NJ. Guide to HIV/AIDS Therapy 2016–17 Pocket Edition, twenty fourth ed.
Crum-Cianlone, N., Huppler Hullsiek, K., Marconi, V., et al., 2009. Trends Antimicrobial Therapy Inc., Sperryville, VA.
in the incidence of cancers among HIV-infected persons and the impact Taiwo, B., Zheng, L., Gallien, S., ACTG A5262 Team, et al., 2011. Eficacy
of antiretroviral therapy: a 20-year cohort study. AIDS 23, 41–50. of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir
Marcus, J.L., Leyden, W.A., Chao, C.R., et al., 2014. HIV infection and in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 25,
incidence of ischemic stroke. AIDS 28, 1911–1919. 2113–2122.
Rasmussen, L.D., Engsig, F.N., Christensen, H., et al., 2011. Risk of cere-
brovascular events in persons with and without HIV: a Danish nationwide
population-based cohort study. AIDS 25, 1637–1646.

Useful websites
University of Liverpool HIV drug interaction website: http:// Clinical Care Option: https://www.clinicaloptions.com
www.hiv-druginteractions.org British HIV Association (BHIVA): http://www.bhiva.org
University of Liverpool HEP drug interactions website: http:// HIV Pharmacy Association: http://www.hivpa.org
www.hep-druginteractions.org NAM aidsmap: http://www.aidsmap.com
QRISK2 Prediction algorithm for cardiovascular disease: https:// Centers for Disease Control and Prevention: https://www.cdc.gov/hiv
www.qrisk.org British Association for Sexual Health and HIV: https://www.bashh.org

727
 THERAPEUTICS

43 Fungal Infections Manjusha Narayanan

Some fungi like Histoplasma capsulatum, Coccidioides immitis

Key points and Blastomyces dermatitidis are known as dimorphic fungi (see
• Fluconazole, a triazole, is considered to be standard therapy Table 43.2) because they are found in the infected host in yeast
for oropharyngeal, oesophageal and vaginal candidiasis. form at 35–37 °C temperature but grow as moulds, in vitro, at
• Itraconazole and terbinafine are efficacious, non-toxic alterna- room temperatures (22 °C incubation).
tives to griseofulvin when systemic treatment of dermatophyto- Fungi mainly reproduce by forming spores through mitosis
sis is required. giving rise to two daughter cells. They are known by names
• Fungi can cause overwhelming deep-seated or systemic given to this imperfect state (asexual reproduction), but the
infections in immunocompromised hosts that are refractory to same fungus, for example, Scedosporium apiospermum (asex-
antifungal treatment alone.
ual form), is also known as Pseudoallescheria boydii (sexual
• Incidence of non-Aspergillus mould infections has increased in
form). However, for all practical purposes, only the oldest
transplant recipients over the past decade, and these can be lethal.
and best-established name for the fungi is used in diagnostic
• Most therapy for deep-seated fungal infection in the immuno-
laboratories.
compromised host is empirical due to the difficulties in reach-
ing a rapid, accurate diagnosis of systemic fungal infection. Fungal spore are spread by air, water and direct contact with
• Lipid-complexed formulations of amphotericin offer a less toxic infected source. Humans usually become infected by inhalation
alternative to conventional amphotericin in the treatment of of airborne spores or by inoculation into traumatised skin and
systemic fungal infection. mucous membrane.
• Voriconazole, a triazole, appears to be an effective alternative
to amphotericin in the treatment of invasive aspergillosis.
Laboratory diagnosis
• Caspofungin is an alternative agent to amphotericin for inva-
sive aspergillosis and may have a role to play in the empirical Microscopical examination and culture of fungi is the main-
treatment of febrile neutropenic patients. stay of laboratory diagnosis. Appropriate staining of his-
• Anidulafungin is an alternative to fluconazole in treatment of tological sections of affected tissue is helpful in making a
invasive candidiasis in adult non-neutropenic patients. diagnosis when culture growth may or may not be positive.
Yeast colonies and moulds are characteristic in their appear-
ance on culture plates and can be preliminarily identified by
their shape, colour and temperatures at which they grow. For
Introduction the genus and species identification of yeasts, microscopic
examination and biochemical tests are necessary. Moulds are
Fungi are ubiquitous micro-organisms that differ from bacte- identified by their morphology and the nature of sporulation
ria in their cellular structure, and this makes them naturally on agar medium.
resistant to antibacterial agents (Table 43.1). Fungi are broadly Antifungal sensitivity testing for yeast is done by determining
divided into yeasts and moulds. Yeasts are typically round or the minimum inhibitory concentration (MIC) of the antifungal
oval-shaped microscopically; grow lat, round colonies on cul- agent in the E-test strip method, which has now replaced the mea-
ture plates; and reproduce by forming buds from their cells. surement of ‘inhibition zone’ by disc testing. E-test strips are also
Moulds (e.g. Aspergillus, Mucor) appear as a collection or mass available for determining sensitivity of antifungal agents against
(mycelium) of individual tubular structures called hyphae that moulds. Molecular diagnosis utilising polymerase chain reaction
grow by branching and longitudinal extension. They appear is not available for use in routine practice, but it can be avail-
as a fuzzy growth on appropriate conducive medium (e.g. able as a send-away test to specialised laboratories. Serological
Penicillium colonies on stale bread or Sabouraud’s agar). The diagnosis to look for antibodies in patient’s blood is of use only
most commonly seen yeast, Candida, occasionally produces in Coccidioides infection. Enzyme-linked immunosorbent assay
pseudohyphae. methods to look for galactomannan antigen in deep Aspergillus
Hundreds of species of fungi are in the environment, but only infection are available but not fully evaluated. A positive test
the important human fungal pathogens and their treatment will be needs to be interpreted in conjunction with other indings.
discussed in this chapter. The fungi of medical importance can be Antigen detection is useful in disseminated Histoplasmosis and
728 divided into four groups (Table 43.2). Cryptococcosis.
 FUNGAL INFECTIONS 43
Table 43.1 Important characteristics of a fungal cell Fungal infection
It is important to distinguish harmless colonisation with fungi
Fungi Bacteria
and signiicant clinical infection, because only the latter would
Eukaryotes Prokaryotes, eubacteria beneit from antifungal treatment.
More often, fungi are a cause of supericial infections of the
Cell and cytoplasm Cell and cytoplasm skin and mucous membranes.
In some susceptible hosts whose immune system is heavily
Nucleus with multiple chromo- No nucleus or nuclear mem- compromised, deep-seated infections involving organs like lungs
somes enclosed in a nuclear brane has single chromo-
membrane some
and brain can manifest as ‘dificult to cure’ infections, for exam-
ple, pulmonary aspergillosis or cryptococcal meningitis.
Contains endoplasmic reticulum, Other structures absent
Golgi apparatus, mitochondria except ribosomes
and ribosomes Antifungal agents
Cytoplasmic membrane Cytoplasmic membrane Topical and systemic antifungal agents are available to treat
mucocutaneous candidiasis, various forms of tinea (ring-
Contains phospholipids and Contains phospholipids and worm) and other dermatophytosis, onychomycosis and deep-
sterols no sterols seated systemic infections (e.g. candidaemia, mucor mycoses,
fungal endocarditis, osteomyelitis). Some infective conditions
Cell wall Cell wall
and their treatment are dealt with in the sections that follow.
Contains chitins, mannans,+/− Contains peptidoglycan,
The side effects of a range of antifungal agents are set out in
cellulose lipids and proteins Table 43.3.

