Neumococo en Nac

Published online: 2020-06-13
The Role of Streptococcus pneumoniae in CAP

Charles Feldman, MBBCh, DSc, PhD, FRCP, FCP (SA)1 Ronald Anderson, PhD2
1 Department of Internal Medicine, Faculty of Health Sciences, Address for correspondence Charles Feldman, MBBCh, DSc, PhD,
University of the Witwatersrand, Johannesburg, South Africa FRCP, FCP (SA), Department of Internal Medicine, Faculty of Health
2 Department of Immunology and Institute of Cellular and Molecular Sciences, University of the Witwatersrand Medical School, 7 York
Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Road, Parktown, 2193 Johannesburg, South Africa
South Africa (e-mail: charles.feldman@wits.ac.za).
Semin Respir Crit Care Med
Abstract With the notable exceptions/of the United States and Canada in particular, the global
burden of disease in adults due to invasive infection with the dangerous respiratory,
bacterial pathogen, Streptococcus pneumoniae (pneumococcus) remains. This situation
prevails despite the major successes of inclusion of polysaccharide conjugate vaccines
(PCVs) in many national childhood immunization programs and associated herd
Downloaded by: Imperial College London. Copyrighted material.

protection in adults, as well as the availability of effective antimicrobial agents.
Accurate assessment of the geographic variations in the prevalence of invasive
pneumococcal disease (IPD) has, however, been somewhat impeded by the limitations
imposed on the acquisition of reliable epidemiological data due to reliance on often
insensitive, laboratory-based, pathogen identification procedures. This, in turn, may
Keywords result in underestimation of the true burden of IPD and represents a primary focus of
► antibiotic resistance this review. Other priority topics include the role of PCVs in the changing epidemiology
► β-lactams of IPD in adults worldwide, smoking as a risk factor not only in respect of increasing
► cigarette smoking susceptibility for development of IPD, but also in promoting pneumococcal antibiotic
► fluoroquinolones resistance. The theme of pneumococcal antibiotic resistance has been expanded to
► inflammation include mechanisms of resistance to commonly used classes of antibiotics, specifically
► macrolides β-lactams, macrolides and fluoroquinolones, and, perhaps somewhat contentiously,
► persistent the impact of resistance on treatment outcome. Finally, but no less importantly, the
antigenemia role of persistent antigenemia as a driver of a chronic, subclinical, systemic
► pneumococcal proinflammatory/procoagulant phenotype that may underpin the long-term sequelae
conjugate vaccine and premature mortality of those adults who have recovered from an episode of IPD, is
► vaping considered.
Streptococcus pneumoniae As a Cause of CAP and respiratory syncytial virus. In 2016, there were
2,377,697 deaths (2,145,584–2,512,809) from LRTIs in peo-
The Global Burden of Disease Study 2016 estimated the ple of all ages in those countries, with the pneumococcus
global, regional, and national morbidity and mortality, as identified as being the most common cause of LRTI morbidity
well as the etiologies of lower respiratory tract infections and mortality, causing more deaths than all the other
(LRTIs; defined as pneumonia or bronchiolitis) in 195 coun- etiologies combined. With the introduction of pneumococcal
tries between 1990 and 2016.1 The study also estimated the conjugate vaccines (PCVs) in the childhood national immu-
number of cases attributable to Streptococcus pneumoniae nization programs (NIPs) of many countries, moderate
(pneumococcus), Haemophilus influenzae type b, influenza, reductions in the mortality of LRTIs were seen in children
Issue Theme Community Acquired Copyright © by Thieme Medical DOI https://doi.org/

Pneumonia: A Global Perspective; Guest Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1702193.
Editors: Richard G. Wunderink, MD, New York, NY 10001, USA. ISSN 1069-3424.
Charles Feldman, MBBCh, DSc, PhD, Tel: +1(212) 760-0888.
FRCP, FCP (SA)
Role of Streptococcus pneumoniae in CAP Feldman, Anderson
under the age of 5 years, while the burden of LRTIs in adults fied a pathogen in 87% of the cases compared with 39% with
>70 years of age remained particularly high. culture alone, the two most common pathogens being H.
Nevertheless, it is clear when reviewing data from different influenzae (40%) and S. pneumoniae (36%). Viruses were
parts of the world, that there are regional differences in the detected in 30% of the cases with 82% being co-infected with
epidemiology (including burden, risk factors, etiology, preva- bacterial pathogens. The authors concluded that comprehen-
lence of antimicrobial resistance, and outcome) of patients with sive molecular testing significantly increases detection of CAP
community-acquired pneumonia (CAP) and there have also pathogens from a single lower respiratory tract specimen.
been global changes in the epidemiology of CAP over the While earlier studies evaluating the clinical and economic
years.2–5 One recent literature review evaluating the etiology burden of CAP in North America,12 Latin America,13 the Asia-
of CAP in adults published in PubMed in English through to Pacific region14 and Europe15 all indicated that the pneumo-
December 2015 noted the following trends; (1) there was an coccus was the most common cause of CAP, that antibiotic
unexplained decrease in the prevalence of pneumococcal infec- resistance was an issue, and that the morbidity and mortality
tions, particularly in the United States/Canada, (2) the pneumo- were high, more recent studies, largely from the United States,
coccus, nevertheless, remained the most common bacterial have noted a much lower incidence of pneumococcal infec-
pathogen identified, especially in critically ill cases, (3) there tions in CAP.9,10 Interestingly, in the latter study, additional use
was a much greater frequency of pneumococcal infections in of a novel serotype-specific urine antigen detection assay, as
Europe compared with the United States, (4) respiratory viruses opposed to the commercially available urine antigen detection
were noted to play a greater role than previously documented, test, increased the detection rate of pneumococcal cases from
(5) more recently, infections with Mycoplasma pneumoniae and 4.4 to 9.7% overall.16 Furthermore, an active surveillance study
Legionella pneumophila were less frequently reported, and (6) for pneumococcal CAP and invasive pneumococcal disease

