REVIEW
10.1111/j.1469-0691.2005.01217.x
Antimicrobial therapy for pulmonary pathogenic colonisation and
infection by Pseudomonas aeruginosa in cystic fibrosis patients
R. Cantón1, N. Cobos2, J. de Gracia2, F. Baquero1, J. Honorato3, S. Gartner2, A. Alvarez2, A. Salcedo4,
A. Oliver5 and E. Garcı́a-Quetglas3 on behalf of the Spanish Consensus Group for Antimicrobial Therapy
in the Cystic Fibrosis Patient*
1
Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal, Madrid, 2Unidad de Fibrosis
Quı́stica, Hospital Vall d’Hebron, Barcelona, 3Servicio de Farmacologı́a Clı́nica, Clı́nica Universitaria,
Pamplona, 4Sección de Neumologı́a Pediátrica, Hospital Materno Infantil Universitario Gregorio
Marañón, Madrid and 5Servicio de Microbiologı́a, Hospital Son Dureta, Palma de Mallorca, Spain
ABSTRACT
Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients.
The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density
is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological
culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be
performed at least every 2–3 months in patients with well-established colonisation, and always during
exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but
with no clinical signs of colonisation, should be with oral ciprofloxacin (15–20 mg ⁄ kg twice-daily for
3–4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment
can be used as an alternative), while patients with acute infection should be treated for 14–21 days with high
doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of
the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection ⁄ colonisation (pathogenic colonisation) in stable patients (aged > 6 years) should be with inhaled
tobramycin (300 mg twice-daily) in 28-day cycles (on–off) or, as an alternative, colistin (1–3 million units
twice-daily). Colistin is also a possible choice for patients aged < 6 years. Treatment can be completed with
oral ciprofloxacin (3–4 weeks every 3–4 months) for patients with mild pulmonary symptoms, or
intravenously (every 3–4 months) for those with severe symptoms or isolates with ciprofloxacin resistance.
Moderate and serious exacerbations can be treated with intravenous ceftazidime (50–70 mg ⁄ kg threetimes-daily) or cefepime (50 mg ⁄ kg three-times-daily) plus tobramycin (5–10 mg ⁄ kg every 24 h) or
amikacin (20–30 mg ⁄ kg every 24 h) for 2–3 weeks. Oral ciprofloxacin is recommended for patients with
mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity
are recommended and epidemiological control measures should be established.
Keywords
Colonisation, cystic fibrosis, Pseudomonas aeruginosa, pulmonary colonisation, review, therapy
Accepted: 7 April 2005
Clin Microbiol Infect 2005; 11: 690–703
Corresponding author and reprint requests: R. Cantón, Servicio de Microbiologı́a, Hospital Universitario Ramón y Cajal,
28034 Madrid, Spain
E-mail: rcanton.hrc@salud.madrid.org
*Grupo Español de Consenso del Tratamiento Antimicrobiano
del Paciente con Fibrosis Quı́stica, con participación de la
Sociedad Española de Fibrosis Quı́stica (SEFQ): J. Dapena,
L. Máiz, C. Vázquez; Sociedad Española de Neumologı́a
Pediátrica (SENP): C. Antelo, N. Cobos, S. Gartner, A. Salcedo;
Sociedad Española de Enfermedades Infecciosas y Microbiologı́a Clı́nica (SEIMC): R. Cantón, L. Martı́nez-Martı́nez and
A. Oliver; Sociedad Española de Quimioterapia (SEQ):
F. Baquero, E. Garcı́a-Quetglas, J. Honorato; Sociedad Española de Neumologı́a y Cirugı́a Torácica (SEPAR): A. Álvarez,
L. Borderı́as, J. de Gracia, M. Vendrell.
INTRODUCTION
The quality of life and life-expectancy of cystic
fibrosis (CF) patients have improved considerably
as a result of the control of bronchopulmonary
bacterial colonisations and exacerbations [1–3].
Pseudomonas aeruginosa is the most prevalent
organism in the airway colonisation of CF
patients. Up to 30% of patients aged < 2 years
can have positive P. aeruginosa cultures, and this
figure rises to 80% in patients aged > 18 years
[4]. P. aeruginosa colonisation, generally with
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Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 691
environmental isolates, occurs in a large number
of patients before the age of 3 years [5]. The
antibody response to this pathogen can be detected before cultures from respiratory tract samples
are positive for this organism [6]. Colonisation
occurs initially with low bacterial density nonmucoid morphotypes, which are usually susceptible to antimicrobial agents [6–9]. Later, and for a
variable period of time, cultures tend to provide
intermittent positive and negative results.
P. aeruginosa colonisation clearly has a negative
effect on pulmonary function [2,9–13]. Initially,
colonisation is associated with a slight reduction
in pulmonary function [14] but, as colonisation
progresses, the cell density and the collective
growth pattern of P. aeruginosa change and its
capacity for survival improves. There is a tendency for it to form complex multicellular
mucosa-attached aggregates (biofilms), and the
organism generates a large quantity of alginate
(mucoid phenotype), which results in an impediment to antimicrobial treatment and the phagocytic process [15]. Under these conditions,
pulmonary colonisation by P. aeruginosa becomes
chronic, with eradication becoming almost
impossible. Thus, this pathogen can be eliminated
only in the early stages [9].