Table 43.2 Classification of fungi of medical importance

Group Examples Infections caused

Yeast Candida spp. Oral and vaginal thrush

Deep seated: candidaemia, empyema
Cryptococcus neoformans Meningitis
Saccharomyces cerevisiae Rare systemic infection in immunocompromised host
Malassezia furfur

Yeastlike Geotrichum candidum

Trichosporon beigelii

Dimorphic fungi Blastomyces dermatitidis For first three: deep systemic organ involvement, more commonly
in the immunocompromised host
Coccidioides immitis Deep subcutaneous infection following trauma
Histoplasma capsulatum
Paracoccidioides brasiliensis
Sporothrix schenckii

Moulds

1. Hyaline
a. Zygomycoses Rhizopus Infections in patients with neutropenia and those with diabetic
Mucor ketoacidosis
Absidia
b. Hyalohyphomycosis Aspergillus fumigatus and other Systemic infection: invasive pulmonary or central nervous system
Aspergillus spp. involvement
Fusarium Fusarium keratitis
Scedosporium apiospermum Deep infection in immunocompromised host, e.g. transplant patients

2. Dermatophytes Trichophyton spp. For all three: various skin (ringworm), hair and nail infections
Microsporum spp.
Epidermophyton

3. Dematiaceous Alternaria spp. Deep tissue infection with granulomas

Cladophialophora spp. Chromomycosis, mycetomas
729
 43 THERAPEUTICS

Table 43.3 Side effects of systemic antifungal agents

Drug Side effects

Griseofulvin Mild: headache, gastro-intestinal side effects; hypersensitivity reactions such as skin rashes, including
photosensitivity
Moderate: exacerbation of acute intermittent porphyria; rarely, precipitation of systemic lupus erythematosus
Contraindicated in acute porphyria, systemic lupus erythematosus, pregnancy and severe liver disease

Terbinafine Usually mild: nausea, abdominal pain; allergic skin reactions; loss and disturbance of sense of taste
Not recommended in patients with liver disease

Amphotericin Immediate reactions (during infusion) include headache, pyrexia, rigors, nausea, vomiting, hypotension;
occasionally, there can be severe thrombophlebitis after the infusion
Nephrotoxicity and hypokalaemia
Anaemia due to reduced erythropoiesis
Cardiac failure (exacerbated by peripheral neuropathy [rare] hypokalaemia due to nephrotoxicity)
Immunomodulation (the drug can both enhance and inhibit some immunological functions)

Flucytosine Mild: gastro-intestinal side effects (nausea, vomiting); occasional skin rashes
Moderate: myelosuppression (dose related), hepatotoxicity

Fluconazole Mild: nausea, vomiting and occasional skin rashes; occasionally, elevated liver enzymes (reversible)
Moderate or severe: rarely, hepatotoxicity and severe cutaneous reactions, especially in patients with AIDS

Itraconazole Mild: nausea and abdominal pain; occasional skin rashes

Moderate or severe: rarely, hepatotoxicity

Voriconazole Similar to fluconazole and itraconazole

Mild: reversible visual disturbances occur in about 30% of patients

Caspofungin, Mild: gastro-intestinal side effects; occasional skin rashes

anidulafungin

AIDS, Acquired immune deficiency syndrome.

Candida folliculitis may present in unkempt, bearded men. Nail

Superficial infection infection with Candida (onychomycosis) or subcutaneous tis-
Candida infections sue involvement under the nail (paronychia) is seen in people
Epidemiology whose occupation involves prolonged hand immersion in water.
In severe oesophageal candidiasis, ulceration or formation of
Candida is a normal commensal of the human gastro-intestinal tract pseudomembranes and, rarely, perforation of the lower third of
and skin. Loss of skin and mucosal integrity or use of broad-spectrum the oesophagus may occur.
antibiotics which alter normal bacterial lora allow overgrowth of Candida can be a cause of hospital-acquired infection in
endogenous Candida. There are more than 100 species of Candida, patients, because it is found in the hospital environment on inani-
but only a few are important as common human pathogens. mate objects or on skin of healthcare workers.
Thrush is candidal infection of the mucous membrane. It can
manifest as oral infection, for example, oral thrush in various
patient groups, vulvovaginal thrush in females, balanitis in the Treatment
uncircumcised man or intertrigo infection in moist skin surfaces in Oral and vaginal candidiasis may be treated by either topical or sys-
close proximity, for example, groin area. Patients with diabetes and temic antifungal agents. The drugs currently available for topical
corticosteroid users, whether inhaled or oral, are also prone to infec- use fall into two groups: the polyenes, of which only amphotericin
tions. Dysphagia due to candidal oesophagitis presents in patients and nystatin are used clinically; and the imidazoles, such as econ-
with acquired immune deiciency syndrome (AIDS) and cancer. azole, clotrimazole, miconazole and fenticonazole. These agents
are essentially identical in their antifungal activity, and the only
Clinical presentation
reasons to choose between them are price and differing prepara-
Oral thrush typically presents as a sore mouth with white curd- tions. The two irst-line systemic agents are both triazoles (lucon-
like patches on the tongue or oral mucosa which can bleed on azole and itraconazole) and can be given by mouth. Voriconazole,
scraping. Females with vaginal thrush present with itching and a triazole, should be considered as second-line treatment if the
a creamy vaginal discharge. Skin infection in babies can present Candida is resistant to irst-line triazoles. Skin infections may also
730 as pustular body rash or nappy rash in the moist perianal area. be treated topically, but nail infections are unlikely to respond to
 FUNGAL INFECTIONS 43
a topical antifungal agent alone and require systemic treatment. edge and associated skin scaling. However, presentation is inlu-
Oesophagitis will invariably require systemic treatment. enced by the site of infection, for example, tinea pedis (athlete’s foot)
Topical treatment. The polyenes are broad-spectrum antifun- between the toes or tinea cruris on the body, and by the actual spe-
gal agents that are virtually insoluble in water and which are not cies of fungus causing the infection. In general, less severe lesions
absorbed from the gastro-intestinal tract or from skin or mucous are produced by human fungal strains, whereas those acquired
membranes. Both nystatin and amphotericin (but particularly from animals can produce quite intense inlammatory reactions.
nystatin) are available in a wide range of formulations including Dermatophytosis of the nail results in thickened, discoloured
pessaries, creams, gels, tablets, pastilles, etc. The choice of formu- nails, whereas in the scalp, infection presents with itching, skin
lation clearly depends on the site of infection and patient preference. scaling and inlammation, and patchy hair loss (alopecia).
Systemic treatment. Three triazole agents – luconazole, itra- Rarely, deep dermatophytosis may be seen in immunocom-
conazole and voriconazole – are available for systemic treatment promised patients with involvement of subcutaneous tissue
of oral and vulvovaginal candidiasis. A good source of advice on (granuloma).
treatment is that from the Infectious Diseases Society of America
(Pappas et al., 2009)
Diagnosis
Vulvovaginal candidiasis.
• Several topical antifungal agents provide effective therapy; The diagnosis of dermatophyte infection is conirmed by collecting
no agent is clearly superior. appropriate specimens such as material from infected nails and skin.
• A single 150 mg dose of luconazole is recommended for The fungi can be seen microscopically and specimens may also be
the treatment of uncomplicated cases. cultured, but antifungal susceptibility testing is not required.
• Complicated vulvovaginal candidiasis requires topical therapy
for 7 days or multiple doses of luconazole (150 mg every 72
Treatment
hours for 3 doses). Recurrent infections with non-albicans
Candida, for example, C. glabrata, may be more dificult to treat. Small or medium areas of skin infection can be treated with topi-
Candida balanitis. cal therapy, but nail, hair and widespread skin infection should be
• Candida balanitis can be treated with topical polyenes or systemically treated with oral antifungal agents.
imidazoles, or with systemic luconazole at the same dose as The most commonly used topical agents are the imidazoles, of
for vaginal infection (e.g. luconazole 150 mg for 1 dose). which a wide variety is available, including clotrimazole, econazole,
miconazole and tioconazole. There is little to choose between these
It is sometimes stated that when treating a woman with vaginal agents, all of which are usually applied two or three times daily,
candidiasis, the male partner should be treated simultaneously continuing for up to 2 weeks after the lesions have healed. Side
to prevent reinfection. Although there is no evidence to support effects are uncommon and usually consist of mild skin irritation.
this approach, it may be considered in women who suffer from Other topical agents include amoroline, terbinaine and tolnaftate.
repeated vaginal candidiasis. The main oral antifungals used for dermatophytosis are terbin-
Guidance on the treatment of topical and systemic therapy aine, itraconazole and luconazole. Griseofulvin is an alternative
(Pappas et al., 2009) is also available for treatment of mild, mod- treatment for tinea capitis.
erate and severe oropharyngeal and oesophageal candidiasis and Terbinaine. Terbinaine was the irst member of a new class of
suppressive therapy for patients with human immunodeiciency antifungal agents, the allylamines, which became available for sys-
virus (HIV) infection. temic use. These agents act by inhibition of the fungal enzyme squa-
lene epoxidase, an enzyme involved in the synthesis of ergosterol, an
essential component of the fungal cytoplasmic membrane. Although
Dermatophytosis
terbinaine has a very broad antifungal spectrum in the laboratory,
its in vivo eficacy does not correspond to its in vitro activity, and it
Epidemiology
is used only for the treatment of dermatophyte infection.
Dermatophytosis, or tinea, is a condition caused by three gen- About 70% of an oral dose of terbinaine is absorbed, and the
era of dermatophyte fungi: Trichophyton, Epidermophyton and drug appears in high concentrations in the skin. The half-life is
Microsporum. Unlike Candida, these are moulds which have a pre- about 16–17 hours; therefore, the drug can be given once per day.
dilection for keratinised tissue such as skin, nail and hair. These fungi Terbinaine is metabolised in the liver and the metabolites are
are very widely distributed throughout the world and may be acquired excreted in the urine so that hepatic or renal dysfunction will pro-
from the soil (anthrophilic, e.g. Trichophyton rubrum), from animals long the elimination half-life.
(zoophilic) or from humans (geophilic) infected with the fungus. Terbinaine is the treatment of choice for tinea infections
Some species are prevalent throughout the world, for example, at 250 mg/day for 2–6 weeks, depending upon the infection.
Microsporum canis, whereas some are area speciic, for example, However, for nail infections a longer course of terbinaine is
Trichophyton mentagrophytes in Europe and New Zealand. required (e.g. ingernails infections may be for ≥6 weeks at 250
mg/day and for toenail infections it may need to be continued
for 12 weeks).
Clinical presentation
Itraconazole is the second preferred agent at 200 mg twice a
The classical clinical presentation of dermatophyte infection of the day for 1 week and longer with repeated courses for inger and
skin is ringworm (tinea), a circular, inlamed lesion with a raised toenail involvement. 731
 43 THERAPEUTICS

