829

Antibiotic Resistance in Community-Acquired

Pneumonia Pathogens
Richard G. Wunderink, MD1 Yudong Yin, MD2

1 Division of Pulmonary and Critical Care, Department of Medicine,
Northwestern University Feinberg School of Medicine, Chicago,
Illinois
2 Department of Infectious Disease and Clinical Microbiology, Beijing
Chao-Yang Hospital, Capital Medical University, Beijing, China
Address for correspondence Richard G. Wunderink, MD, Division of
Pulmonary and Critical Care, Department of Medicine, Northwestern
University Feinberg School of Medicine, 676 North St. Clair Street, Arkes
14-015, Chicago, IL 60611 (e-mail: r-wunderink@northwestern.edu).

Semin Respir Crit Care Med 2016;37:829–838.

Abstract The overwhelming majority of cases of community-acquired pneumonia (CAP) can be

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treated with the standard antibiotic regimens of a macrolide and cephalosporin or a
fluoroquinolone. Despite high rates, current levels of β-lactam resistance generally do
not result in treatment failure for patients with CAP when appropriate agents and doses
are used. Following the introduction of the pneumococcal conjugate vaccines, the
incidence of invasive pneumococcal disease declined drastically, coinciding with a
decrease in penicillin resistance. Risk factors for methicillin-resistant S. aureus follow two
patterns: (1) healthcare-associated risk factors and (2) pneumonia from exotoxin-
producing community-acquired strains. The latter is associated with need for antibiotics
which inhibit protein synthesis for optimal management. Since 2000, macrolide-
Keywords resistance in M. pneumoniae has rapidly emerged worldwide, especially in Asian
► antibiotic resistance countries. The inability to routinely culture H. influenzae suggests that macrolide and
► pneumococcus β-lactam resistance, while present, is not a big issue. Unless risk factors for a hospital-
► S. aureus associated strain are present, the most common Enterobacteriaceae to cause CAP,
► hemophilus influenza including Escherichia coli and Klebsiella, are generally susceptible to usual CAP anti-
► pneumonia biotics. Given the limited role of antibiotic resistance in CAP, a strong rationale is needed
► community-acquired for use of antibiotics other than the standard β-lactam/macrolide or fluoroquinolone
pneumonia regimens.

Concern regarding antibiotic resistance to the usual anti-
biotics used for treatment of community-acquired pneumo-
nia (CAP) has driven substantial overuse of broad-spectrum
antibiotics. While the overall population-based effect of
antibiotic overtreatment in CAP on antibiotic resistance is
unclear, the major concern is that broad-spectrum antibiotic
therapy actually leads to worse outcomes in individual pa-
tients, particularly if they have no risk factors for multidrug
resistant (MDR) pathogens.1,2
The standard antibiotic regimens for CAP are the combi-
nation of a β-lactam (usually a cephalosporin) and a macro-
lide or monotherapy with a respiratory fluoroquinolone. For
severely ill patients, combination therapy with a β-lactam
and either a macrolide or a fluoroquinolone is recommended.
Our discussion on resistance will therefore focus predomi-
nantly on these antibiotics. The most common pathogens for
CAP are listed in ►Table 1 and resistance in each will be
discussed.
Resistant gram-negative pathogens previously included in
the healthcare-associated pneumonia (HCAP) category will
be discussed briefly.3 The HCAP category is likely to undergo
substantial revision and potential renaming to more accu-
rately classify patients at greatest risk for these MDR
pathogens.

Issue Theme Community-Acquired Copyright © 2016 by Thieme Medical DOI http://dx.doi.org/