the frequency of pathogen identification remained low, being (IPD) was undertaken in adults hospitalized across five Cana-
undetected in more than 50% of the cases.6 The authors dian provinces from 2010 to 2013.17 Diagnostic testing for
indicated that the possible reasons for differences in prevalence pneumococcal CAP was undertaken using sputum and blood
of pneumococcal infections when comparing Europe and the culture, a commercial pneumococcal urine antigen detection
United States may be related to differences in vaccination test and a serotype-specific pneumococcal urine antigen
practices and in the smoking habit. detection test. Of the total of 4,769 patients with all-cause
Differences in the documented etiology of CAP in the CAP, testing for S. pneumoniae was undertaken in 3,851 of
various studies may also be attributed, at least in part, to the these, identifying 23.2% (144/621) of cases among CAP patients
laboratory diagnostic techniques used. Standard culture tech- in whom all four tests were performed. Among these latter
niques, with blood cultures considered a “gold standard,” have cases, 14.8% were PCV13 type pneumococcal isolates, indicat-
yielded low rates of pathogen detection, because of the low ing that 3 years after introduction of PCV13 immunization
sensitivity of blood cultures.7 Furthermore, although of good programs in Canada, vaccine preventable pneumococcal CAP
specificity and improved sensitivity, urine antigen tests for S. was still a significant problem. A matched nested case-control
pneumoniae and L. pneumophila, are still only 70 to 80% study of two prospectively recruited cohorts of hospitalized
sensitive. Thus because of the limitations of diagnostic testing patients with CAP in Buenos Aires undertaken during 2001 to
for nonbacteremic pneumococcal infections, most studies 2002 and 2015 to 2016, observed a reduction in the number of
reporting on the incidence of pneumococcal infections report cases of CAP due to pneumococcus (23.4 vs. 8.3%; p < 0.001)
on the occurrence of invasive, bacteremic infection and un- and an increase in pneumococcal vaccination (polyvalent
derestimate the true pneumococcal burden.8 One recent sys- pneumococcal vaccine; PPV23) before admission (4.1 vs.
tematic literature review of studies, which included 22.8%; p < 0.001). The authors indicated that routine child-
information on the diagnostic yield of various assays for hood PCV13 vaccination, which was initiated in 2012, may
pneumococcal infections (urine antigen detection testing, have also contributed.18 A systematic review of studies pub-
and blood and/or sputum culture), estimated that for every lished on CAP etiology in Asia, concluded that while S. pneumo-
case of bacteremic pneumococcal pneumonia there were at niae was the most common cause, it was of relatively less
least three nonbacteremic cases, thus significantly underesti- importance than that found in western studies.19
mating the burden of pneumococcal disease when using the In contrast to this, a literature review evaluating the
former investigation alone.8 Two recent studies in the United etiology (and antibiotic management) of CAP in Europe
States using standard culture microbiology, urine antigen reported on 33 published studies that recorded pathogens
testing, and commercially available polymerase chain reaction and noted that the pneumococcus was the most commonly
(PCR) techniques identified pneumococcal infections in <10% isolated pathogen and was identified in between 12.0 and
of the cases, respiratory viruses in 20 to 27% of the cases, and no 85.0% of the patients in the different regions.20 A meta-analysis
pathogen in approximately 55 to 62% of the cases.9,10 More of the role of the pneumococcus in adults with CAP in Europe
recently, Gadsby et al evaluated quantitative multipathogen concluded that the observed prevalence varies in the different
molecular testing of respiratory samples in hospitalized adults European regions, that the probability of detecting S. pneumo-
with CAP.11 They collected mucopurulent sputum (96%), and niae was significantly higher if PCR was performed compared
endotracheal aspirates (3%) from 323 patients with radiologi- with any other diagnostic test and that S. pneumoniae was
cally-confirmed CAP and undertook culture and multiplex more likely to be isolated in studies with intensive care unit
real-time PCR analyses of the samples. Using PCR, they identi- (ICU) patients, as opposed to those with in-hospital or
Seminars in Respiratory and Critical Care Medicine

community-treated patients only.21 A recent systematic re- Table 1 Risk factors for invasive pneumococcal infections
view conducted in the United Kingdom (UK) noted that
vaccine-type pneumococcal disease still has a high burden Age
in the UK despite the impact of PCV13 vaccination in chil- < 2 or "65 y
dren.22 Furthermore, a prospective study of consecutive hos- Ethnic groups
pitalized adults with CAP in Reykjavik, in Iceland, in which PCR
African descent
analysis of airway samples was included in the diagnostic
testing, recorded a potential pathogen in 52% (164/310) of Alaskan native
admissions and 74% (43/58) in those with complete datasets.23 American Indians
S. pneumoniae was the most common pathogen detected (20%; Underlying clinical pulmonary diseases
61/310) and viruses were noted in 15%.
Chronic obstructive pulmonary disease
There is no doubt that a significant reason for the
changing epidemiology of pneumococcal disease and the Asthma
disease burden has been the use of PCVs in children, which, Other chronic clinical conditions
when included in childhood routine NIPs, prevents disease Chronic liver disease
not only in the targeted group, but also in nonvaccinated
Chronic renal failure
children, as well as adults, as a result of herd protection.24
Recent studies from most regions of the world25 including Nephrotic syndrome
North America,26 Europe,27 and South Africa,28 have docu- Diabetes mellitus
mented the significant direct and indirect effects of child-

Functional or anatomical asplenia
hood vaccination. Furthermore, two recent systematic
Sickle cell disease
reviews and meta-analyses of the global literature indicated
Splenectomy
that rates of IPD and pneumonia in adults in most countries
decreased following PCV introduction in the childhood Substance abuse
NIPs, that the herd protection is dependent on the PCV Alcohol abuse
coverage rate and the duration of the implementation of Smoking habit
the NIPS and that substantial protection for the whole
Crack use
population would be evident within a decade of introduc-
tion of childhood PCV programs.29,30 However, it has been Cocaine use
noted that the decline in adult pneumococcal infections in Immunosuppressive conditions
the United States was attenuated with increasing age and HIV infection
also in those with comorbidities26 and that a residual
Congenital immunodeficiency
burden of PCV13 vaccine-type CAP still remains in the
U.S. population.31 Malignancy
B-cell defects
Risk Factors for Severe Pneumococcal Multiple myeloma