Treatment
Griseofulvin. The irst orally administered treatment for der-
matophytosis was griseofulvin, which has been available since Pityriasis versicolor is treated with topical terbinaine cream
the late 1950s. Griseofulvin is active only against dermatophyte or a topical imidazole cream such as clotrimazole, econazole
fungi, and it is inactive against all other fungi and bacteria. To or miconazole. Cheaper topical alternatives are 2% selenium
exert its antifungal effect, it must be incorporated into keratinous sulphide lotion or 20% sodium thiosulphate applied daily for
tissue, where levels are much greater than serum levels; there- 10–14 days. Relapses are common, and treatment may need to
fore, it has no effect if used topically. be repeated. In severe cases, oral itraconazole (200 mg once
Griseofulvin is well absorbed and absorption is enhanced if daily for 7 days) may be given. Treatment of seborrhoeic der-
taken with a high-fat meal. In children, it may be given with milk. matitis and folliculitis is undertaken with topical azole creams
A 1000 mg dose produces a peak serum level of about 1–2 mg/L and 1% hydrocortisone. This condition can also often relapse.
after 4 hours, with a half-life of at least 9 hours. An ultra-ine
preparation of griseofulvin exists which is almost totally absorbed
Ear infection
and permits the use of lower dosages (typically 330–660 mg
daily). This preparation is not available in the UK. Elimination is Fungi sometimes infect the external auditory canal, causing otitis
mainly through the liver, and inactive metabolites are excreted in externa, with the most common causative organisms being vari-
the urine. Less than 1% of a dose is excreted in urine in the active ous species of Aspergillus (such as A. niger and A. fumigatus) and
form, but some active drug is excreted in the faeces. C. albicans and other Candida species. A variety of other fungi
The usual adult dosage is 500 mg daily or 1 g for severe infec- found in the environment can also cause this condition. The use
tions. The duration of treatment will depend upon the infection; it of topical antibacterial agents in the ear may predispose to local
may require 6 weeks for treatment of larger lesions in tinea corporis. fungal infection.
The duration of treatment with griseofulvin is dependent entirely
on clinical response. Skin or hair infection usually requires 4–12
Clinical presentation
weeks of therapy, but nail infections respond much more slowly; 6
months of treatment is often required for ingernails and a year or Fungal infection of the ear usually presents as pain and itching in
longer for toenail infections. Unfortunately, the rate of treatment the auditory canal, sometimes with a reduction in hearing caused
failure or relapse in nail infection is high and may reach up to by blockage of the canal. There may be an associated discharge
60%; hence terbinaine and itraconazole may be preferred agents. from the ear. Clinical examination shows a swollen red canal,
and the fungal mycelium is sometimes visible as an amorphous
white or grey mass.
Pityriasis versicolor
Pityriasis versicolor is a common supericial skin infection
Diagnosis
caused by a yeastlike fungus, Malassezia furfur. The organism
is a member of the normal skin lora and lives only on the skin The diagnosis of a fungal infection of the external canal can be
because it has a growth requirement for medium-chain fatty acids made by microscopy and culture of material obtained from the ear.
present in sebum.
Treatment
Clinical presentation
Aural toilet with removal of obstructing debris is very important
Pityriasis versicolor usually appears as patches scattered over the in the management of fungal infections of the external auditory
trunk, neck and shoulders. These patches produce scales and may canal. A topical antifungal agent such as nystatin or amphoteri-
be pigmented in light-skinned individuals, appearing light brown cin, or an imidazole can also be applied.
in colour. In dark-skinned patients, the lesions may lose pigment
and appear lighter than normal skin.
Infections with saprophytic fungi
In some patients, Malassezia yeast is also associated with dan-
druff and seborrhoeic dermatitis, although the exact role of the Most mouldy fungi are saprophytes; they obtain their nutrition
yeast in causing this condition remains uncertain. In patients with from dead organic matter. Some saprophytic fungi can cause
AIDS, seborrhoeic dermatitis may be quite extensive and sudden signiicant human infections. An example of such an infection
in onset. Malassezia folliculitis can appear as greasy papules or in a host with a normal immune system is fusarium keratitis
pustules on the trunk or face of an HIV-infected individual. in contact lens wearers. Penicillium marneffei can cause skin
infection and disseminated fatal infection in HIV-infected
patients in South East Asia. Scedosporium pulmonary infec-
Diagnosis
tions are seen in lung transplant recipients. A large trial of
The diagnosis of pityriasis versicolor is made by microscopy retrospective data from the USA revealed that the three most
of scrapings from the lesion. The specimen is examined for the common non-Aspergillus saprophytic moulds that cause inva-
presence of yeast cells and short hyphae. Culture is not usually sive fungal infection among patients receiving haemopoietic
required for diagnosis and, because it requires special culture stem cell transplants (HSCT) were Fusarium, Scedosporium
media, is not routinely attempted. and Zygomycetes (Marr et al., 2002).
732
 FUNGAL INFECTIONS 43
Table 43.4 Conditions predisposing to systemic or deep-seated fungal infection

Infection Predisposing conditions

Systemic candidiasis Neutropenia from any cause (disease or treatment)

Use of broad-spectrum antibiotics which eliminate the normal body flora
Indwelling intravenous cannulae, especially when used for total parenteral nutrition
Haematological malignancy and hematopoietic stem cell transplantation
Solid organ transplantation
AIDS (particularly associated with severe mucocutaneous infection)
Intravenous drug abuse
Cardiac surgery and heart valve replacement, leading to Candida endocarditis
Gastro-intestinal tract surgery
Oesophagectomy leak leading to pleural space infection (empyema)

Aspergillosis Neutropenia from any cause, especially if severe and prolonged

Acute leukaemia
Solid organ transplantation (mainly lungs)
Chronic granulomatous disease of childhood (defect in neutrophil function)
Pre-existing lung disease (usually leads to aspergillomas; fungus balls form in the lung rather than invasive
or disseminated infection)

Cryptococcosis AIDS
Systemic therapy with corticosteroids
Renal transplantation
Hodgkin’s disease and other lymphomas
Sarcoidosis
Collagen vascular diseases

Zygomycosis Diabetic hyperglycaemic ketoacidosis (leading to rhinocerebral infection)

Severe, prolonged neutropenia
Burns (leading to cutaneous infection)

AIDS, Acquired immune deficiency syndrome.