A single basic P. aeruginosa genotype usually
persists throughout the lifespan of a CF patient
[16,17]. Despite this, there is genetic diversification in the different pulmonary compartments,
with the appearance of multiple colony morphotypes, auxotypes and sensitivity profiles for antimicrobial agents [16]. A high bacterial load, and
the change from a non-mucoid to a mucoid
morphotype, correlate with the production of
antibodies, accompanied by changes in pulmonary function parameters and a higher number of
exacerbations [18–20]. In contrast, pulmonary
function remains relatively stable in patients
without mucoid morphotype conversion [21].
Hyper-mutability is one of the factors that
characterises P. aeruginosa isolates from the lung
of the CF patient [22]. This property accelerates
the adaptation of this organism to the lung
environment, which facilitates the chronicity of
the process. Hyper-mutability also promotes the
early emergence of variants with a mucoid
morphotype and a modified antigenic structure
[23,24], as well as the emergence of antimicrobialresistant mutants that can be selected during
treatment, particularly in patients in an advanced
stage of CF [11,25]. In such circumstances, the
possibility of controlling colonisation with antimicrobial agents is severely hampered; thus, it is
critical to stop the progression of the initial
colonisation in order to avoid or delay the
development of a chronic infection.
MICROBIOLOGICAL ASSESSMENT
OF P. AERUGINOSA
BRONCHOPULMONARY
COLONISATION ⁄ INFECTION
Microbiological studies are generally performed
using sputum samples. In the absence of sputum,
retropharyngeal samples or bronchial aspirates
should be obtained. However, the diagnostic
value of the latter samples are inferior to that of
sputum. Bronchoalveolar lavage should be
reserved for assessing new treatments, or for
investigating patients who fail to respond to
treatment and have a poor evolution [26,27].
In patients with an early diagnosis of CF, it is
essential to undertake continuous microbiological monitoring that will permit early detection
of the initial P. aeruginosa colonisation. In these
patients, the aggressive use of antimicrobial
agents can prevent the persistence of colonisation and delay the establishment of chronic
infection [9,28]. Mucoid morphotype P. aeruginosa is usually detected, as a marker, at the start
of chronic infection [3]. This stage requires
treatment for maintenance and ⁄ or exacerbations
[2,29]. Although there is some controversy,
microbiological monitoring in the chronic phase
is essential for monitoring the colonisation
pattern and for determining the susceptibilities
of the different morphotypes [30]. In general,
antimicrobial treatment of exacerbation is based
on the findings of the most recent microbiological culture [31].
The practical ⁄ optimal frequency for performing a microbiological sputum culture is controversial [25,30–32]. A monthly, or at least
3-monthly, culture is advisable for patients
without evidence of P. aeruginosa colonisation,
in order to detect the initial colonisation event
and initiate early treatment. Cultures should be
taken from other patients whenever exacerbations present, or at least every 2–3 months in
periods without exacerbations [26,31,32]. Gramstains of sputum are not generally recommended, as they give no relevant information for
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703
692 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005
the CF patient [33]. The sputum sample must be
liquefied and homogenised before plating.
Microbial culture must include selective and
differential media for isolating Staphylococcus
aureus, Haemophilus influenzae and Burkholderia
cepacia, as well as general and differential media
for Gram-negative bacilli. Quantitative counting
of the different pathogens is recommended
whenever possible, particularly with exacerbations or when it is necessary to record treatment
effectiveness [34].
All P. aeruginosa morphotypes identified in the
culture should be tested for susceptibility to
antimicrobial agents [34,35]. The precise susceptibility testing method remains a matter of debate,
although there is consensus that incubation of
susceptibility tests should be for at least 24 h to
facilitate growth of mucoid and small-colony
variants. Methods must permit calculation of the
MIC. Microdilution is considered to be the standard, although not all automated systems incorporating the microdilution technique have
demonstrated their accuracy for testing P. aeruginosa CF isolates [6,36,37]. The difficulty of testing
the susceptibility of hyper-mutable strains has
been described recently [38]. The high frequency
at which spontaneous resistant mutants are generated makes it difficult to distinguish true resistance (produced by selection during previous
exposure to the antimicrobial agent) from that
produced by mutant selection during the susceptibility testing procedure, particularly when using
the microdilution technique. Etest and diskdiffusion techniques are useful for detecting
hyper-mutable strains and can differentiate
between these two effects [39]. The accuracy of
classical routine methods, which always use
planktonic bacteria and not those forming biofilm
growth, has also been debated [31,40,41]. At the
same time, the criteria used in the antibiogram
interpretation for defining the clinical categories
(susceptible, intermediate and resistant) have
been questioned, particularly for patients receiving inhaled antibiotherapy.
MICROBIOLOGICAL PATTERNS OF
P. AERUGINOSA PULMONARY
COLONISATION ⁄ INFECTION
The interaction between P. aeruginosa and the CF
patient (summarised in Fig. 1) is described normally as colonisation ⁄ infection, indicating the
pathogenic ambivalence of this organism in these
patients. ‘Colonisation’ usually refers to bacterial
development on a surface, often without a harmful effect [3]. In contrast, the term ‘infection’
indicates a pathogenic effect resulting from microbial invasion of the tissues, although this is rare in
CF patients [8], where it indicates a pathogenic
effect resulting from the mere presence of the
organism. Thus, ‘infection’ should be considered
as colonisation with pathogenic effects, resulting
from the biological exploitation of a large mucosal
surface by a bacterial population with a very high
cell density (> 1010 cells ⁄ g in the adult) [3,34].
Even without an active virulent process, such
heavy epi-mucosal (external to the host tissues)
colonisation is expected to produce a passive
pathogenic effect [3,42,43], and can be termed
‘pathogenic colonisation’. A population of this
size facilitates the appearance of bacterial variants, some of which develop antimicrobial resistance or hyper-express virulence factors (active
pathogenesis). It is obvious that reduction of the
bacterial mass should be beneficial for the host.