Disease Patients undergoing treatment
These are well recognized and are often associated with Alkylating agents
immunosuppression, mostly acquired and secondary, as well Antimetabolites
as with certain types of primary immunodeficiency disorder, Systemic glucocorticoids
particularly antibody and complement deficiency disorders32
Patients with cerebrospinal fluid leaks
and are summarized in ►Table 1. Given the increasing
Cochlear implant recipients
realization of the multifactorial involvement of smoking in
promoting pneumococcal infection, including antibiotic resis- Solid-organ or hematopoietic cell transplant recipients
tance, this risk factor represents the primary focus of this Patients with influenza
section of the review.
Abbreviation: HIV, human immunodeficiency virus.
Source: Reproduced with permission from Aspa and Rajas.32
Smoking
Nuorti et al in their seminal report published in the “New
England Journal of Medicine” in 2000, identified active concordant antibiotic therapy.34 In the case of all-cause CAP,
cigarette smoking as being “the strongest independent risk a recent systematic review and meta-analysis, encompassing
factor for IPD among immunocompetent, nonelderly adults” 27 studies and 460,592 participants, revealed that current
(odds ratio [OR] 4.1; 95% confidence interval [CI], 2.4–7.3).33 smokers have a significantly increased risk for development
In addition to these findings, current smokers who develop of CAP relative to never-smokers (OR 2.17; 95% CI, 1.70–2.76,
pneumococcal CAP have been reported to have a striking n ¼ 13 studies).35 Passive smoking is associated with a 64%
fivefold increase in the risk of 30-day mortality, irrespective increase in the risk for development of CAP, but only for those
of age, comorbidities, and early implementation of guideline- aged >65 years (OR 1.64; 95% CI, 1.17–2.30, n ¼ 2 studies).35

Smoking-related increased susceptibility for development lide antibiotic, clarithromycin, resulted in significant upregu-
of severe pneumococcal disease has generally been attributed lation of expression of the erm(B) gene relative to that observed
to cigarette smoke-mediated suppression of innate and adap- in the presence of the antibiotic alone.45 Unexpectedly, expo-
tive pulmonary host defenses.36 Our research findings, some sure of this strain of the pneumococcus to CSC in the absence of
very recent, have, however, revealed additional pathogen- the antibiotic also resulted in significant upregulation of
targeted mechanisms that are likely to contribute to smok- expression of erm(B), albeit to a lesser extent than that
ing-related susceptibility for development of severe pneumo- observed in the presence of clarithromycin alone.45 These
coccal disease. In this context, exposure of an antibiotic- findings raise the possibility that CSC-mediated, spontaneous
susceptible strain of the pneumococcus (strain 172, serotype induction of erm(B) (in the absence of clarithromycin), as well
23F) to cigarette smoke in vitro was found to trigger events at as augmentation of clarithromycin-mediated induction of this
the level of gene expression, which may promote antibiotic macrolide resistance gene, result from a common mechanism
resistance. The first of these events involves initiation of activated in response to smoke-related stress.
biofilm formation, a strategy utilized by microbial pathogens In this context, it is noteworthy that like strain 172, expo-
to confer broad protection against penetration of antibiotics.37 sure of strain 2507 of the pneumococcus to CSC also resulted in
Biofilm is an extensively-hydrated, viscoelastic, extracellular upregulated expression of the genes encoding TCS11.48 Al-
matrix comprised of various types of bacterium-derived poly- though unproven, it is plausible that induction of both ribo-
meric materials, such as cell-wall components and deoxyri- somal methylation and biofilm formation by CSC may converge
bonucleic acid (DNA), in which pathogens are insulated against on TCS11 as a coordinated stress response to smoke exposure.
antibiotics, as well as host defenses.38 Smoke-mediated en- This contention is supported by the findings, albeit in bacterial
hancement of biofilm formation by the pneumococcus is pathogens other than the pneumococcus, that methylation of

preceded, within 15 to 60 minutes of exposure, by increased ribosomal ribonucleic acid (RNA), like biofilm formation, is
expression of several stress response-related genes.39 These associated with protection against environmental/oxidative
include the genes encoding a sensor kinase, known as hk11, stressors in Escherichia coli and Staphylococcus aureus.49,50 In
and its cognate response regulator, rr11, which, together, addition, it is also noteworthy that ribosomal methylation as a
comprise the two-component regulatory system 11, mechanism of antibiotic resistance is not restricted to macro-
TCS11,39,40 implicated in streptococcal biofilm formation41,42 lides, lincosamides, and streptogramins B. This type of mecha-
and resistance to vancomycin.43 Other genes upregulated nism is broadly operative in mediating resistance to other
following exposure of the pneumococcus to cigarette smoke categories of ribosome-targeted antibiotics, implying that
include the SP1857 cat eff (cation efflux system protein) and induction of ribosomal methyltransferases by cigarette smoke
SP2003 abc (adenosine triphosphate [ATP]-binding compo- exposure may pose the threat of multidrug resistance.51
nent of an ATP-binding cassette transporter) genes.39 These The pneumococcus possesses a second major gene-based
are likely to be involved in the expulsion of heavy metal and mechanism of macrolide resistance, which is mediated via
pro-oxidative, organic chemical toxicants present in cigarette induction of the macrolide efflux protein A-encoding gene, mef
smoke. Interestingly, the SP 2003 abc gene, has also been (A).47 However, unlike its erm(B)-expressing counterpart, ex-
reported to be induced following exposure of the pneumococ- posure of a mef(A)-expressing strain (strain 521, serotype 23F)
cus to vancomycin, suggestive of a role for its encoded adeno- of the pneumococcus to CSC failed to cause either spontaneous
sine triphosphate-binding cassette (ABC) transporter in induction or augmentative induction of the mef(A) gene in the
promoting antibiotic multidrug resistance.44 absence or presence of clarithromycin, respectively.45
More recently, we have described a second mechanism by In addition to induction of biofilm formation and expres-
which exposure of the pneumococcus to cigarette smoke sion of the erm(B) gene, the SP2003 abc gene, which is
promotes antibiotic resistance. This mechanism relates spe- significantly upregulated following exposure of the pneumo-
cifically to macrolide/macrolide-like antibiotics, and involves coccus to CSC, has also been implicated in antibiotic resistance
smoke-mediated augmentation of expression of the inducible as alluded to above. Although the role, if any, of the ABC
erm(B) macrolide resistance gene.45 This gene encodes a transporter encoded by this gene in mediating macrolide
ribosomal dimethyl transferase enzyme, which abrogates resistance remains to be established, its potential involvement
macrolide-mediated inhibition of bacterial protein synthesis. in promoting resistance to vancomycin has been implied in an
This results from dimethylation of a critical adenine nucleotide earlier study.43 The authors of this study reported that expo-
(A2058) located in the peptidyl transferase region of domain V sure of two different strains of the pneumococcus, one vanco-
of the 23S rRNA component of the 50S subunit of the bacterial mycin-susceptible (T4, serotype 4) and the other—resistant
ribosome, thereby interfering with the affinity of members of (Tupelo, serotype 14) to vancomycin (5 µg/mL) for 10 and
this class of antibiotics for their microbial target.46,47 Antibi- 20 minutes resulted in altered expression (up- or downregu-
otic resistance mediated by the erm(B) gene encompasses all lated) of 175 genes.43 Of these genes, 19 encoded ABC trans-
types of macrolides (14-,15- and 16-membered), lincosamides porters (of which more than 60 are encoded by the genome of
(clindamycin, lincomycin), and streptogramins B.47 the pneumococcus).52 However, only two of the ABC trans-
In this context, our recent studies have revealed that porter-encoding genes, viz. SP1715 and SP2003, demonstrated
exposure of an erm(B)-expressing, macrolide-resistant strain prominent upregulation of expression following exposure to
of the pneumococcus (strain 2507, serotype 23F) to cigarette vancomycin in both strains of the pneumococcus at both time
smoke condensate (CSC) in vitro in the presence of the macro- intervals tested.43