Pneumonia: A Global Perspective; Guest Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1593753.
Editors: Charles Feldman, MBBCh, DSc, New York, NY 10001, USA. ISSN 1069-3424.
PhD, FRCP, FCP (SA), and James D. Tel: +1(212) 584-4662.
Chalmers, MBChB, PhD, FRCPE
830 Antibiotic Resistance in CAP Pathogens
Table 1 Most common bacterial CAP pathogens
Streptococcus pneumoniae
Staphylococcus aureus
Hemophilus influenzae
Mycoplasma pneumoniae
Chlamydophila pneumoniae
Legionella pneumophila
Enterobacteriaceae
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Streptococcus pneumoniae Resistance
Despite the decreasing rate of CAP caused by this pathogen
after the introduction of pneumococcal conjugate vaccine,4 S.
pneumoniae still remains one of the most common pathogens
of CAP.5–7 S. pneumoniae is commonly treated with β-lactams,
macrolides, or fluoroquinolones. But the emergence and
spread of drug-resistant S. pneumoniae in recent years pres-
ent an important challenge to the successful treatment.
Resistance to Beta-Lactams
S. pneumoniae possesses five high-molecular-weight penicil-
lin-binding proteins (PBPs)—PBP1a, PBP1b, PBP2a, PBP2b, and
PBP2x—and the low-molecular-weight PBP3. Those PBPs are
bifunctional enzymes that polymerize the glycan chains
which constitute the bacterial cell wall. Beta-lactams act by
binding to those PBPs to inhibit cell wall synthesis. Beta-
lactam resistance in S. pneumoniae is mediated mainly by
multiple mutations in the genes encoding the PBP1A, PBP2X,
and PBP2B enzymes.8
For decades, the standard treatment for pneumococcal
infections was penicillin. Penicillin nonsusceptible isolates
were first identified in North America during the 1970s.9 Now
prevalence rates of penicillin nonsusceptible S. pneumoniae
(PNSSP) vary widely among countries. In the United States,
penicillin resistance is much less common after nearly two
decades of conjugate vaccine use.10,11 High prevalence of
PNSSP can still be seen in the countries with less conjugate
vaccine use and higher antibiotic consumption.12
Compared with penicillin, cephalosporin drug resistance
still remains low. Better in vitro antibiotic activity remains for
most of the cephalosporins.10,11,13
Clinical Impact of PNSSP: Still in Debate
Despite the high rates of PNSSP, studies indicate that current
levels of β-lactam resistance generally do not result in
treatment failure for patients with CAP when appropriate
agents and doses are used. Most clinical studies have not
found that penicillin resistance negatively impacts the clinical
outcomes of patients with invasive nonmeningeal pneumo-
coccal infections. Garcia-Vidal and colleagues studied 1,041
adult patients with pneumococcal pneumonia, of whom 114
Seminars in Respiratory and Critical Care Medicine Vol. 37
Wunderink, Yin
(10.9%) had septic shock at admission. Independent risk
factors for shock were current tobacco smoking, chronic
corticosteroid treatment, and serotype 3 pneumococcus. No
significant differences were found in genotypes and rates of
antibiotic resistance between the groups with or without
septic shock.14 Moroney et al15 performed a laboratory-based
surveillance study of hospitalized invasive pneumococcal
pneumonia. Compared with control subjects infected with
susceptible S. pneumoniae (minimum inhibitory concentra-
tion [MIC] of cefotaxime
0.0625 mg/Ml), patients infected
with resistant S. pneumoniae (MIC of cefotaxime 0.25 mg/
mL) did not differ significantly in mortality or the need for
admission to an intensive care unit (ICU). When adjusted for
do-not-resuscitate (DNR) orders, severe illness at presenta-
tion, and underlying disease, no statistical association was
found in cefotaxime resistance with ICU admission and
mortality. Interestingly, Cillóniz and colleagues found a great-
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er distribution of pulmonary complications (38% of all pneu-
mococcal pneumonias) in the penicillin and erythromycin
susceptible group, rather than the resistant ones.16 Inconsis-
tency between the in vitro antimicrobial resistance to peni-
cillin and clinical outcomes led the Clinical and Laboratory
Standards Institute (CLSI)17 to revise the penicillin suscepti-
bility breakpoints for nonmeningeal pneumococcal infections
in 2008.
These results suggest that the clinical outcome of pneu-
mococcal pneumonia is more likely associated with the
clinical conditions at presentation than the antibiotic suscep-
tibility status of S. pneumoniae. Pharmacokinetic (PK) and
pharmacodynamic (PD) characteristics may be another factor
responsible for the inconsistency between in vitro suscepti-
bility and clinical outcomes. The MIC50 and MIC90 are not the
only indicators of antibacterial activity. Area under the
inhibitory curve (AUIC) is a pharmacological measure that
integrates the principles of PK/PD. AUIC represents the ratio
of the antibiotic area above the organism’s MIC on the
concentration–time curve over 24 hours (AUC24). The β-
lactams with satisfactory PK/PD parameters, such as ceftriax-
one, provide excellent balance between in vitro antimicrobial
activities and pharmacokinetic profiles and therefore re-
mains effective against PNSSP infection.13
Another potential explanation for the clinical paradox is
the biological fitness of antibiotic-resistant pathogens.
Achievement of antimicrobial resistance sometimes comes
with a cost and may be associated with a decrease in speed of
growth, virulence, or transmission.18,19 Little is currently
known about the fitness of antimicrobial-resistant S. pneumo-
niae. More experimental studies are needed to clarify wheth-
er this mechanism exists in the pathogenesis of
antimicrobial-resistant S. pneumoniae.
Macrolide Resistance
Macrolide resistance in S. pneumoniae occurs via two major
mechanisms: methylation of ribosomal macrolide target
sites, encoded by the ermB gene, and drug efflux, encoded
by mefA. In the United States, macrolide resistance in S.
pneumoniae is mainly mediated by drug efflux, which is
usually associated with a low-level resistance (MICs of
No. 6/2016