Initial colonisation (primary colonisation or
pioneer colonisation)
The term ‘initial colonisation’ corresponds to the
first documented contact between P. aeruginosa
and the host (first positive culture), but with
neither clinical evidence of infection nor appearance of specific antibodies (Table 1). Initial colonisation is usually with non-mucoid strains, and
there is no diversity in colonial morphotypes or
antimicrobial resistance, which is generally of
minor importance [7,8]. A positive culture
indicates that colonisation has reached a sufficient
level for detection, although the counts are usually still low. A negative culture after the first
positive culture can indicate: (1) an aborted initial
colonisation that has been spontaneously eliminated, as not all P. aeruginosa strains have the same
colonising capacity [43]; (2) a cryptic colonisation,
which could indicate that secretions from the
colonised pulmonary areas are not represented in
the sample or that the bacteria are so scarce that
they are not recovered in the culture [9]; or
(3) eradication of P. aeruginosa after treatment. The
reappearance of a positive culture after 1 year of
negative cultures following completion of antimicrobial treatment should be managed as a new
initial colonisation event.
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Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 693
Absence of
colonisation
1)
2)
Initial
colonisation l
Fig. 1. Summary of the sequence of
colonisation and infection events
involving Pseudomonas aeruginosa in
cystic fibrosis patients, and the
theoretical objectives of antimicrobial treatment at each stage.
3)
4)
5)
Sporadic
colonisation
Chronic
Infection/
colonisation
Exacerbation
Theoretical aims of antimicrobial treatment at each stage
1
2
3
4
5
Prevention of initial colonisation (prophylaxis treatment)
Eradication of initial colonisation
Clearance and tentative eradication of sporadic colonisation
Clearance of bacterial density in chronic infection/colonisation
Clearance of bacterial mass during exacerbations
Table 1. Microbiological patterns and criteria in pulmonary Pseudomonas aeruginosa colonisation ⁄ infection in cystic fibrosis
patients
Infection ⁄ colonisation
Definition
I: Initial colonisation (first
colonisation event or pioneer
colonisation)
First positive P. aeruginosa culture
Detection of the first positive
P. aeruginosa culture in the bronchial
tree. No clinical symptoms
or specific immunological
response
II: Sporadic or intermittent
colonisation
Intermittent presence of positive and
negative P. aeruginosa cultures in
consecutive samples after initial
colonisation. No signs of infection
or immunological response
Detection, within a period of
Possible recovery of strains with mucoid
6 months of the initial colonisation,
colonies and other colonial morphotypes
of a positive P. aeruginosa culture among
at least three cultures, with at least
1 month between each positive culture
III: Colonisation with
bronchopulmonary infection
Initial or sporadic colonisation with
presentation of clinical or
immunological signs of infection
As for initial or sporadic colonisation.
In patients without microbiological specimens, the
appearance or increase of antibodies in two successive
blood samples, with at least 3 months between each
sample, can be used as a diagnostic criterion
IV: Chronic colonisation
Persistent positive P. aeruginosa
cultures without new clinical signs
of infection, but with an
immunological response consistent
with the presence of P. aeruginosa
Detection within a period of 6 months
of a minimum of three positive
P. aeruginosa cultures, with at least 1
month between the positive cultures
Usually produced by strains with mucoid
colonies and other colonial morphotypes.
This is the common pattern during
advanced periods of the disease
As for chronic colonisation
In patients with microbiological
specimens, an increase of antibodies in
two successive blood samples can be used
as a diagnostic criterion
V: Chronic bronchopulmonary Presentation of clinical signs of
infection (exacerbation)
infection and an increased
immunological response during the
course of a chronic colonisation
Microbiological criteria
Sporadic or intermittent colonisation
Sporadic or intermittent colonisation occurs after
an initial P. aeruginosa colonisation event and is
indicated by intermittent positive and negative
cultures [25], albeit still in the absence of apparent
signs of infection or immunological response.
This stage can be defined microbiologically as a
6-month period following initial colonisation,
during which only one positive culture is obtained from a minimum of three cultures taken at
least 1 month apart (Table 1). Note that one
negative culture during a sporadic colonisation
phase should not be considered to indicate true
Comments
A positive culture following 1 year of negative
cultures after finishing treatment is considered as a
new initial colonisation. The strains are usually
non-mucoid colonies, with little diversity in
morphotypes or antimicrobial susceptibilities
elimination, since it generally reflects a low-grade
colonisation that cannot be detected in the culture,
or is a sampling effect derived from the heterogeneity of the samples cultured, some of which
might represent material from pulmonary areas
still free of colonisation. It is quite common in this
period to obtain mucoid strains and variability in
colony morphotypes [9].
Colonisation with bronchopulmonary infection
In this case, the initial or sporadic colonisation
stages are associated with clinical or immunological signs of infection. For the reasons mentioned
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703
694 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005
above, this might include patients who, even with
negative cultures, have a specific immunological
response.
Chronic colonisation
From the microbiological viewpoint, chronic
colonisation is considered to be established when
at least three cultures are positive for P. aeruginosa
among samples taken at least 1 month apart
during a 6-month period (Table 1). The immunological response in this phase is generally consistent with P. aeruginosa colonisation, and mucoid
colonies and a great variety of other morphotypes
are usually found [16,25]. Most frequently, chronic colonisation is the result of the progressive
adaptation of a bacterial clonal population to the
ecological niches of the lung, and leads to a large
bacterial mass that induces the pathogenic consequences of colonisation. Exacerbations, in which
the presentation of more virulent variants cannot
be excluded, usually coincide with increases in
the bacterial mass or with the emergence of
antigenic variants [3,44].