phorylcholine.58 In addition, and of possible relevance to the

pneumococcus, exposure of methicillin-resistant S. aureus to
nicotine per se, as well as to e-cigarette vapors, has been
reported to augment biofilm formation and resistance to host-
derived antimicrobial peptides such as cathelicidin LL-37.59
Causes and Mechanisms of Antibiotic

Resistance
Factors such as immunosuppression, clonal spread of resistant
strains of bacterial pathogens due to excessive use of antibiotics,
as well as smoking, in the case of the pneumococcus, and
possibly other respiratory bacterial pathogens, represent major
contributors to the development of antibiotic resistance. On the
other hand, and as mentioned above, the widespread practice of
immunization of the very young in particular, as well as the
elderly, with serotype-restricted pneumococcal PCVs, most
commonly PCV13 and its predecessor, PCV7, has been associ-
ated with substantial reductions in both the use of antibiotics
and development of resistance in some settings.60,61 These

benefits of PCV-based immunization strategies are, however,
Fig. 1 Exposure of both antibiotic-susceptible (A) and erm(B) mac- threatened by the emergence of antibiotic resistance among
rolide resistance gene-expressing (B) strains of the pneumococcus nonvaccine serotypes of the pneumococcus.61 Although incom-
(depicted as ##) to cigarette smoke results in induction of genes pletely understood, the association of serotype replacement
which trigger biofilm formation and expression of an ABC transporter, with antibiotic resistance has been attributed to elimination of
seemingly involved in efflux of antibiotics. These mechanisms may
competition by antibiotic-susceptible vaccine serotypes in the
attenuate the therapeutic efficacy of a broad range of antibiotics. In
addition, exposure to cigarette smoke also results in spontaneous nasopharynx, enabling emergence of previously suppressed,
induction of the erm(B) gene, as well as augmentation of expression of resistant nonvaccine serotypes.62 In this setting, antibiotic
this gene following exposure of the macrolide-resistant strain of the resistance comes at the expense of reduced fitness of these
pneumococcus to macrolides and macrolide-like antibiotics, confer- nonvaccine serotypes.63 This may be overcome, however, via
ring high-level resistance to these agents.
genetic transfer of metabolic and virulence components from
vaccine to nonvaccine serotypes of the pathogen, conferring
Not surprisingly, the aforementioned putative mechanisms both fitness and persistence on the latter serotypes.63
of smoke-mediated antibiotic resistance described for the As recently reported in a study originating from Canada,
pneumococcus may be of broader relevance, encompassing other potential mechanisms of PCV vaccine-related antibiotic
various types of respiratory bacterial pathogens. This conten- resistance include differential induction of herd protection by
tion is supported by reports that exposure of S. aureus to vaccine serotypes.64 In this context, herd protection conferred
cigarette smoke is also associated with increased biofilm by the highly-invasive serotype 3 of the pneumococcus (rep-
formation and virulence, as well as antibiotic resistance.53–55 resented in PCV13, but not PCV7) has been disappointing,
The proposed mechanisms of antibiotic resistance associ- possibly due to poor, postimmunization opsonophagocytic
ated with exposure of the pneumococcus to cigarette smoke activity of antibodies produced in response to the capsular
are summarized in ►Fig. 1. These are, distinct from the point polysaccharides of this strain.65 Poor immunogenicity appears
mutations described in the genes encoding DNA-gyrase and to be associated with the emergence of the predominant global
RNA polymerase following exposure of Pseudomonas aerugi- clonal complex of serotype 3 of the pneumococcus, CC180,
nosa to mutagens found in cigarette smoke, conferring resis- within which the emerging Clade II exhibits increased viru-
tance to ciprofloxacin and rifampicin, respectively.56 lence and possibly antibiotic resistance.65
Irrespective of the mechanisms that may be operative in the
E-cigarettes/Vaping and Pneumococcal Infection setting of pneumococcal, nonvaccine serotype antibiotic re-
Studies focused on the direct effects of e-cigarette vapors on sistance in particular, the findings of a very recently reported
the pneumococcus are sparse. However, two studies have international whole-genome sequencing study are notewor-
reported that exposure of airway alveolar macrophages and thy.66 This study was focused on pneumococcal lineages
epithelial cells to nicotine-containing vapors promotes associated with serotype replacement and antibiotic resis-
changes in these cells, which increase susceptibility to pneu- tance based on whole genome sequencing of strains of the
mococcal infection. In the case of alveolar macrophages, pathogen isolated from children aged <3 years hospitalized
exposure to these vapors results in cytotoxicity,57 while expo- with IPD in the pre- and postimmunization periods.66 The
sure of airway epithelial cells facilitates attachment of the authors reported a significant increase in the prevalence of
pneumococcus via upregulation of the platelet-activating resistance to penicillin in nonvaccine serotypes in the post-
factor receptor, the receptor for pneumococcal surface phos- PCV period relative to the pre-PCV13 period (29 vs. 21%,