summarised in Table 43.4. A breach in the body’s mechani-

Deep-seated fungal infections cal barriers may predispose to fungal infection. For example,
fungal infection of the urinary tract occurs most commonly
Most deep-seated or systemic fungal infections seen in the UK are in catheterised patients who have received broad-spectrum
the result of some breakdown in the normal body defences, which antibiotics, whereas total parenteral nutrition (TPN) is strongly
may be due to disease or medical treatment. Fungi that cause super- associated with fungaemia, sometimes with unusual fungi
icial infections can also cause deep-seated infection in immuno- such as Malassezia furfur. This is due to the use of TPN infu-
compromised patients with leukaemia and lymphoma, and those sions containing lipids, which are a growth requirement of
in the post-transplant period of immunosuppression. There are, this organism. Most cases of systemic fungal infection, how-
however, a group of fungi, often referred to rather misleadingly as ever, are associated with a defect in the patient’s immune
the pathogenic fungi, which are able to cause systemic infection in system, and the nature of the organisms encountered is often
a previously healthy person. These infections, which are usually related to the nature of the immunosuppression. Neutropenia,
due to dimorphic fungi, include diseases such as histoplasmosis, for example, is usually associated with Candida species,
blastomycosis and coccidioidomycosis. They are rare in the UK Aspergillus and mucormycosis, whereas defects of cell-
but rather more common in the USA and other parts of the world. mediated immunity, for example, HIV infection, are strongly
associated with infection by Cryptococcus neoformans.
Prolonged diabetic ketoacidosis is a risk factor for develop-
Fungal infections in ment of rhinocerebral zygomycosis, where mortality rates
can be as high as 100% if there is signiicant underlying
the compromised host disease.
Common mycoses Many different fungi have been described as causing systemic
fungal infection, but the most common organisms encoun-
Epidemiology and predisposing factors
tered and the conditions they cause are listed in Table 43.5.
A large number of conditions may predispose the individ- Of these, Candida and Aspergillus are by far the most com-
ual to systemic or deep-seated fungal infection. These are mon in the UK.
733
 43 THERAPEUTICS

Table 43.5 Common causes of systemic and deep-seated Clinical presentation

fungal infection in the UK
Symptoms can be non-speciic, such as low-grade fever, night
Condition/organism Common clinical presentations sweats, weight loss, cough, chest pain and septic shock in extreme
cases (Table 43.6).
Candidiasis (Candida Fungaemia
albicans, C. glabrata, Colonisation of intravenous cannulae
C. krusei, C. tropicalis Pneumonia Diagnosis
other Candida species) Meningitis
Bone and joint infections Organ-speciic radiological indings backed by laboratory tests,
Endocarditis as discussed earlier in this chapter, are the mainstay of diagnosis.
Endophthalmitis
Peritonitis in chronic ambulatory
peritoneal dialysis Treatment
Compared with the vast array of antibacterial agents available
Aspergillosis (Aspergillus Invasive pulmonary aspergillosis
fumigatus, A. flavus, Disseminated aspergillosis to treat bacterial infections, very few systemic antifungal agents
other Aspergillus species) Aspergilloma are available and these comprise four major categories: the poly-
Endocarditis enes (conventional and lipid formulations of amphotericin B), the
triazoles (luconazole, itraconazole, voriconazole and posacon-
Cryptococcosis Meningitis azole), the echinocandins (caspofungin, anidulafungin and mica-
(Cryptococcus Pneumonia fungin) and lucytosine. To provide optimal therapy to the patient,
neoformans) Cutaneous infection
it is necessary to understand the proile, properties and toxicity of
Zygomycosis (various Rhinocerebral infection these agents. Table 43.7 details the antifungal spectrum of activ-
species of the genera Pulmonary mucormycosis ity against common fungi.
Rhizopus, Mucor, Surgical wound and burns infection Antifungal prophylaxis is commonly used to prevent invasive
Absidia) fungal infections in the ‘at-risk’ group of patients.
Polyenes
Malassezia furfur Cutaneous infection (especially in
Amphotericin B. Amphotericin, a member of the polyene
burn patients)
Fungaemia associated with total
group, is obtained from various species of Streptomyces.
parenteral nutrition Chemically, it is a large carbon ring of 37 carbon atoms closed
by a lactone bond. One side of the molecule contains seven

Table 43.6 Clinical presentation of systemic fungal infection

Condition Clinical presentation

Fungaemia (the presence Fever, low blood pressure and sometimes other features of septic shock, especially in patients with
of fungi in the bloodstream), neutropenia
usually due to Candida Relatively low-grade fungaemias such as those associated with colonised intravenous cannulae often
species present only with fever
Disseminated infection to multiple organ systems is quite common with Candida species, leading to
central nervous system disease, endocarditis, endophthalmitis, skin infections, renal disease, and bone
and joint infection

Pneumonia, most frequently Fever, chest pain and cough which may be non-productive; may progress rapidly, especially with
due to Aspergillus species Aspergillus infection, to severe respiratory distress, necrosis of the lung and pulmonary
haemorrhage
Formation of fungal balls in pre-existing lung cavities with or without invasion

Meningitis and other central Candida infection may present as a typical meningitis, although it is often more insidious
nervous system infection Aspergillosis is associated with headache, confusion and focal neurological signs due to the presence of
brain infarcts
Cryptococcosis most frequently presents as a chronic, insidious meningitis with headache and alteration
in mental state

Mucormycosis Angioinvasive; the most common presentation of mucormycosis is rhinocerebral infection

Initially an infection of the sinuses, it then spreads locally to the palate, orbit and eventually into the brain,
leading to encephalitis
Pulmonary disease can present as fungal balls radiologically with symptoms of haemoptysis
734
 FUNGAL INFECTIONS 43
Table 43.7 Antifungal spectrum of activity against common fungi

Antifungal agent

Organism AmBa Flu Itr Vor Pos Anidulafungin Caspofungin Micafungin Flucytosine

Aspergillus species + − + + + + + + −

A. flavus ± − + + + + + + −

A. fumigatus + − + + + + + + −

A. niger + − ± + + + + + −

A. terreus − − + + + + + + −

Candida species + + + + + + + + +

C. albicans + + + + + + + + +

C. glabrata + ± ± + + + + + +

C. krusei + − ± + + + + + ±

C. lusitaniae − + + + + + + + ±

C. parapsilosis + + + + + ± ± ± +

C. tropicalis + + + + + + + + +

Cryptococcus neoformans + + + + + − − − +

Coccidioides species + + + + + ±b ±b ±b −

Blastomyces + + + + + ±b ±b ±b −

Histoplasma species + + + + + ±b ±b ±b −

Fusarium species ± − − + + − − − −

Scedosporium apiospermum ± − ± + + − − − −

Scedosporium prolificans − − − ± ± − − − −

Zygomycetes ± − − − + − − − −

Plus signs (+) indicate that the antifungal agent has activity against the organism specified. Minus signs (−) indicate that the antifungal agent does not have activity
against the organism specified. Plus/minus signs (±) indicate the agent has variable activity against the organism specified.
aIncludes lipid formulations.
bIn vitro data show that the echinocandins (specifically, micafungin) may have variable activity against the dimorphic fungi, depending on whether they are in the

mycelial or yeastlike form.