Chronic bronchopulmonary infection
Chronic bronchopulmonary infection is characterised by presentation with clinical signs of infection,
or by an increase in antibody titres, during the
course of a chronic colonisation. Cultures have the
same characteristics as during chronic colonisation. Antibody detection in successive blood samples can be used as a diagnostic criterion for
patients without microbiological cultures.
BACTERIAL ERADICATION AND
BACTERIAL CLEARANCE IN CF
PATIENTS
CF antimicrobial treatment is directed ideally at the
elimination of P. aeruginosa [2,29,45–47]. Microbiologically, presumptive eradication means at least
three consecutive negative cultures during the year
after treatment, with each one separated by a
minimum interval of 1 month (Table 1). In most
cases, bacterial eradication in cases of pathogenic
chronic colonisation is unobtainable, as it would
imply the elimination of all the ‘germ nuclei’,
including those established in areas with higher
nutritional resources. Cell multiplication probably
occurs preferentially in particular advantageous
juxtamucosal sites, so that an important part of the
intraluminal bacterial cells represent the product of
multiplication in these ‘germ nuclei’. Eradication
seems to be possible only during initial colonisation, and the likelihood is inversely proportional to
the microbial mass present in the lung [9]. If there is
an important intraluminal population, elimination
of the bacteria from the ‘germ nuclei’ will result in
their immediate replacement by intraluminal
bacterial cells. Moreover, a high bacterial inoculum
is difficult to eradicate with antimicrobial agents, as
the appearance of resistant mutants is also proportional to the bacterial cell density, which is particularly the case for hyper-mutators and
monotherapy. Also, when the inoculum is raised,
a part of the bacterial population exposed to an
antimicrobial agent becomes refractory to its killing effect—a state of ‘phenotypic tolerance’—and
can therefore survive the treatment [48]. The
presence of large microbial masses usually coincides with advanced stages of CF, anatomical
alterations and compartmentalisation of the colonised space, without an adequate interaction
between the antimicrobial agent and all the microbial cells [41]. Negative cultures during or after
antimicrobial treatment, particularly inhaled treatment, do not necessarily indicate true eradication.
Such negativity can reflect reduced bacterial counts
or carryover of antimicrobial agents in the sample
obtained. Even molecular methods can give false
indications of eradication [17].
The term ‘bacterial clearance’ delimits the
objective obtainable with antimicrobial treatment
during chronic colonisation, including periods of
exacerbation. A significant clearance of bacterial
load is defined as a reduction of at least two logs
in P. aeruginosa bacterial counts when comparing
cultures taken immediately before and after treatment [17,49,50]. A reduction in density and, more
rarely, negativity can be observed in non-quantitative cultures.
USE OF ANTIMICROBIAL AGENTS
IN P. AERUGINOSA LUNG
COLONISATION ⁄ INFECTION
Preferably, bactericidal drugs should be used to
reduce the bacterial cellular mass in cases of CF,
and they should, if possible, be fast-acting to avoid
the selection of resistant mutants and prevent
phenotypic tolerance. Bacterial death with some
antimicrobial agents, such as b-lactams, is
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Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 695
obtained only after prolonged contact with the
bacteria, independent of the concentration used,
but with others, such as aminoglycosides, is fast
and proportional to the dose [51]. The bactericidal
activity of fluoroquinolones is somewhat slower,
and is also proportional to the dose, but paradoxically, very high doses can be less efficient [52,53].
With colistin, the bactericidal activity is not quite
as rapid, but the lethal effect is proportional to the
dose [54]. As a general rule, in bactericidal drug
combinations, the effects of the individual drugs
are additive or synergic.
The antimicrobial agents must reach an adequate active concentration in the bacterial environment to give an efficient reduction in the bacterial
mass. Normally, a significant proportion of the
antimicrobial agent administered never reaches its
bacterial target, or its effect is reduced because of
the local physico-chemical conditions in the endobronchial environment. Reduction of the bacterial
mass is usually achieved only after the use of high
doses and a number of successive, correctly spaced
exposures to the bactericidal agents. As stated
above, part of the bacterial population may not be
in full contact with the antimicrobial agent, or may
enter a state of phenotypic tolerance. At this stage,
and in the absence of antimicrobial agents during
dose intervals or between cycles, the bacterial
population reacquires the capacity for death.
Different situations for use of antimicrobial
agents in CF patients can be distinguished, each
of which requires a different therapeutic approach.
• Prophylactic treatment. These protocols, established initially to prevent S. aureus colonisation,
do not constitute recommended routine practice,
as they have been associated with acquisition of
P. aeruginosa in a high percentage of patients [55].
Antimicrobial agents have only been used occasionally with the intention of delaying the initial
P. aeruginosa colonisation event, and their benefits have not been assessed properly [47].
• Treatment of initial colonisation. Aggressive initial
treatment can eradicate P. aeruginosa, with cultures remaining negative for several years after
therapy [9,13,17,56,57]. Previous strategies using
intravenous antimicrobial agents for 2 weeks
[55] or a sole oral (ciprofloxacin) [58] or nebulised
(colistin or tobramycin) antimicrobial agent
[2,59,60] have now been replaced by combined
oral and inhaled treatment [2,28,61]. The duration of this strategy is not standardised, and
varies from 3–4 weeks to 6–12 months.