erythromycin of 1–32 mg/mL). Ribosomal methylation is
associated with high-level resistance (MIC of erythromycin
>64 mg/mL), which is more common in Spain20 and Asian
countries.21
Although the incidence of macrolide resistance in S. pneu-
moniae is increasing, the clinical relevance of macrolide
resistance has not been clearly established yet. Several stud-
ies22,23 have reported the treatment failures or breakthrough
bacteremia infected with macrolide-resistant pneumococci.
An open-label, noncomparative study in Japanese pa-
tients with mild-to-moderate CAP was performed to ex-
amine the clinical effectiveness of a 3-day course of oral
azithromycin. The clinical response was judged upon four
outcomes: resolution of fever; resolution of leukocytosis;
improvement of serum C-reactive protein (CRP), and sig-
nificant improvement of chest X-ray findings. Six of seven
patients in whom high-level resistance was documented
(MICs > 256 μg/mL and carrying ermB genes) exhibited
good clinical responses, indicating that azithromycin might
be clinically effective for the treatment of CAP with macro-
lide-resistant S. pneumoniae.24
Kohno and colleagues evaluated clinical efficacy and safety
of azithromycin intravenous therapy followed by oral admin-
istration against CAP. Clinical efficacy and bacterial eradica-
tion were achieved in 10 of 11 patients (90.9%). Intravenous-
to-oral azithromycin therapy demonstrated excellent clinical
and bacteriological effects on moderate-to-severe pneumo-
coccal pneumonia despite a high MIC and resistance gene
development.25
A retrospective, observational study performed in Spain
reviewed adult patients hospitalized with pneumonia who
had positive cultures for S. pneumoniae. Outcomes such as
bacteremia, pulmonary complications, acute renal failure,
shock, ICU admission, need for mechanical ventilation, length
of hospital stay, and 30-day mortality were examined. In
contrast with the results of Lonks and colleagues,23 patients
with macrolide-resistant organisms were less likely to have
bacteremia, pulmonary complications, and shock, and were
less likely to require noninvasive mechanical ventilation. No
increase in incidence of acute renal failure, the length of
hospital stay, or the 30-day mortality was found in patients
Table 2 Prevalence of S. pneumoniae penicillin resistance in different countriesa
United States
Penicillin V (oral) 20.7
Penicillin Gb 1.5
Ceftriaxone 1.6
Cefotaxime 24.3
Erythromycin 42.7
Clarithromycin / 15.9
Levofloxacin 1.0
10,12,69–74
Source: Data taken from references.
a
CLSI (2008) interpretive breakpoints.
b
Parenteral nonmeningitis dose.
Antibiotic Resistance in CAP Pathogens Wunderink, Yin 831
with (invasive or noninvasive) macrolide-resistant S. pneu-
moniae pneumonia.26
Two reasonable explanations for this phenomenon are
possible. Macrolides could work not only for their antimicro-
bial properties but also for their immunomodulatory and
anti-inflammatory properties.27 Macrolides can downregu-
late prolonged inflammation, increase mucus clearance, in-
crease mucociliary clearance, prevent the formation of
bacterial biofilm, decrease bacterial adhesion to the epitheli-
um, etc. Those characteristics may make macrolides more
useful than other types of antibiotics. A second possibility is
that, in the case of pneumonia caused by extracellular patho-
gens such as S. pneumoniae, antimicrobial concentrations in
the lung are likely more important for determining therapeu-
tic efficacy than are plasma concentrations. Macrolides may
achieve greater concentrations in the lung than plasma
concentrations.28
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Fluoroquinolone Resistance
Since the late 1990s, newer fluoroquinolones with enhanced
pneumococcal activity and coverage of atypical pathogens,