AmB, Amphotericin B; Flu, fluconazole; Itr, itraconazole; Pos, posaconazole; Vor, voriconazole.
Adapted from Dodds Ashley et al. (2006).

carbon-to-carbon double bonds (polyene), and the other side con- Aspergillus terreus, Scedosporium spp., Trichosporon spp. and
tains seven hydroxyl groups. It dissolves in organic polar solvents Candida lusitaniae.
but forms a colloidal suspension of micelles in water which is ren- Pharmacodynamically, the ratio of the peak serum concentra-
dered stable by the addition of the surfactant sodium deoxycholate. tion to the MIC is important for its eficacy.
Amphotericin B binds to the ergosterol in fungal cytoplasmic Amphotericin B deoxycholate. Released in 1950, colloidal
membrane affecting its integrity by forming pores and, therefore, in nature, amphotericin B deoxycholate is highly protein bound
cell death. Nystatin, the other polyene, is only used topically (99%) and insoluble in water. It penetrates poorly into cerebro-
because of toxicity associated with its systemic use. spinal luid (CSF). Initial elimination of the drug occurs with a
Amphotericin is active against a vast majority of fungi, and half-life of 24–48 hours, but this is followed by very slow elimi-
this is the same for all formulations. Development of resistance nation (half-life about 14 days). As a consequence, it may take 10
is uncommon, although primary resistance has been identiied for weeks for the drug to disappear from the circulation. 735
 43 THERAPEUTICS

Amphotericin B deoxycholate is given by slow intravenous to experience more immediate side effects than with liposomal
(IV) infusion (manufacturer recommends between 2 and 6 hours) amphotericin. There is less clinical trial evidence for the use of this
in 5% dextrose with a dose range of 0.25–1 mg/kg increased to agent compared with the liposomal preparation. Amphotericin B
1.5 mg/kg for serious invasive infections. The duration of treat- colloidal dispersion (Amphocil) is a formulation consisting of
ment can vary from 1 to 2 weeks to longer, depending on the tiny discs of amphotericin and cholesterylsulphate. Like the lipid
severity of the infection and the organ system involved. complex, it too produces low peak serum levels but high liver
The most serious side effect of amphotericin is nephrotoxic- concentrations compared with the conventional drug. There is
ity. Renal failure should be monitored regularly at least every less clinical experience with this preparation than with the lipo-
other day, and if the serum creatinine exceeds 250 mmol/L, the somal preparation, and it appears to have a higher incidence of
drug should be discontinued until the creatinine level is below certain adverse reactions than conventional amphotericin.
this limit. Hypokalaemia is also a problem and may be severe, Choosing a lipid preparation. At present, the greatest clini-
necessitating replacement therapy. cal experience is with liposomal amphotericin B, and by reason
Azotaemia may be seen in patients after the irst few infusions of this and the reduced incidence of side effects it is the preferred
of amphotericin B deoxycholate. Chills, fever and tachypnoea may agent of the three in many UK centres. Ideally all patients who
occur but can be avoided by prescribing hydrocortisone 25–50 mg. require amphotericin would receive the conventional preparation
The manufacturer recommends that before commencing treat- initially, being changed to a lipid formulation only if they do not
ment, a 1 mg test dose should be given in 50 mL of 5% dex- respond to or cannot tolerate the side effects of the conventional
trose over a 20- to 30-minute period and the patient monitored form. However, the incidence of side effects and the dificulty in
for fever, rigors and hypotension. True allergic reactions are rare. administration of conventional amphotericin have in practice led
Amphotericin B lipid formulations. The advantage of deliv- to its replacement in most centres with a lipid formulation.
ering amphotericin encapsulated in liposomes or as a complex Other Antifungal Agent
with lipid molecules is that a higher unit dose can be given and Flucytosine. Amphotericin B and griseofulvin were the only
there is reduction in toxic effects. Three such preparations are systemic antifungal agents available until the early 1970s, when
currently available: liposomal amphotericin B (AmBisome), lucytosine became available for patient use.
amphotericin B lipid complex (Abelcet) and amphotericin B col- Flucytosine (5-luorocytosine) is a synthetic luorinated nucle-
loidal dispersion (Amphocil). otide analogue. The mode of action is twofold. Following uptake
Liposomal amphotericin B. In liposomal amphotericin B by the cell, which is dependent on the presence of cytosine per-
(AmBisome), the drug is contained in small vesicles, each mease, lucytosine is deaminated to 5-luorouracil by cytosine
consisting of a phospholipid bilayer enclosing an aqueous envi- deaminase. This in turn is incorporated into fungal RNA in place
ronment. This permits the delivery of higher doses (3 mg/kg of uracil, leading to impairment of protein synthesis. Further
once daily is recommended, but doses up to 10 mg/kg have been metabolism of 5-luorouracil leads to a metabolite that inhib-
used in some centres) compared with conventional amphoteri- its the enzyme thymidylate synthetase, leading to inhibition of
cin, with very little of the immediate toxicity which is such a DNA synthesis. Mammalian cells have absent or weak cytosine
problem with the conventional formulation. Higher peak serum deaminase activity which accounts for the selective toxicity of
concentrations are obtained with the liposomal formulation com- lucytosine.
pared with equivalent doses of the conventional drug, although For all practical purposes, lucytosine is only active against
it is not certain whether this is clinically relevant. Liposomal yeasts and yeastlike fungi. Inherent resistance occurs in approxi-
amphotericin is concentrated mainly in the liver and spleen, mately 10% of clinical isolates of Candida species, and acquired
where it is taken up by cells of the reticuloendothelial system. resistance develops rapidly if the drug is used alone. There are
Concentrations in the lung and kidneys are much lower, which several resistance mechanisms, some of which result from a
may or may not be clinically important. single-step mutation giving a high frequency of acquired resis-
There is reduced nephrotoxicity with this formulation, and tance in organisms exposed to the drug. For this reason, lucyto-
some of the renal dysfunction which has been described in clinical sine should always be given in combination with another agent
trials of liposomal amphotericin may have been due to concomi- such as amphotericin, with which it is synergistic.
tant drugs. Comparative clinical trials of liposomal amphotericin Flucytosine is highly soluble in water, and more than 90% of
versus conventional amphotericin B have shown reduced toxic- an oral dose is absorbed from the gastro-intestinal tract. Virtually
ity because of the liposomal preparation (Cagnoni, 2002; Hamill, all of the absorbed dose is excreted unchanged in the urine by
2013; Walsh et al., 1999). It is this comparative lack of toxicity glomerular iltration. The elimination half-life is about 4 hours,
which accounts for much of the popularity of this agent, despite but this is greatly prolonged in renal failure, and dosage modii-
its expense. This agent performs as well as the conventional prep- cation is required in patients with renal dysfunction. The degree
aration in patients with febrile neutropenia (Cagnoni, 2002). of protein binding is very low and lucytosine penetrates well into
Amphotericin B lipid complex and amphotericin B colloidal all tissues, including the aqueous humour of the eye, where about
dispersion. Amphotericin B lipid complex (Abelcet) is not a 10% of the serum level is achieved, and the cerebral spinal luid,
liposomal formulation, but consists of large sheets of amphoteri- where about 80% of the serum level is achieved.
cin combined with phospholipids. This formulation gives lower Flucytosine is given orally or by short IV infusion. The dosage
peak serum levels compared with the conventional drug because administered by either route in patients with normal renal func-
it is rapidly taken up by tissue macrophages, whereas concentra- tion is 100–200 mg/kg per day in four divided doses. This must
736 tions in the lungs and the liver are much higher. Patients seem be reduced in renal failure, but the degree of reduction depends
 FUNGAL INFECTIONS 43
on the degree of renal impairment, and it is obligatory to moni- some animals and is not recommended in pregnant women for
tor the serum levels of lucytosine. Unfortunately, because the relatively trivial infections such as a fungal urinary tract infec-
lucytosine assay is now rarely carried out routinely in UK labo- tion. In cases of a life-threatening fungal infection, which is
ratories, the sample is sent to a specialist laboratory. Monitoring rare in pregnancy, the potential beneits of lucytosine must be
is usually only carried out if there is a concern about the patient’s weighed against the possible risks.
renal function. Flucytosine is usually given in conjunction with Azoles
amphotericin, which will probably cause some degree of renal Systemic azoles: Triazoles. Four triazoles are licensed in the
dysfunction, therefore requiring modiication of the lucytosine UK: luconazole, itraconazole, voriconazole and posaconazole.
dose. Blood levels should be taken as per local guidelines to They differ substantially from one another in their pharmaco-
avoid dose-related marrow toxicity. kinetic and antifungal activity (Table 43.8). Their main side
Some of the side effects of lucytosine are given in Table 43.3. effects are listed in Table 43.3.
The most important toxic effect is a dose-related myelosuppres- The basic chemical structure of the triazoles is the azole ring, a
sion with neutropenia and thrombocytopenia. This is usually ive-membered ring containing three nitrogen atoms. Their princi-
reversible and can be avoided by monitoring serum levels of pal mode of action involves one of the nitrogen atoms of the azole
lucytosine and adjusting the dose accordingly. Hepatotoxicity is ring binding to fungal cytochrome P450 enzymes. This inhibits the
also probably a result of high serum levels, and liver function demethylation of lanosterol and leads to a reduced concentration of
tests should be performed regularly. The drug is teratogenic in ergosterol necessary for a normal fungal cytoplasmic membrane.