• Treatment of chronic colonisation (maintenance or
chronic suppressive therapy). Maintenance therapy aims to minimise the harmful effects
produced by the presence of heavy P. aeruginosa colonisation even in the absence of exacerbations [30]. It is directed towards a decrease
in the bacterial load, passive release of proinflammatory substances, and a reduction in
the consequent inflammatory response. This
approach not only avoids deterioration in
pulmonary function, but also helps in its
recovery [62]. There are differences of opinion
regarding the options, and even as to whether
antibiotics should be administered. Some CF
units have promoted the regular use of intravenous b-lactams every 3–4 months, regardless
of the respiratory symptoms [63]. The results,
although promising, have not formed part of
controlled clinical trials [64]. Although continuous colistin (1–3 million units ⁄ 12 h) or tobramycin (80 mg ⁄ 12 h) inhalation seems to
produce a beneficial effect in the evolution of
the chronic infection [65,66], the inhaled nonphenol tobramycin formulation (300 mg ⁄ 12 h)
in 28-day cycles (on–off cycles) has been shown
to give a clear improvement in pulmonary
function, and a consistent decrease in
P. aeruginosa density in the sputum [67].
• Treatment of acute respiratory exacerbations. It is
accepted generally that if the patient has two
or more of the symptoms or signs included in
Table 2, then antimicrobial therapy should be
started to avoid further deterioration of pulmonary function [31]. Treatment of acute
exacerbations is aimed at immediate reduction
of the bacterial inoculum, which is frequently
higher than the average colonisation levels
[46]. The recommended drugs are anti-pseudomonal penicillins (piperacillin, ticarcillin) or
cephalosporins (ceftazidime, cefepime), a
monobactam (aztreonam) or a carbapenem
(imipenem, meropenem, but not ertapenem),
in combination with an aminoglycoside (usually tobramycin) for 2–3 weeks [47,68]. The
treatment should be intravenous, except for
mild exacerbations, when oral drugs are indicated [29]. In this case, there should be an
interval of at least 3 months between the cycles
to reduce the possibility of resistance becoming
established. For chronic P. aeruginosa colonisation, inhaled antimicrobial agents should be
maintained if they are already being used [69].
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696 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005
Table 2. Symptoms and signs used to define exacerbations
in cystic fibrosis patients
Symptoms
Increased cough
Increased sputum production and ⁄
or change in colour
Increased respiratory difficulty and
decreased tolerance of physical activity
Haemoptisis
Anorexia, tiredness and loss of weight
Increased sensation of ‘thoracic congestion’
Signs
Fever ‡ 38C on more than one occasion
in the previous week
Deterioration of FEV1 of > 10% (spirometry) with
respect to basal volumes obtained in the last 3 months
Deterioration of haemoglobin saturation of > 10%
(oximetry) with respect to basal values of the last 3 months
Changes in pulmonary auscultation
Increased trapped air or presentation of new radiological infiltrates
Modification or increase in antibodies against P. aeruginosa
the clinical viewpoint, the beneficial effect on
pulmonary function is maintained during the rest
periods. Such dosing intervals are also microbiologically justified, as the rest periods facilitate
overgrowth of the susceptible and non-hypermutable populations, which tend to grow better
than the resistant and hyper-mutable populations
in the absence of antibiotic selection, thus reducing their displacement by resistant populations.
ANTIMICROBIAL TREATMENT IN
PRACTICE: PROTOCOLS TO
CONTROL P. AERUGINOSA
COLONISATION ⁄ INFECTION
FEV1, forced expiratory volume in 1 s.
There is scarce experience with inhaled administration during acute exacerbations.
The risk of developing resistance must be considered in the choice of therapy. In CF patients
chronically colonised with P. aeruginosa, there is no
single antimicrobial agent for monotherapy that is
capable of preventing the development of resistance, particularly when administered systemically. This fact is even more evident in bacterial
populations that include hyper-mutators [38]. As a
result, the use of combinations is recommended
strongly, whenever possible, to avoid a greater
development of resistance and to obtain a synergic
effect. Possible exceptions may be inhaled antimicrobial agents, such as tobramycin, as the concentrations reached in the respiratory airway are up to
100-fold higher than those reached with systemic
administration, and are usually higher than the
mutant prevention concentration for most P. aeruginosa strains [70]. However, generalised use for
prolonged periods can, in some cases, result in a
gradual increase in the MIC to > 128 mg ⁄ L, which
is the cut-off value of resistance proposed for
nebulised tobramycin [49,62,71,72].
The first evidence that maintenance therapy in
CF patients with chronic P. aeruginosa colonisation
reduces progressive pulmonary deterioration was
found when comparing patients receiving intravenous antimicrobial agents in three or four
programmed yearly cycles with patients receiving
them only during exacerbations [63]. There have
been many studies with inhaled formulations,
particularly tobramycin, that have obtained good
short- and long-term results [62,73]. The recommended regimen includes alternate 4-weekly
cycles of treatment and no treatment [62]. From
Treatment of patients following the first
isolation of P. aeruginosa
The aim of treatment is the eradication of P.
aeruginosa in order to delay chronic colonisation
[9,28,61,74]. There are two possible situations,
depending on the clinical state of the patient
(Table 3).