including levofloxacin and moxifloxacin, have been a first-line
choice for the treatment of CAP. Fluoroquinolones are the only
class of antimicrobial agents that could directly inhibit the
bacterial DNA-directed protein synthesis via inhibition of DNA
gyrase and topoisomerase IV. The most common mechanism
of resistance to fluoroquinolones is mutations in the quinolone
resistance–determining regions (QRDRs) of genes encoding
subunits of topoisomerase IV (parC) or DNA gyrase (gyrA).
Although failures of levofloxacin in the treatment of
lower–respiratory-tract infections have been reported,29 flu-
oroquinolone resistance still remains low. In the United
States, fluoroquinolone activity as measured by levofloxacin
susceptibility ranged from 98.7 to 98.8%.11 The highest fluo-
roquinolone resistance prevalence also emerged in the coun-
tries with higher penicillin- and macrolide-resistant rates
(shown in ►Table 2).
Association between Vaccine and Drug Resistance
Following the introduction of the pneumococcal 7-valent
conjugate vaccine (PCV7) and PCV13, the incidence of
Canada China Spain
6.7–15.9 24.5 37
2.5 1.9 0
0.8 10.2 /
8.5 42.1 9.7
54.5 93.8 19–21.1
87.4 20.9
0–1.4 2.6 0.5–5.6
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
832 Antibiotic Resistance in CAP Pathogens Wunderink, Yin
invasive pneumococcal disease (IPD) declined drastically,
coinciding with a decrease in penicillin resistance.30,31 Before
the introduction of PCV7, seven serotypes—4, 6B, 9V, 14, 18C,
19F, and 23F—were the most prevalent among IPD in North
America. The five serotypes—6B, 9V, 14, 19F, and 23F, includ-
ed in the coverage of PCV7—represent the majority of drug-
resistant isolates (over 80%). Therefore, PCV7 vaccination
could potentially reduce the rate of drug resistance among
S. pneumoniae isolates. New generation of PCV13 vaccine
covered all the PCV-7 serotypes plus 1, 3, 5, 6A, 7F, and 19A.
The greater effectiveness on the prevention of IPD can also
help decrease in penicillin resistance.
Between 1998 and 2008, a study in the United States found
a 64% decrease in antibiotic-resistant pneumococci among
children and a 45% decrease among adults older than
65 years.31 From 2009 to 2013, rates of antibiotic-nonsuscep-
tible IPD caused by serotypes included in PCV13 but not in
PCV7 decreased from 6.5/100,000 to 0.5/100,000 in children
younger than 5 years and from 4.4/100,000 to 1.4/100,000 in
adults aged 65 years or older.31
However, the introduction of those vaccines was associat-
ed with a subsequent increase in serotype replacement:
nonvaccine serotypes increasing as a cause of infection.
Vaccine failure might occur due to this kind of serotype
replacement. A new generation vaccine providing protection
for additional serotypes is therefore highly desirable.
Mycoplasma pneumoniae Resistance
M. pneumoniae is a common pathogen of CAP, generally
associated with mild-to-moderate self-limited CAP.6,32 Lack
of cell walls in mycoplasmas makes them intrinsically resis-
tant to β-lactams. Macrolides, tetracyclines, and fluoroqui-
nolones are the recommended choices for the treatment of M.
pneumoniae infection.
Since 2000, macrolide-resistant M. pneumoniae (MRMP)
have rapidly emerged worldwide, especially in Asian coun-
tries.33–35 Currently, 60 to 90% of Chinese isolates are resis-
tant to erythromycin and azithromycin.34,36 In the United
States and European countries, the prevalence of MRMP still
remains at a low level.
M. pneumoniae can develop macrolide resistance by point
mutations in the 23S rRNA gene, which reduces the affinity of
the antibiotic for the ribosome. Among those mutations in the
sequence of 23S rRNA, A2063G was the most prevalent,
Table 3 MIC (mg/L) range of selected antimicrobial agents against M. pneumoniae
United states China
Erythromycin
0.008–  256 0.004–  256