Table 43.8 Comparative pharmacokinetics of antifungal agents

Antifungal agent

Pharmacokinetic Anidu- Caspo- Mica- Flucyto-

parameter AmB ABCD ABLC LAB Flu Itra Vor Pos lafungin fungin fungin sine

Oral bioavailability <5 <5 <5 <5 95 50 96 ND <5 <5 <5 80

(%)

Food effect NA NA NA NA NE ES ES Food NA NA NA NE

Distribution

Total Cmax (micro- 0.5–2 4 131 0.1 0.7 11 4.6 7.8 0.83 0.27 0.24 80
grams/mL)

AUC (mg × h/L) 17 43 14 555 400 29.2 20.3 8.9 99b 119 158b 62

Protein binding (%) >95 >95 >95 >95 10 99.8 58 99 84 97 99 4

CSF penetration 0–4 <5 <5 <5 >60 <10 60 NR <5 <5 <5 75
(%)

Vitreal penetra- 0–38c,d 0–38c,d 0–38c,d 0–38c,d 28– 10c 38c 26c,d 0d 0c <1d 49d
tion (%) 75c,d

Urine penetration 3–20 <5 <5 4.5 90 1–10 <2 <2 <2 <2 <2 90
(%)e

Metabolism Minor Unknown Unknown Unknown Minor Hep Hep Hep None Hep Hep Minor
Hep Hep intestinal

Elimination Faeces Unknown Unknown Unknown Urine Hep Renal Fae- Faeces Urine Faeces Renal
ces

Half-life (h) 50 30 173 100–153 31 24 6 25 26 30 15 3–6

aData are for oral solution.
bFor dosages of 100 mg/day.
cHuman.
dAnimal.
ePercentage of active drug or metabolites.
ABCD, Amphotericin B colloidal dispersion; ABLC, amphotericin B lipid complex; AmB, amphotericin B; AUC, area under the concentration curve; Cmax, peak drug
concentration; CSF, cerebrospinal fluid; ES, empty stomach; Flu, fluconazole, Hep, hepatic; Itra, itraconazole; LAB, liposomal amphotericin B; NA, not applicable;
ND, no data; NE, no effect; NR, not reported; Pos, posaconazole; Vor, voriconazole.
Adapted from Dodds Ashley et al. (2006). 737
 43 THERAPEUTICS