p ¼ 0.0016), as well as a corresponding increase in erythromy- only those which mediate resistance to classes of antibiotic
cin resistance (11 vs. 1%, p ¼ 0.0031).66 Although indicative of commonly used in the treatment of pneumococcal infection,
an emerging threat, these findings should, however, be viewed specifically β-lactams, macrolides and respiratory fluoroqui-
in the context of a recently reported point-of-prevalence study, nolones (levofloxacin, moxifloxacin), are covered here.
which reported low, global rates of antibiotic resistance in
adult patients with proven pneumococcal pneumonia, diag- Resistance of the Pneumococcus to β-Lactam
nosed within 24 hours of admission to 222 hospitals spanning Antibiotics
54 countries.67 Continental prevalence rates of S. pneumoniae The antibacterial action of β-lactam antibiotics results pre-
drug resistance were 7.0 and 1.2% for Africa and Asia, respec- dominantly from the irreversible binding of these agents to
tively, with a corresponding rate of 1% for Europe, South one or more of the six enzymes involved in the synthesis of the
America, and North America, most commonly macrolide peptidoglycan backbone of the cell-wall of gram-positive
(0.6%) and penicillin resistance (0.5%).67 bacteria.11,75 Inhibition of these enzymes, known collectively
as penicillin-binding proteins (PBPs), results in weakening of
the cell-wall and eventual bacteriolysis. Acquisition of resis-
Genetic Determinants of Pneumococcal
tance results from horizontal transfer of genes encoding PBPs
Antibiotic Resistance
which have reduced affinity for β-lactams. The resultant
Genetically determined antibiotic resistance of the pneumo- “mosaic” genes generated via homologous recombination
coccus, as well as other types of respiratory bacterial patho- confer mostly low-level β-lactam resistance, which, with the
gens, is mediated by various mechanisms, most commonly exception of central nervous system infections, may be over-
altered target binding and accelerated efflux in the case of the come by administration of high doses of these antibiotics.11,75

pneumococcus. Exploitation of these mechanisms by the In the pneumococcus, resistance to β-lactams is associated
pneumococcus results predominantly from horizontal trans- most commonly with structural alterations to three PBPs, viz.
fer of antibiotic resistance genes. In this context, bacterial PBP1a, 2x, and 2b, occurring predominantly in clinical isolates
horizontal gene transfer is achieved via several mechanisms, of the pneumococcus, which harbor mosaic genes.11,47,78
these being conjugation, transduction, and transformation, Although not recognized as a β-lactamase-producing path-
with the pneumococcus being particularly adept at acquiring ogen,79 one study has, however, described the apparent in-
antibiotic resistance genes via transformation. This may occur volvement of a novel metallo-β-lactamase in mediating
either by unidirectional transfer between viable organisms, or resistance of strain ATC 49136 of the pneumococcus to
by uptake of naked, fragmented DNA released by disintegrat- ampicillin.80
ing bacteria, most commonly of the same strain and species.
During the course of transformation, it has been estimated that Resistance of the Pneumococcus to Macrolide
fragments of DNA comprising up to ten genes attach to DNA- Antibiotics
binding proteins expressed by competent, recipient bacterial As described above, development of genetically determined
cells, enabling entry of genetic material and integration into resistance of the pneumococcus to macrolide and macrolide-
the bacterial genome via homologous recombination.68 Effi- like antibiotics occurs via transformation. This, in turn, results
cient transformation is dependent on the recipient micro- in the acquisition of genes, which confer resistance either by
organisms being primed for both competence and expression enzymatic modification of target ribosomal antibiotic-binding
of essential DNA-binding proteins.68 sites, or by driving antibiotic efflux. In the case of the former
Competence has been described as a “transient state mechanism, expression of the ribosomal, dimethylase-
marked by a shift in both transcriptomic and proteomic expressing erm(B) gene results in dimethylation of A2058
profiles.”69 In the pneumococcus, acquisition of competence situated in domain V of the 23S component of the large
is under the control of a transcriptomic initiation complex (50S) ribosomal subunit. The consequence is interference
consisting of: (1) the alternative sigma specificity factor pro- with the binding of macrolides to the inner wall of the lumen
tein, SigX, known as the master regulator of competence; (2) a peptide exit tunnel, thereby attenuating the inhibitory effects
competence coregulator (activator of SigX) known as ComW, of these antimicrobial agents on peptide chain elonga-
which is responsive to quorum sensing mechanisms; and (3) tion.47,77,81 This type of erm(B) gene-mediated mechanism
RNA polymerase.69–73 Resultant formation of the RNA poly- results in high-level resistance, which is unlikely to be over-
merase holoenzyme, consisting of the core enzyme and SigX, come by high-dose administration of macrolides,77 despite the
enables correct transcription by directing the enzyme to propensity of these agents to concentrate intracellularly in
specific sites in the promotor regions of target genes.69 These eukaryotic cells.82
cooperative interactions between bacterial RNA polymerase Two macrolide efflux pumps, macrolide efflux protein A
and sigma bacterial transcription initiation factors have been and macrolide efflux protein E, encoded by the mef(A) and mef
identified as attractive targets for development of novel anti- (E) genes, respectively, are utilized by the pneumococcus to
microbial agents, including those with antipneumococcal expel these antibiotics.76,83 However, unlike resistance medi-
activity.74 ated via the erm(B) gene, acquisition of the mef genes only
Mechanisms involved in promoting resistance of the pneu- confers resistance to 14- and 15-membered macrolides, but
mococcus to various classes of antibiotics have been covered not to 16-membered macrolides, lincosamides or streptogra-
extensively in several recent reviews.11,47,75–77 Accordingly, mins B.47 In addition, the level of resistance resulting from

macrolide efflux is lower than that conferred by the erm(B) DNAse1 to patients with cystic fibrosis infected with P. aeru-
gene.77 ginosa.92 This enzyme, which targets both bacterial and human
DNA, reduces sputum viscosity via dismantling of both biofilm
Resistance of the Pneumococcus to Fluoroquinolone and neutrophil extracellular traps.92
Antibiotics
Fluoroquinolones are the only class of antibiotics which target
Impact of Antibiotic resistance in S.
bacterial DNA synthesis, most importantly, moxifloxacin and
pneumoniae
levofloxacin, which are known as the “respiratory fluoroqui-
nolones” due to their potency against bacterial respiratory Several review articles published over several years have
pathogens, including the pneumococcus.11,47,76 With respect highlighted the emergence of antibiotic resistance among S.
to their mechanism of antimicrobial action, fluoroquinolones pneumoniae isolates worldwide, describing not only the epi-
target the type II class topoisomerase enzymes, DNA gyrase, demiology, mechanisms of resistance, and risk factors, but also
and topoisomerase IV. These enzymes, each of which is the clinical relevance and appropriate approach to antibiotic
comprised of two subunits (gyrA and gyrB; parC and parE), management.93–98 Emerging resistance has been documented
promote unravelling of the coiled structure, as well as break- to all the major classes of antibiotics including β-lactams,
age and re-ligation, of DNA, which are critical events in macrolides, and even fluoroquinolones. Data from the SENTRY
bacterial DNA synthesis.84 However, as mentioned below, Antimicrobial Surveillance Program, a continuously active
acquisition of resistance necessitates stepwise, progressive global antibiotic resistance surveillance network, describe
accumulation of point mutations in the subunits of DNA gyrase very succinctly the changes in antimicrobial resistance that
and topoisomerase IV, with those in gyrA alone or gyrA/parC, have occurred among S. pneumoniae isolates between 1997