Stable patient with or without mild respiratory
symptoms
Treatment should be initiated with oral ciprofloxacin (30–40 mg ⁄ kg ⁄ day) divided into two doses
(maximum 2 g ⁄ day) for 3–4 weeks, regardless of
the age of the patient, combined with inhaled
tobramycin or colistin [28,60,61,75]. Intravenous
treatment can be used as an alternative, with or
without inhaled treatment [17]. A sputum culture
should be performed 1 month after the start of
treatment; if this culture is negative, the inhaled
treatment should be maintained for at least
6–12 months to avoid early reoccurrence,
whereas, if the culture is positive, the treatment
cycle should be repeated. When colistin is used,
the dose should be increased, as should the
frequency of administration. A new sputum
culture should be performed at the end of the
second cycle and, if this is still positive, the
protocol for chronic colonisation should be
applied. An antibiogram should be determined
for positive P. aeruginosa cultures and, if resistance is detected, the antimicrobial treatment
should be adapted accordingly.
Patient with acute infection
The cycle should be initiated with high doses of
two intravenous antimicrobial agents, a b-lactam
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Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 697
Table 3. Antimicrobial treatment for Pseudomonas aeruginosa colonisation and infection
Clinical situation
Preferred treatment
First positive P. aeruginosa culture
Without clinical signs
Oral ciprofloxacin,
30–40 mg ⁄ kg ⁄ day,
3–4 weeks
+
Inhaled tobramycin,
> 6 years: 300 mg ⁄ 12 h
< 6 years: 80 mg ⁄ 12 h
or
Inhaled colistin,
1–3 million U ⁄ 12 h
Acute infection
Comments
IV treatmenta ± inhaled treatmentb
A culture should be taken after treatment for 1 month:
if negative, inhaled treatment should be maintained
for 6–12 months while negative cultures persist;
if positive, a new oral and inhaled therapeutic cycle
should be started, or IV treatmenta ± inhaled
treatment. A new culture should then be performed
and, if still positive, the patient should be treated as
for chronic colonisation
IVa treatment,
14–21 days
±
Inhaled treatmentb
Chronic P. aeruginosa colonisation
Stable clinical situation
> 6 years:
Inhaled tobramycin, 300 mg ⁄ 12 h
with alternate cycles (on–off, 28 days)
< 6 years:
Inhaled tobramycin, 80 mg ⁄ 12 h
without alternate cycles
or inhaled colistin, 1–3 million U ⁄ 12 h
Exacerbation stage
Alternative
Commence inhaled treatment during or at the end of IV
treatmenta
For multiresistant strains, treatment should be adapted
for the susceptibility profile
After clinical post-treatment remission, another culture
should be taken and criteria applied as above
Inhaled colistin,
1–3 million U ⁄ 12 h
±
Oral ciprofloxacin,
2–4 weeks every
3–4 months
IV ceftazidime,
50–70 mg ⁄ kg ⁄ 8 h
or
IV cefepime,
50 mg ⁄ kg ⁄ 8 h,
2–3 weeks
+
IV tobramycin,
5–10 mg ⁄ kg ⁄ 24 h
or
amikacin,
20–30 mg ⁄ kg ⁄ 24 h,
2–3 weeks
Maintain inhaled regimen while the risk ⁄ benefit ratio
is favourable
For cases of moderate pulmonary involvement, oral
ciprofloxacin can be added for 3–4 weeks every 3–4
months
For cases of severe pulmonary involvement or
ciprofloxacin resistance, change to an IV treatmenta
regimen (cycles every 3–4 months). IV treatmenta can be
used in any state of chronic colonisation
Maintain inhaled regimen if previously established
Prolong IV treatment if no improvement or severe
involvement
For mild exacerbation, oral ciprofloxacin should be
administered 30–40 mg ⁄ kg ⁄ day, 2–3 weeks
For multiresistant isolates, treatment should be adapted
to the susceptibility profile
a
Treatment as in exacerbation.
b
Tobramycin or colistin.
IV, intravenous.
(ceftazidime or cefepime) and an aminoglycoside
(tobramycin or amikacin), for 14–21 days,
depending on the clinical response [17,76,77].
An inhaled treatment can be given during or at
the end of the intravenous treatment. The duration is as mentioned above. The aminoglycosides
should be administered in a single daily dose [78].
If multiresistant P. aeruginosa is isolated, antimicrobial agents retaining activity in the antibiogram should be used. In such cases, intravenous
colistin is an alternative, despite its potential
nephrotoxic and neurotoxic risks. Ciprofloxacin
should be reserved for oral administration. The
intravenous antimicrobial cycle must be repeated
if the first culture after treatment is positive for P.
aeruginosa. If the culture is negative, inhaled
treatment must be maintained for at least 6–
12 months to avoid early reoccurrence.
Maintenance treatment after development of
chronic P. aeruginosa infection ⁄ colonisation
Stable patient
The aim of the maintenance treatment in such
cases is to avoid respiratory exacerbations and
delay progression of the pulmonary disease [93].
The patients usually have few clinical respiratory
symptoms. Treatment with inhaled tobramycin
(300 mg ⁄ 12 h) in 28-day cycles with rest periods
of 28 days is advised [62], or as an alternative,
colistin (1–3 million units ⁄ 12 h) [49,79,80] (Table 3). Colistin is also a possible choice for patients
aged < 6 years. The length of inhaled treatment is
not defined clearly, and treatment should be
maintained while the risk ⁄ benefit ratio is favourable. Treatment can be completed in cases with
moderate pulmonary symptoms with the oral
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703
698 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005
administration of ciprofloxacin for 3–4 weeks
every 3–4 months [2,58], or with an intravenous
programme every 3–4 months when the effects are
severe or ciprofloxacin resistance is detected [81].
Treatment of patients with exacerbations
The aim of treatment in such cases is a return to
the basal situation presented by the patient before
the exacerbation, coupled with a decrease in the
inoculum (clearance) of P. aeruginosa in the sputum [29,46,82,83]. Moderate and serious exacerbations must be treated with intravenous
antimicrobial agents [3,31,68], while oral antimicrobial agents (ciprofloxacin at the same dose and
duration as for first isolations) are recommended
for patients with mild pulmonary disease.