The propensity, in humans, to also inhibit the metabolism of drugs pharmacokinetic/pharmacodynamics parameters, therapeutic drug
by cytochrome P450 results in a considerable number of drug monitoring is not required. Fluconazole is a substrate for inhibi-
interactions. tion of CYP450 isoenzymes, including CYP3A4, CYP2C9, and
Fluconazole. Fluconazole is available both orally and par- CYP2C19; therefore, medications should be reviewed for poten-
enterally and is used only in the treatment and prophylaxis of tial drug interactions. Amongst antibiotics, rifampicin is the single
infections due to yeasts and yeastlike fungi. It is not used for CYP450 inducer that has been shown to markedly reduce lucon-
the treatment of infections caused by moulds. It is highly effec- azole serum concentrations.
tive in the treatment of Cryptococcus infection, but the irst- Itraconazole. Itraconazole is available for both oral and IV
line treatment of cryptococcosis of the central nervous system use (IV formulation may not always be available). The drug is
(CNS) is the combination of amphotericin B plus lucytosine available as capsules and as a liquid; however, the liquid formu-
for CNS infection caused by this organism. This may be fol- lation gives better absorption and pharmacokinetic proile than
lowed by luconazole, which in HIV-infected patients will be the capsule preparation, leading to signiicantly greater bio-
required lifelong as suppressive treatment to prevent relapse. availability and higher serum levels. Systemic bioavailability of
In immunocompetent hosts, luconazole may be used as the itraconazole oral solution is around 55% optimised under fast-
primary treatment for disease not involving the CNS, such as ing conditions. Itraconazole is extensively metabolised by the
pulmonary infection. liver, predominantly by the CYP 3A4 isoenzyme system, and
In patients with candidaemia due to colonised IV cannulae, is known to undergo enterohepatic circulation. This is a broad-
the most important treatment is removal of the infected cannula, spectrum antifungal which is effective against yeasts, dermato-
but it is common practice to give a short course of luconazole phytes, the ‘pathogenic’ fungi and some ilamentous fungi, such
(until Candida speciation and susceptibility results are avail- as Aspergillus.
able) to prevent disseminated infection elsewhere. Although In deep-seated infection, itraconazole is used to treat infec-
not proven in randomised clinical trials, changing potentially tions caused by the ‘pathogenic’ fungi, but there is less published
infected central-line catheters in patients with candidaemia is evidence of its use in the treatment of systemic candidiasis,
probably the most important part of therapy. and it cannot be recommended for this purpose (Maertens and
In non-neutropenic patients, studies have shown luconazole Boogaerts, 2005). However, although not a irst-line agent for
and caspofungin to be as eficacious as and less toxic than con- systemic candidiasis, it may be useful in patients who are infected
ventional amphotericin B. In such patients, where the infect- with strains resistant to luconazole, some of which may remain
ing organism and its susceptibility to luconazole are known, it sensitive to itraconazole, and in patients who are for some rea-
would be reasonable to commence treatment with luconazole; son unable to tolerate luconazole. It has also been used to treat
caspofungin is a potential alternative. In patients with neutro- cryptococcosis, despite its poor penetration of CSF, and in that
penia and in patients infected with luconazole-resistant organ- condition it is an alternative to luconazole for patients who can-
isms, amphotericin continues to be the treatment of choice. not take the latter drug.
Fluconazole has also been successfully used as prophylaxis There is now considerable evidence to support the use of
against Candida infections in patients with neutropenia and itraconazole as a prophylactic agent in immunocompromised
patients with AIDS, but this in turn has been associated with an patients. It has been shown to be effective in reducing the inci-
increasing incidence of systemic infections with luconazole- dence of systemic fungal infection compared with placebo and
resistant strains. to be more effective than luconazole, although this is due to a
Some units that use luconazole extensively have noted an greater reduction in infections caused by ilamentous fungi,
increase in the isolation of yeasts resistant to the drug, with the including Aspergillus.
prevalence of resistance related to the extent of use of lucon- A loading dose of itraconazole 200 mg three times a day for 3
azole. Resistance in Candida species is mainly seen in patients days is administered to achieve steady-state serum concentration,
who are given long-term prophylactic luconazole. This selects followed by 200 mg daily or twice a day. Therapeutic drug moni-
out those Candida species such as C. krusei and C. glabrata toring is essential to optimise clinical eficacy for prophylaxis or
that are inherently less susceptible to luconazole. Resistance for treatment of invasive fungal infection.
in C. albicans, the most common species infecting humans, is Voriconazole. Voriconazole is available for both oral and IV
seen mainly in patients with AIDS, partly because of the exten- administration. It has advantages over itraconazole in that its
sive use of luconazole in treating severe oral and pharyngeal absorption from the gastro-intestinal tract is signiicantly better
candidiasis in such patients and partly because of the very large and is not affected by reductions in gastric acidity due to disease
numbers of yeasts in the oropharynx of patients with AIDS with or concomitant medication. Its spectrum of activity is similar
candidiasis, which increases the chance of resistance due to to that of itraconazole, but it is more active against Fusarium
spontaneous mutation. species, a mould which causes supericial infection of the nails
Depending on the type of deep infection and the organ involved, and cornea, and occasionally systemic infection in immunocom-
luconazole is used between the range of 200 and 800 mg/day. It promised patients.
is available for oral and IV use. Oral luconazole has very good Voriconazole given orally is rapidly and almost fully absorbed
bioavailability (nearly 90%) and with a long half-life of about (oral bioavailability >90%), with a maximum serum concentration
34 hours, it is given once a day. It has good penetration in most being achieved in about 2 hours after administration under fast-
tissues and all body luids including the CSF. Because there is ing conditions. It is extensively distributed into tissue and pen-
738 good correlation between clinical outcome and luconazole’s etrates well into the CSF and into vitreous and aqueous humour.
 FUNGAL INFECTIONS 43
It is cleared by hepatic cytochrome P450 metabolism and is target which does not exist in mammalian cells, providing selec-
involved in many clinically relevant drug–drug interactions. tive toxicity against fungi. Caspofungin has a signiicant advan-
Therapeutic drug monitoring may be indicated in some clinical tage over the triazoles in that it does not inhibit the cytochrome
settings. P450 system and, therefore, is not associated with such a wide
The main clinical indication for the use of voriconazole is range of drug interactions.
aspergillosis (Karthaus, 2011). Studies have shown improved The drug has a rather unusual spectrum of activity. It is active
eficacy compared with conventional amphotericin B in sys- against most species of Candida, although some are less suscep-
temic Aspergillus infection. The largest randomised control tible than others, but Cryptococcus is resistant. The commonly
trial demonstrates that voriconazole is superior to amphoteri- encountered species of Aspergillus are susceptible, but the drug
cin B deoxycholate as primary therapy of aspergillosis (Walsh is inactive against the dermatophytes, and activity against other
et al., 2008). One particular indication is cerebral aspergillosis. fungi is variable.
Although rare, this carries a high mortality rate (≥90%), and one Caspofungin is available only for administration via the IV
study has shown this to be reduced by voriconazole, presumably route and does not penetrate into the CSF. Due to its spectrum
because of its better penetration into the CNS (Schwartz et al., of activity, caspofungin is indicated only for empirical treatment
2005). In addition to aspergillosis, voriconazole is also licensed (in patients with neutropenia) and targeted treatment of candidia-
for the treatment of Fusarium infection and for the management sis and aspergillosis. A comparative study showed caspofungin
of patients infected with strains of Candida resistant to luco- to be as eficacious as conventional amphotericin B in invasive
nazole. It has been shown to be as eficacious as amphotericin candidiasis (Mora-Duarte et al., 2002). It has been shown to be
B followed by luconazole in the treatment of candidaemia in effective in patients with aspergillosis who did not respond to or
patients who were not neutropenic, but it is not licensed for this could not tolerate other antifungal agents. Finally, caspofungin
indication. was also shown to be as effective as liposomal amphotericin B
For invasive pulmonary aspergillosis, a loading dose of 6 mg/kg in the empirical treatment of fungal infection in patients with
IV every 12 hours for 2 doses was given followed by 4 mg/kg neutropenia, and it had a lower incidence of unwanted effects
every 12 hours and converted to oral therapy 200 mg every (Walsh et al., 2004). The dosage for adults is 70 mg on the irst
12 hours depending on clinical review to decide duration of day, then 50 mg once daily (70 mg once daily if body weight is
treatment. more than 80 kg).
Voriconazole has a side-effect proile similar to that of other Anidulafungin. Anidulafungin is only available for admin-
triazoles. Two adverse effects associated with voriconazole are istration via the IV route and is used in the treatment of inva-
visual disturbance (appearance of bright lights, colour changes or sive candidiasis in adult non-neutropenic patients (Reboli et al.,
wavy lines) in 45% of patients and cutaneous phototoxicity (rash) 2007). Like caspofungin, it does not penetrate into the CSF. It
in 8% patients. Both side effects are reversible after discontinu- is given as a single 200 mg loading dose by IV infusion on day
ation of therapy. 1, followed by 100 mg daily thereafter. No dose adjustment is
Posaconazole. Posaconazole is the latest triazole to be made required for renal or hepatic impairment.
available for clinical use. It has activity against a wide range of Micafungin. Micafungin is very similar to caspofungin and
yeasts (including Cryptococcus and many species of Candida) anidulafungin. It is used for treatment of candidaemia, invasive
and a variety of moulds. Like itraconazole, it is absorbed slowly, candidiasis in adults and children if other antifungals are not
is highly protein bound (>98%) and reaches a steady state after appropriate. It is also used for treatment of oesophageal candi-
a period of 7–10 days. In contrast with voriconazole, optimal diasis if IV therapy is required and for prophylaxis of Candida
absorption is achieved when taken with a high-fat meal. It is infections in immunocompromised patients following HSCT. It
available for oral use only in the form of tablets and oral suspen- is used between 1 and 3 mg/kg per day in patients ≤40 kg body
sion. Posaconazole penetrates very well in most tissues and luid weight and between 50 and 100 mg/day in greater than 40 kg
including CSF and the eye. body weight. No dose adjustment is necessary for renal or mild-
In adults it is indicated for treatment of invasive aspergillosis to-moderate hepatic failure.
and fusariosis refractory to amphotericin, chromoblastomycosis
and mycetoma refractory to itraconazole, and for prophylaxis
Choice of treatment
of invasive fungal infections in patients with HSCT with graft-
versus-host disease and haematological malignancies with pro- A recent development has been the use of combinations of anti-
longed neutropenia. fungal agents to improve on the results of single agents. Currently,
Posaconazole oral suspension is used 200 mg four times daily there is little irm evidence to support the use of such combina-
or 400 mg twice daily, and tablets are used 300 mg twice daily on tions. Amphotericin B plus lucytosine in the treatment of cryp-
irst day followed by 300 mg daily. tococcosis is the only combination where evidence exists of
Echinocandins. The echinocandin group of antifungal agents increased eficacy over either agent alone. However, faced with
acts by inhibiting synthesis of fungal cell wall glucan. a seriously ill patient who is not responding to single agents, it is
Caspofungin. Caspofungin was the irst of the echinocandins not surprising that many clinicians attempt the use of a combina-
to become available for routine use; others, such as micafun- tion of antifungals, even though the evidence is that the results
gin and anidulafungin, are now available. These agents inter- are no better than monotherapy.
fere with the production of the fungal cell wall by inhibiting the Practice points regarding the drug toxicity in systemic antifun-
synthesis of an important component, 1,3-β-d-glucan. This is a gal agents are detailed in Table 43.9. 739
 43 THERAPEUTICS

Table 43.9 Practice points

Drug toxicity in systemic antifungal agents

Infusion-related side effects • Particularly with conventional amphotericin B

• Lipid-based preparations also show these, but to a lesser extent

Nephrotoxicity • Particularly with conventional amphotericin B

• Results in renal dysfunction
• Cessation of treatment may be required
• Drug-level monitoring is not helpful in prevention
• Potassium loss and hypokalaemia are a serious complication
• Renal toxicity may be potentiated by concomitant nephrotoxic agents

Hepatotoxicity • Associated with the azole antifungals

• Was particularly severe with ketoconazole
• The newer triazoles may also cause serious liver damage

Bone marrow suppression • Associated with flucytosine

• Dose-related problem, so drug-level monitoring may help prevent it
• Tends to preclude the use of flucytosine in patients whose marrow is already damaged (e.g. in
haematological malignancy or following bone marrow transplant)

Drug interactions • Associated particularly with the azoles

• Due to their mode of action in inhibiting the cytochrome P450 system
• A wide range of drugs may be affected, some with serious interactions

Difficulties in drug administration

Drug precipitation • Amphotericin B will precipitate out if given in electrolyte-containing infusions

• This may also happen in 5% dextrose due to acidity resulting from the manufacturing
process

Need for a test dose • Required for all amphotericin B preparations

Long infusion times and/or large • A particular problem with conventional amphotericin
infusion volumes • Long infusion times mean reduced access to intravenous cannulae for other purposes
• Large infusion volumes may be undesirable in patients with renal or cardiac dysfunction

Variable absorption when taken • A known problem with itraconazole

by mouth • Absorption is reduced in the presence of raised gastric pH (e.g. following the use of antacids or
drugs such as omeprazole)
• Absorption is increased in the presence of food or if taken with a cola drink
• Subtherapeutic levels may occur because of poor absorption
• Therapeutic drug monitoring is recommended to avoid low levels

Resistance to antifungal agents

Amphotericin B • Usually seen as a very broad-spectrum antifungal, but inherent resistance is seen in several clinically
significant species:
Aspergillus terreus
Candida lusitaniae
Scedosporium apiospermum
• Acquired resistance developing during treatment is very uncommon
• Lipid preparations have identical in vitro antifungal activity to the conventional form

740
 FUNGAL INFECTIONS 43
Table 43.9 Practice points—cont’d

Flucytosine • Acquired resistance during treatment is very common in Candida species