conferring high-level resistance.47,76 Resistance is also associ- and 2016,99–101 highlighting the impact of the introduction of
ated with horizontal transfer of the mutated genes.85 PCV immunization of children on resistance evolution. Ini-
Acquisition of resistance to fluoroquinolone antibiotics also tially, between 1998 and 2001 among U.S. isolates there was a
results from overexpression of genes encoding drug efflux decrease in susceptibility among pneumococcal isolates to
pumps, specifically the PatAB ABC drug transporter,86,87 as amoxicillin/clavulanate, penicillin, and ceftriaxone (and other
well as the PmrA transporter,11 most likely achieved via antibiotics), followed by improved susceptibility to β-lactams
horizontal gene transfer. during 2002 and 2003, attributed to introduction of PCV 7.99
However, between 2004 and 2009 antimicrobial resistance
among these β-lactam antibiotics increased99 and continued
Nonantibiotic Strategies to Overcome
to increase further through 2011.100 The subsequent increase
Antibiotic Resistance
in antibiotic resistance that occurred a few years after intro-
Notwithstanding implementation of strategies targeted at duction of PCV 7 was attributed to the emergence of serotype
overcoming risk factors for development of antibiotic resis- 19A, a serotype not covered by PCV 7, which expressed
tance such as undiscerning use of antibiotics, smoking, antimicrobial resistance.102 However, in more recent years
immunosuppression, and under-utilization of vaccines, phar- through to 2016, susceptibility of S. pneumoniae isolates from
macological targeting of biofilm formation remains an attrac- North America, Europe, Asia Pacific region, and Latin America
tive strategy to counter this ominous threat. In the case of has increased for many antibiotics and in all regions, attribut-
pneumococcus, encasement of this, as well as other types of able to the introduction of PCV 13 immunization in 2010.101
respiratory pathogen, in biofilm promotes antibiotic resis- However, there has been some debate as to whether antibiotic
tance by several mechanisms. These include decreased bacte- resistance is clinically relevant or whether there is a paradox
rial metabolism and growth in the setting of exposure of between the reported in vitro sensitivity and clinical out-
pathogens to low concentrations of antibiotics due to restrict- comes, with many studies failing to show a clear impact of
ed permeation of these agents, a combination of circumstances antibiotic resistance on outcome, possibly as a consequence of
which is highly conducive to development of resistance.88 In methodological limitations.93
addition, close proximity of antibiotic-susceptible organisms
to resistant strains facilitates antibiotic resistance via horizon- β-Lactam Resistance
tal gene transfer, while exposure of the pneumococcus to β- Several studies over several years have attested to the fact
lactamase-producing organisms in polymicrobial biofilms that the levels of penicillin and cephalosporin resistance in S.
may induce passive antibiotic resistance.88 pneumoniae are such that they are unlikely to impact on β-
As mentioned in detail in one of our earlier reviews on this lactam resistance and on the outcome of patients with
topic,88 pharmacological targeting of bacterial biofilm forma- pneumococcal pneumonia.103–110 On the other hand, a few
tion via development of inhibitors of quorum sensing mech- studies have suggested that resistance to β-lactam agents is
anisms was then, and remains,37,89,90 an attractive strategy to indeed associated with worse outcomes in invasive pneu-
overcome biofilm formation. More recent strategies, include mococcal pneumonia.111–113 Turett et al showed an inde-
pharmacological targeting of two-component regulatory sys- pendent association between pneumococci with an MIC to
tems involved in initiation of biofilm formation.91 To date, penicillin of "2 µg/mL and mortality; however, 50% of the
however, the only clinically available, biofilm-targeted strate- patients in that study were HIV-infected and the authors did
gy involves administration of nebulized, human recombinant not adjust for severity of illness.111 Furthermore, only two

patients in that study had actually received penicillin thera- with bacteremic CAP and infected with nonsusceptible strains
py (see discordant therapy below). Feikin et al documented had a worse outcome than patients infected with susceptible
that when deaths in the first 4 days were excluded, mortality strains.122
was significantly higher in isolates with a penicillin MIC " 4 Thus while bacteriological failures of less active penicillins
µg/mL (high level penicillin resistance) and cefotaxime MIC (ticarcillin) and cephalosporins (cefazolin, cefuroxime, and
"2 µg/mL.113 At least partly because of these inconsistencies ceftazidime) have been documented there are also case reports
and the demonstration, using appropriate PK/PD principles, of apparent failures of the more active cephalosporins.123 One
that adequate serum and tissue levels of parental β-lactams study documented the occurrence of pneumococcal meningi-
and oral amoxicillin could be achieved with appropriate tis in a child with sickle cell anemia treated with vancomycin
dosing, the Clinical Laboratory Standards Institute (CLSI) and cefotaxime.124 However, low-dose cefotaxime was used
increased the breakpoints for cefotaxime, ceftriaxone, and and the patient was also immunocompromised. High-dose
amoxicillin for nonmeningeal pneumococcal infections ini- oral and intravenous amoxicillin, as well as high dose intrave-
tially and subsequently for penicillin.114,115 Tleyjeh et al116 nous penicillin, ceftriaxone and cefotaxime, should achieve
evaluated 10 studies that examined the association between successful treatment of infections caused by pneumococcal
penicillin-non-susceptible pneumococci and outcome in isolates with penicillin minimum inhibitory concentrations
pneumococcal pneumonia and found a significant difference (MICs) of $ 4 µg/mL.123 Another case of breakthrough bacter-
in the mortality rate of 19.4% in the penicillin nonsusceptible emia and meningitis was seen in a patient with pneumococcal
group and 15.7% in the penicillin-susceptible group. The pneumonia treated with cefotaxime; however, the antibiotic
authors indicated that despite these findings, they will not was changed to cefuroxime on the second day and immuno-
significantly affect our empiric treatment for CAP as current compromise was not excluded in the child.125 Lastly, failure of