The choice of intravenous antimicrobial agents is
usually based on the most recent set of microbiological results obtained before the exacerbation.
The combined use of two antimicrobial agents for
2–3 weeks is usually recommended (Table 3),
although this can be prolonged in special cases
(e.g., severe exacerbation without improvement, or
patients with severe pulmonary effects in a basal
situation). The patient can be treated in hospital or
at home [47,62,68]. Hospital treatment is necessary
for patients with severe exacerbation, haemoptysis
or an incapacity to undertake domiciliary treatment, or for patients who require intensive physiotherapy or other supportive therapies.
Domiciliary intravenous therapy is becoming more
common, as it reduces the number of hospital
admissions and allows the patient a better quality
of life [84–86]. Patients suitable for domiciliary
treatment are those with moderate exacerbations,
normal renal function, no requirement for any
other type of therapeutic support, no adverse
reactions and good vein status. The first dose
should be administered in hospital, with weekly
follow-up visits recommended. Patients receiving
inhaled antimicrobial treatment should usually
maintain this regimen during intravenous treatment, and renal function must be monitored [62].
Administration of inhaled antimicrobial agents is
contraindicated in patients with haemoptysis.
Use of antimicrobial agents with
immunomodulating activity
Use of azithromycin, 250 or 500 mg three-timesweekly, has been recommended for patients with
chronic P. aeruginosa colonisation [87], as use of
this agent has been shown to result in a decrease
in the number of exacerbations and improvement
in pulmonary function. As neither a bacteriostatic
nor a bactericidal effect of macrolides against
P. aeruginosa has been reported, it has been
suggested that an anti-inflammatory effect is
responsible for the observed improvement in CF
patients [88,89]. Moreover, it has been shown that
macrolides may limit the quorum-sensing interbacterial signals that affect the pathogenicity of
P. aeruginosa and its capacity to form biofilms [90].
It has also been suggested that the combination of
macrolides with anti-pseudomonal antimicrobial
agents may have a synergic effect.
Combination of P. aeruginosa with B. cepacia
or other Gram-negative bacteria
Antimicrobial treatment is more difficult when
there is co-infection with P. aeruginosa and B. cepacia
because of the inherent multiresistance of the latter
organism. A combination of three drugs, including
a b-lactam (meropenem or ceftazidime), ciprofloxacin, chloramphenicol, minocycline or rifampicin, can be beneficial for some patients. B. cepacia is
not susceptible to colistin, and rarely to aminoglycosides, although the use of amikacin in combination with two other antimicrobial agents has been
recommended on some occasions [80]. In many
cases, in-vitro susceptibility or resistance does not
guarantee clinical success or failure. Stenotrophomonas maltophilia and Achromobacter xylosoxidans
are also resistant to most antimicrobial agents, but
are usually susceptible to trimethoprim–sulphamethoxazole, which is considered to be the drug of
choice. The use of minocycline, doxycycline, moxifloxacin, levofloxacin and ticarcillin–clavulanic
acid has also been recommended. Different combinations are recommended for A. xylosoxidans,
including piperacillin–tazobactam, an aminoglycoside and a fluoroquinolone [91].
ASSESSMENT AND
EPIDEMIOLOGICAL CONTROL
MEASURES FOR THE CF PATIENT
WITH P. AERUGINOSA
COLONISATION ⁄ INFECTION
Before, during and after antimicrobial treatment
Different parameters can be used to assess the
response to treatment of P. aeruginosa pathogenic
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703
Cantón et al. Antimicrobial therapy for P. aeruginosa in CF patients 699
colonisation. Clinical parameters are related to the
subjective symptoms and signs of respiratory
exacerbation, tolerance to physical activity, appetite, stature, subjective changes in the sensation of
dyspnoea or the usual respiratory frequency, and
new pulmonary auscultation findings. Adequate
response to treatment is defined by the number of
exacerbations and the need for hospital admissions and intravenous treatment. Analytical
parameters are necessary in some cases, particularly serological monitoring of antibodies
against P. aeruginosa. These are of great interest
for neonatal screening programmes, as initial
colonisation can be detected up to 6–12 months
before detection of P. aeruginosa in culture [92].
Measurement of exhaled CO (an indicator of
inflammation) can be useful, particularly when
assessing the response to treatment [93].
Among the functional parameters, the forced
expiratory volume in 1 s (FEV1) is helpful for
studying the progression of pulmonary disease,
and has a good correlation with mortality in CF
[18,94]. The annual deterioration index of this
parameter is also useful [95]. Although forced
vital capacity (FVC), FEV1 and the FEV1 ⁄ FVC
ratio are reproducible parameters, they are not
very sensitive. To detect initial changes so that
early aggressive treatment can be commenced,
calculation of the forced expiratory flow rate
between 25% and 75% of the vital capacity
(FEF25)75) can be useful, as can other techniques
for measuring effects on the small airway and
pulmonary hyper-insufflation markers (residual
volume ⁄ total pulmonary capacity [96]. Techniques for neonates and infants should be directed at assessing pulmonary volumes and forced
expiratory flows [97].
Microbiological parameters should assess bacterial density, as well as the presence of mucoid
morphotypes and strains that are multiresistant
or have a high capacity for transmission [68,98].
Antimicrobial susceptibilities can be extremely
helpful, although they are not always adequate
for predicting the success of antibiotic therapy, as
treatment response can vary independently of the
in-vitro results [30,99].