• Monotherapy promotes the rapid development of resistance
• Combination therapy with amphotericin will reduce the possibility of acquired resistance developing
during treatment

Fluconazole • Some species of Candida are inherently resistant or less susceptible to fluconazole:
C. krusei
C. glabrata
• Long-term use of fluconazole may result in increased infections with these more resistant strains
• Long-term use may also result in reduced susceptibility in strains of C. albicans

Case studies Answer

Fungal infections of prosthesis and deep subcutaneous tissues are dif-
Case 43.1 ficult to treat. Mrs DM will need a two- or three-stage procedure. The
prosthetic joint will need removal, and antifungal treatment (depend-
Ms TH, a 66-year-old woman with carcinoma of the oesophagus, ing on sensitivity results) will be required for an 8- to 12-week period.
undergoes sub-total oesophagectomy. She spends the early post- Complete debridement of infected tissues, temporary stabilisation of
operative period on surgical intensive therapy unit (ITU) and is the femur and thorough washout of the joint will be required. In some
sent to the surgical ward for further management. On day 6 post- instances, the antifungal agent in orthopaedic cement can be used to
operation, she begins to show signs of sepsis, for which antibiot- pack the joint space along with systemic antifungal treatment. A new
ics are commenced. However, 48 hours later she has difficulty in total knee replacement can be planned for a minimum of 3 months
breathing, takes a turn for the worse and is transferred to ITU. (or longer if antifungal treatment is prolonged beyond 3 months for
Chest imaging revealed a leak from the oesophagectomy site and satisfactory clearance of the infection).
fluid collection in the pleural space. Gram stain of aspirated pleu-
Case 43.3
ral fluid reveals budding yeast cells, and mucopurulent sputum
Ms KR, a 27-year-old woman, visits her primary care doctor report-
culture grows Candida albicans.
ing that her toenails have become distorted and discoloured. It
looks unattractive, so she would like it corrected before her summer
beach holiday. The primary care doctor makes the clinical diagnosis
Question of tinea unguium (dermatophytosis of the nail), which is confirmed
How should Ms TH’s infection be managed? by laboratory culture of nail scrapings. The doctor knows that this
condition is unlikely to respond to topical treatment and therefore
consults the British National Formulary for a systemic agent. He
finds that griseofulvin, terbinafine and itraconazole are all available
Answer
for this condition. However, the situation is complicated by the fact
The immediate management of this patient would involve drainage that his patient tells him that she is trying to become pregnant and
of pleural fluid through an intercostal drain and commencement of does not want to take anything which might harm a baby. At this
systemic antifungal therapy. The source is very likely to be oral thrush. point, the doctor seeks specialist advice.
Fluconazole at 800 mg once a day, normally for 14–21 days, should
be commenced awaiting antifungal sensitivity result. Urgent patient
review is indicated to discuss surgical intervention to close the leak. Question
Re-collection of yeasts in inadequately treated spaces can be a
What is the most appropriate and safe treatment for Ms KR?
problem. It may be useful to consider the addition of a second anti-
fungal agent to fluconazole.
Answer
Case 43.2 This is a complex decision. Griseofulvin is contraindicated in preg-
nancy because of its known teratogenicity in animals; therefore, it
Mrs DM, a 38-year-old woman with diabetes, sustained severe is not an appropriate choice for Ms KR. Itraconazole should only
trauma to the right leg requiring total knee replacement and inser- be used in life-threatening situations where the potential benefits
tion of metal rod into the right femur. She had an uneventful post- to the mother outweigh the potential harm to the foetus (Actavis,
operative course. Four months later, she had to undergo washout 2016a). Therefore, it would be difficult to recommend itraconazole
and debridement of her prosthetic joint, thigh tissues and removal to Ms KR.
of the metal rod. Ten deep specimens grew Candida tropicalis. Terbinafine could be used if the potential benefit outweighs the risk
(Actavis, 2016b); foetal toxicity and fertility studies in animals suggest
no adverse effects. However, because this is not a serious condition,
Question treating Ms KR with terbinafine would be difficult to justify.
How should Mrs DM’s infection be managed? 741
 43 THERAPEUTICS

After some discussion, Ms KR decided that she wanted the condition Candida krusei is known to be resistant to fluconazole. It is difficult
treated more than she wanted to become pregnant and returned to to treat IV catheter and other line infections with systemic antibiotics
using her oral contraception. Griseofulvin decreases the effectiveness and antifungals alone. It is imperative that these lines are removed
of oral contraceptives, and there are reports of contraceptive failure and treatment given through temporary peripheral lines for at least
with imidazoles and oestrogens. Therefore, following this discussion 48 hours before a new central line is inserted. New lines are very likely
Ms KR decided to take a course of terbinafine. to become colonised with the same micro-organisms if inserted too
early. Both C. albicans and C. krusei can be treated with a lipid formu-
lation of amphotericin. The use of non-lipid conventional formulations
Case 43.4 of amphotericin should be avoided because Mr DF has a moderate
degree of renal failure. The duration of treatment should be decided
Mr DF, an 18-year-old boy with acute myeloblastic leukaemia, sus- by reviewing the patient daily; this would include imaging and echo-
tained 20% accidental burns injury on face, upper body and right cardiograms for up to 2 weeks to look for seeding of Candida in other
arm at a family barbecue. (He had only just recently left hospital organs. Choice of antifungals can be reviewed after antifungal sensi-
after successful antibiotic treatment for a febrile neutropenic epi- tivity is available, and amphotericin can be switched to caspofungin
sode post-chemotherapy.) if necessary.
Two weeks after admission to ITU for management of burns, Mr
DF underwent a septic episode with septic shock. A blood culture
was taken through a central line which showed Gram-negative Case 43.5
bacilli. He was commenced on broad-spectrum antibiotics. His
peripheral blood count was 3 × 109/L, and he had a markedly Mr TH, a 78-year-old male gardener, sustained an eye injury while
raised C-reactive protein level. Mr DF suffered a moderate degree cleaning out old dried plants from his client’s garden. He sustained
of renal failure. Two days later another blood culture was taken a laceration to the cornea and presented to eye casualty 48 hours
through an arterial line and showed yeast cells on Gram stain. after the incident. He was started on topical and systemic antibi-
IV fluconazole was added to his treatment. Culture growth from otics. A corneal scrape revealed no organisms on Gram stain but
the central line blood culture revealed Pseudomonas aeruginosa grew Fusarium species on culture plates 4 days later.
and C. albicans. The arterial blood culture grew Candida krusei.
Antifungal sensitivities have been requested.
Question

Question How will Mr TH be managed, and what are the further associated risks
to his eye?
How should Mr DF be managed?

Answer
Answer
If there is no bacterial growth, the antibiotics can be stopped. Topical
Treatment of infections in burn patients can be challenging because antifungal agents in the form of eye drops like natamycin or ampho-
the loss in skin integrity increases the risk of being colonised with vari- tericin B (if available) should be commenced and administered
ous endogenous and hospital-acquired bacteria and fungi. Patients frequently.
with haematological malignancies and chemotherapy treatment are The associated risk is from the spread of infection to the back of the
more vulnerable to opportunistic infections. eye with development of endophthalmitis. Urgent surgical vitrectomy
Ideally antibiotics should be avoided in a patient who has an inva- and washout, with instillation of intravitreal antifungal agent (ampho-
sive fungal infection because it is believed that killing the bacterial tericin B 5 micrograms) would be indicated, along with systemic anti-
flora helps fungi thrive in the absence of commensal competition. fungal therapy with amphotericin B 1.5 mg/kg or voriconazole 4 mg/
In this case, Mr DF has concomitant Gram-negative sepsis and lacks kg every 12 hours and converted to oral therapy 200 mg every 12
a strong bodily defence system because of his underlying disease hours.
condition.

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Cagnoni, P.J., 2002. Liposomal amphotericin B versus conventional am- tious Diseases Society of America. Clin. Infect. Dis. 48, 503–553.
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Eur. J. Med. Res. 16, 145–152. Walsh, T.J., Tepple, R.H., Donowitz, G.R., et al., 2004. Caspofungin versus
Maertens, J., Boogaerts, M., 2005. The place for itraconazole in treatment. J. liposomal amphotericin B for empirical antifungal therapy in patients
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