guidelines recommend using antibiotics effective against treatment of cephalosporin therapy was noted in a child with
penicillin-resistant pneumococci.114,116 pneumonia infected with a highly resistant pneumococcus.126
Other studies have suggested that patient-related factors However, initial treatment was with cefuroxime, followed by
such as older age and underlying comorbid illnesses,113,117 one dose of ceftriaxone followed by oral ceftibuten, which has
severity of infection, and do-not-resuscitate orders,118 and poor activity against pneumococci and the patient developed a
clinical condition on presentation (shock and multilobar con- pleural effusion.
solidation119) may be more important in predicting outcome
than antimicrobial resistance. Macrolide Resistance
Clearly antibiotic resistance can only be implicated as a The occurrence of macrolide resistance in S. pneumoniae
cause of treatment failure if patients are treated with discor- isolates has been documented for many years and has
dant therapy (therapy with an agent to which the pneumococ- recently been reviewed.127 As opposed to β-lactam
cus is resistant). A prospective, international, observational resistance, the situation with macrolide resistance is much
study of 844 hospitalized patients with pneumococcal bacter- less clear. While there are studies demonstrating benefit of
emia, in which 15% of isolates had intermediate susceptibility macrolides in the treatment of CAP, including macrolide-
to penicillin (MIC 0.12–1 µg/mL) and 9.6% were fully resistant resistant S. pneumoniae, the discrepancy between clinical
(defined as an MIC " 2 µg/mL), documented that discordant and bacteriological outcomes despite high MICs and
therapy (defined as receipt for the first 2 days after the blood expression of macrolide resistance genes (referred to as
sample was obtained for culture of a single antibiotic that was the in vivo in vitro paradox),128,129 there are also numerous
inactive in vitro against the S. pneumoniae isolated) with the reports of macrolide failure in CAP, with both emergence
penicillins (penicillin, ampicillin, amoxicillin-clavulanate), of macrolide resistance, as well as breakthrough bacteremia,
cefotaxime, and ceftriaxone was not associated with a higher in patients with pneumococcal pneumonia treated with
mortality.106 However, 11 patients were infected with what macrolides.130–139 In many of these studies, failure of macro-
was considered to be cefuroxime-resistant pneumococci and lide therapy has occurred in the setting of both low-level
eight of these cases, including all four cases that died, had been (efflux mechanism) and high-level (ribosomal methylation
treated with cefuroxime at a dose of 750 mg 8 hourly. mechanism) macrolide resistance. Cilloniz et al recently
(p ¼ 0.0175). It has been indicated that clinical outcome is documented that hospitalized patients with macrolide-re-
worse when in vitro testing suggests that the antimicrobial sistant pneumococcal pneumonia were not more severely ill
therapy would be ineffective.120 In this respect, an additional on hospital presentation nor had worse outcomes if treated
study suggested that intravenous cefuroxime given at a dose of with guideline-compliant antibiotic treatment regimens.140
1,500 mg every 8 hours would be effective therapy for bacter- Nevertheless, because of increasing macrolide resistance and
emic pneumococcal pneumonia with penicillin and cephalo- documentation of failure with both low- and high-level
sporin-resistant isolates, at least for strains with a cefuroxime resistance, it has been recommended that macrolide mono-
MIC of up to 4 µg/mL, suggesting that the definition of therapy should not be used for CAP,141 while others contend
cefuroxime resistance was of uncertain clinical relevance that these agents should still be considered for routine use in
(1993 criteria; cefuroxime sodium MIC " 2 µg/mL considered CAP, most commonly as part of combination therapy, togeth-
resistant).121 A very recent study from Spain noted that despite er with β-lactam antibiotics, and particularly in patients
an increasing prevalence of cefotaxime nonsusceptible S. with severe CAP and sepsis, at least partly because of their
pneumoniae there was no evidence that patients hospitalized nonantibiotic, pleiotropic effects.142

Fluoroquinolone Resistance leads to the same conclusions that have been espoused in
There is also emerging evidence of fluoroquinolone resis- review articles published over the years.123,153–157 In the
tance occurring in pneumococcal isolates.143–145 Fluoroqui- case of the penicillins, aminopenicillins, and cephalospor-
nolones target mainly DNA gyrase or topoisomerase IV.143 ins, failure occurs mainly with the use of agents that are
The main mechanism of fluoroquinolone resistance is the poorly active against the pneumococcus, or with the use of
occurrence of mutations in the quinolone resistance-deter- doses of ostensibly efficacious antibiotics with PK/PD
mining regions of parC and gyrA, which encode topoisomer- parameters that likely predict treatment failure, the latter
ase IV and DNA gyrase, respectively.143,146 Fluoroquinolones, being overcome with the use of more appropriate dosing.
which possess dual activity against S. pneumoniae, are less In the case of the macrolides, and despite the suggestion
likely to select for fluoroquinolone resistance than nondual that there may be an in vivo/in vitro paradox, failures have
activity agents, since in the former, mutations in both DNA occurred in patients infected with pneumococcal isolates
gyrase and topoisomerase IV are required for clinically with both low-level and high-level resistance, such that
relevant resistance.143 In general, parC mutations confer macrolide monotherapy is not recommended routinely in
resistance to ciprofloxacin, but not to levofloxacin or moxi- patients with CAP; however, the routine combination of a
floxacin, while mutations in gyrA or both parC and gyrA macrolide with standard β-lactam therapy is recom-
confer resistance to the latter agents.143 Low-level resistance mended in sicker hospitalized and critically ill patients
occurs with one-step mutation in the target genes, whereas with CAP. In the case of the fluoroquinolones, high-level
high-level resistance requires a second mutation, in the other resistance is likely to be associated with treatment failure
target gene.146 Isolates with a single parC mutation are in fluoroquinolone-resistant pneumococcal infections.
usually reported as being susceptible to fluoroquinolones, However, an additional concern is being able to document