The parameters in imaging tests, such as the
appearance of new signs in the chest X-ray, can
also be of interest. High-resolution computed
tomography has been used for diagnosing incipient signs of the disease [100] and also for
assessing the response to intravenous treatment
[101]. Ventilation scintiscan can be a useful tool
for early diagnosis, as it detects objective changes
and can give a prognosis of pulmonary deterioration.
Eradication controls
Assessment of eradication should not be based on
a single culture at the end of treatment, but rather
on long-term monitoring. In general, eradication
following treatment of CF patients with initial
P. aeruginosa colonisation is demonstrated by
negative cultures over a prolonged period and
anti-pseudomonal antibodies that remain or
become negative [56]. If P. aeruginosa reappears
after its theoretical eradication, molecular typing
studies are advisable to determine whether persistent colonisation has remained undetected by
culture, or whether re-infection by a new strain
has occurred [17].
Epidemiological control measures
The environment constitutes a source of P. aeruginosa that will colonise the respiratory tract of the
CF patient. It is necessary, particularly for noncolonised patients, to avoid possible contact with
other colonised patients (including other CF
patients or adults with chronic bronchitis and
bronchiectasis), and to minimise the uptake of
drinks and non-cooked foods that may be colonised by Pseudomonas (including water or milk in
open containers outside a refrigerator), as well as
contaminated systems or drugs used in inhalation
treatment [102]. Therefore, epidemiological control should focus on the protection of CF patients
by avoiding acquisition and minimising the
sources and routes of transmission of
P. aeruginosa. Protective measures should be
applied in the daily life of the patient, during
hospital admission, during management in the
outpatient clinics and in domiciliary treatment.
Standard precautions and epidemiological controls are also applicable to CF patients, although
the following patient features, site of colonisation
and the characteristics of the pathogens involved
should be taken into account [102]:
• All CF patients can harbour transmissible
organisms in the respiratory tract, including
P. aeruginosa. Standard precautions should be
taken to avoid acquisition and transmission to
other patients, with special attention paid to
2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 690–703
700 Clinical Microbiology and Infection, Volume 11 Number 9, September 2005
•
•
•
•
•
the airway route. Many methods have been
tried in CF patients to avoid transmission of
B. cepacia [102], but there is still no consensus
regarding the best approach for P. aeruginosa.
Nevertheless, they should be of the same level
when multiresistant P. aeruginosa is isolated.
Although there is no supporting evidence,
epidemiological measures should be prolonged following eradication or during a
course of antimicrobial therapy.
In order to prevent person-to-person spread,
there must be rigorous infection control practices. Hand-washing by all staff coming into
contact with the patients is crucial, as are the
cleanliness of the stethoscope, changing of
sheets between patients, and the use of gloves
in the handling of objects and devices potentially contaminated with respiratory secretions.
The use of masks and caps by staff is recommended during examination procedures and
monitoring of respiratory parameters.
General hygiene measures should be applied
(sterilisation ⁄ disinfection) [103] for equipment
that comes into contact with CF patients,
particularly in the respiratory tract, such as
humidifiers, nebulisers and compressors. These
measures should be applied in both the hospital
and external environment, and should be extended to surfaces and places where respiratory
function tests are performed.
Management and follow-up of ambulatory
patients should be undertaken according to
their colonisation pattern. It is recommended
that outpatient consultations and functional
tests should be organised to avoid contact
between patients and minimise the possibilities
of transmission. In the case of P. aeruginosa
colonisation, stratified appointments of patients
on different days has been applied successfully
[28].
Hospital inpatients colonised with multiresistant P. aeruginosa should be subjected to barrier
control measures similar to those applied to
patients colonised with methicillin-resistant
S. aureus [102]. Moreover, segregation of patients colonised with multiresistant P. aeruginosa should be considered, similar to that
applied to patients colonised with B. cepacia.
Epidemiological control measures should
include microbiological cultures for monitoring
and follow-up of colonisation at least once
every 2–3 months, whenever there are exacer-
bations and when changes are noted in the
clinical status or during hospitalisation.
Assessing clonality in P. aeruginosa populations
Clonality studies have been essential in demonstrating the high variability that exists between
P. aeruginosa isolates from different patients, the
persistence of the same clonal type in the same
patient, and, rarely, simultaneous colonisation
with different clones [5,6,44,98]. This analysis is
also important for documenting the start of
chronic colonisation in patients for whom eradication treatment following the first isolation of
P. aeruginosa has failed, for demonstrating crosscolonisations between patients, or for identifying
hyper-transmissible clones [5,17,99,102]. Techniques with high reproducibility and discriminatory power should be used, such as pulsed-field
gel electrophoresis or PCR-based techniques
[5,98,102].
Control of emergence of multiresistant isolates
Monitoring of susceptibility profiles and the possible selection of resistant variants in chronically
colonised P. aeruginosa patients should be performed at least every 3 months in cases of exacerbation, during hospital admission, or when there
are doubts about the response to therapy [31,33].
This practice allows close follow-up of the patients
and monitoring of the possible spread of multiresistant organisms between patients [25,71,101].
Every CF unit should record statistics, participate
in national registers, and record susceptibility
patterns for the various antimicrobial agents
[25,71,101]. The relationship of susceptibility patterns to antimicrobial treatment protocols permits
identification of the possible influence of certain
regimens in the selection of antimicrobial-resistant
organisms [55,57], and provides the necessary
feedback to allow the design of alternative strategies for controlling pathogenic colonisation and
infection of CF patients with P. aeruginosa.
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