because the MICs are at, or below, the CLSI breakpoints. those isolates harboring a one-step mutation, and which
Therefore, there is no test that accurately detects the pres- are currently reported as susceptible on MIC testing,
ence of this resistance. Nevertheless, this one-step mutation because they are more likely to develop a second mutation
increases the likelihood of the development of a second gyrA during fluoroquinolone therapy, thereby expressing high-
mutation, which is then associated with high-level resistance level resistance, which may then be associated with treat-
and therapeutic failure.146 As such, failures of fluoroquino- ment failure.
lone therapy have been regularly documented in patients
with pneumococcal respiratory tract infections associated Impact of Vaccination with PCV on Pneumococcal
with fluoroquinolone resistance, with resistance being pres- Antibiotic Resistance
ent either at the beginning of the infection, or emerging One development that has had a very positive impact on
during treatment; risk factors for these infections have been pneumococcal antibiotic resistance and which should en-
determined in various studies and these infections have been sure the ongoing efficacy of standard antibiotic therapy in
noted to have a high mortality.146–150 patients with pneumococcal infections, has been the use of
Most of the reported treatment failures have occurred pneumococcal vaccines, particularly PCVs. Mechanisms by
following administration of either ciprofloxacin or with which vaccines may impact on antibiotic resistance include
levofloxacin at a dose of 500 mg daily,146,148 which is under- first, by eradicating the organisms, particularly the antibi-
standable given the pharmacokinetic/pharmacodynamic otic-resistant serotypes, that are targeted by the vaccine
parameters that predict the likely clinical response of an and, second, by preventing infections, such as otitis media,
antibiotic.143 Fluoroquinolones display concentration-de- for which antibiotics would usually be prescribed.158 Sev-
pendent killing meaning that as the concentration of these eral studies have shown a decrease in the rate of drug-
agents increase, so does their bactericidal activity.143 The resistant S. pneumoniae infections, in both younger children
pharmacokinetic parameter that is commonly used as a and older adults following introduction of PCVs.159–162 In
correlate to bacteriological and clinical response of fluoro- the case of PCV 7, invasive disease caused by penicillin
quinolones is the AUIC (area under the curve over the MIC), nonsusceptible strains decreased by 81% (95% CI 80–82%) in
with a ratio of >30 traditionally considered as being predic- children under 2 years of age, and by 49% in adults " 65
tive of a good outcome in pneumococcal infections.143 Cip- years.159 Rates of resistance to many other antibiotics were
rofloxacin does not achieve this breakpoint value and is, also documented to decrease, as were the rates of multi-
therefore, less likely to eradicate pneumococcal respiratory drug-resistant strains.159,160 There has been, however, an
tract infections. Furthermore, studies by Schentag et al have increase in resistant disease caused by nonvaccine sero-
suggested that AUICs of over 125 should be targeted since types, and in particular serotype 19A as mentioned
values below 100 are associated with resistance develop- above.159 Following introduction of PCV 13, reductions in
ment, regardless of whether the organism is gram-positive the rate of 19A infections, as well as infections with PCV 13
or gram-negative.143,151 We have previously documented serotypes, decreased further in most age groups.161,162
that higher doses of levofloxacin of 500 mg twice daily or Clearly, ongoing surveillance of serotype frequency and
750 mg daily, but not a lower dose of 500 mg daily, are able to antimicrobial resistance are required to assess the impact
achieve these higher AUIC levels recommended (>125).152 of broader use of PCV 13, as well as the use of any newer
In summary, a review of the current literature regarding pneumococcal vaccines that may be introduced in the
the likely impact of antibiotic resistance in S. pneumoniae future.161,162

Outcome of Pneumococcal Pneumonia reported to persist for up to 7 years.177 In this setting of

persistent antigenemia, the interaction of pneumococcal
Despite advances in medicine, particularly the availability capsular and cell wall components, as well as nucleic acids,
of potent antimicrobial chemotherapeutic agents and even with specific antibodies and Toll-like receptors expressed
the establishment of ICU facilities, the mortality due to on cells of the innate immune system, as well as structural
pneumococcal pneumonia remains high. A recent retro- cells, is likely to trigger or exacerbate chronic, mostly
spective observational study in Barcelona, Spain, of hospi- subclinical, systemic inflammation.178,179 These events, in
talized patients with pneumococcal pneumonia, conducted turn, predispose for development of a labile, proinflamma-
over a period of 20 years between 1997 and 2016, which tory/procoagulant phenotype, which may contribute to the
was divided into four 5-year periods, noted that the 30-day pathogenesis of long-term cardiovascular events and other
mortality rate was 8% and did not change significantly noncommunicable diseases.178,179
between periods.163 There was an increase in admissions
to ICU and need for mechanical ventilation, and although
Conclusion
the ICU mortality decreased between periods one and two,
there was no significant difference with adjustments. Even The prevalence of pneumococcal infections appears to have
in the propensity-adjusted multivariate analysis, 30-day declined significantly among adults in the United States and
mortality did not change. Another study of critically ill is largely attributable to comprehensive childhood immuni-
immunocompetent patients with pneumococcal pneumo- zation with PCV 13 and its associated herd protection, as well
nia noted an in-hospital mortality of 18.9%.164 Most studies as a decrease in cigarette smoking. However, in many other
such as these in pneumococcal CAP, as well as many others regions of the world pneumococcal infections are still highly

in all-cause CAP, have arbitrarily examined short-term prevalent, being associated with significant morbidity and
mortality in those patients, such as hospital mortality or mortality. While exposure to cigarette smoke is a well-
30-day mortality.163–165 recognized, major risk factor for pneumococcal infection
It is only more recently that long-term mortality rates in and its associated antibiotic resistance, it is also concerning
patients with CAP have been investigated. These studies have that emerging evidence is implicating vaping as a potential
revealed an unacceptably high long-term mortality, such risk factor for pneumococcal infection. Although escalating
that an episode of CAP is associated with a higher risk of antibiotic resistance has been a concern globally, clear evi-
long-term adverse events in comparison with age-matched dence of a significant impact of current resistance rates on
subjects in the general population who have not suffered an patient outcomes has not been forthcoming, largely because
episode of CAP.165,166 Similar findings have been noted in antibiotic guidelines for CAP take into account the possibility
patients with pneumococcal CAP. One earlier study of long- of antimicrobial resistance. While it is clear that the use of
term survival in patients who had recovered from pneumo- PCVs has resulted in a decrease in the prevalence of vaccine
coccal CAP noted that mortality was increased for up to 10 serotype-specific pneumococcal infections and their associ-
years and that the pneumonia severity index score on ated resistance, ongoing surveillance is essential to monitor
admission, and the presence of bacteremia, were risk factors for nonserotype disease and the possible emergence of
associated with higher mortality.167 Two more recent studies antibiotic resistance in these serotypes.
indicated similar findings.168,169 The former study, in
patients with IPD and bacteremic and nonbacteremic pneu- Conflict of Interest
mococcal pneumonia, documented that in patients with None declared.
both nonpneumonia IPD and pneumococcal pneumonia
who survived 30 days, approximately 40% died within the
following 5 years.168 The study documented that even non- References
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Seminars in Respiratory and Critical Care Medicine

Downloaded by: Imperial College London. Copyrighted material.

Seminars in Respiratory and Critical Care Medicine

Downloaded by: Imperial College London. Copyrighted material.

Seminars in Respiratory and Critical Care Medicine

Downloaded by: Imperial College London. Copyrighted material.

Seminars in Respiratory and Critical Care Medicine

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