Azithromycin / <0.004–  128
Levofloxacin 0.031–1 0.032–0.5
Moxifloxacin / 0.016–0.5
Tetracycline 0.031–1 0.008–1
34,35,38,75
Source: Data taken from references.
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
followed by A2064G, A2063T, and A1290G. A2063G and
A2064G mutations are always responsible for the high-level
macrolide resistance in M. pneumoniae.34
As an alternative to the time-consuming agar- and broth-
based in vitro testing method, point mutations in the 23S
rRNA region can be identified as a marker of macrolide
resistance by polymerase chain reaction (PCR) methods in
respiratory samples. However, whether those point muta-
tions will be responsible for all the MRMP strains can be
argued. Results from clinical specimens revealed that the
aforementioned 23S rRNA point mutations were not detected
in some isolated strains with low-to-moderate level of macro-
lide resistance.37
Controversy exists regarding how in vitro resistance trans-
lates into clinical outcomes. Large-scale clinical trials are
scarce on this subject. Available data indicated that infection
with MRMP will lead to a longer duration of therapy, persis-
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tent cough, and increased time to resolution of fever com-
pared with treatment-susceptible infection.34 Because of in
vitro susceptibility (►Table 3), fluoroquinolones and tetracy-
clines are recommended as the effective alternatives when M.
pneumoniae pneumonia is suspected and the treatment of
macrolide was not effective.34,36,38
Whether macrolides should be removed as the first-line
choice of M. pneumoniae pneumonia is doubtful. Pneumonia
caused by M. pneumoniae is often mild to moderate and, most
of the time, self-limited. An in vitro study indicated that
macrolides could still work in the treatment of MRMP infec-
tion due to its immunomodulatory and anti-inflammatory
properties.39
Legionella pneumophila Resistance
L. pneumophila is an intracellular microorganism that causes
nosocomial pneumonia and CAP. L. pneumophila serogroup 1
is considered to be responsible for up to 80 to 90% of human
infections.
Because of the ability to survive and multiply in human
macrophages, L. pneumophila treatment requires antimicro-
bial agents that are active intracellularly. Macrolides and
fluoroquinolones are the most commonly used antimicro-
bials in the treatment of L. pneumophila. Between macrolides
and quinolones, the latter was suggested to have greater
effectiveness (►Table 4). Meta-analysis found that quinolone
therapy was significantly associated with a shorter length of
Japan South Korea M. pneumoniae
ATCC 29342
128–  128 2–  128 0.004–0.03
16–  128 1–64
0.06
0.5–1 0.016–0.5 0.12–1
0.0625–0.125 0.008–0.06 0.03–0.25
0.25–1 0.016–0.5 0.06–0.5

Table 4 MIC of selected antimicrobial agents against L. pneumophila and C. pneumoniae41
Antibiotics L. pneumophila (n ¼ 146)
MICs range (mg/L)
Azithromycin 0.03–0.5
Clarithromycin 0.008–0.12
Levofloxacin 0.008–0.03
Doxycycline 1–4
hospital stay, reduced mortality, higher clinical cure rate,
shorter time to apyrexia, and a lower rate of complications.40
In vitro susceptibility also demonstrated that levofloxacin
was 20-fold more active than erythromycin, based on MIC90
values of 0.03 and 0.5 mg/L, respectively.41 In an experimental
model of L. pneumophila pneumonia, levofloxacin at 1 mg/L
has been shown to achieve a better bactericidal activity
against intracellular organisms grown in guinea pig alveolar
macrophages than erythromycin.42
Up to now, no macrolide resistance has been reported in
clinical strains. Although acquired resistance to the macro-
lides and fluoroquinolones in L. pneumophila has been select-
ed in vitro, published data are limited on the clinical
prevalence of antimicrobial resistance in L. pneumophila.43
Recently, a fluoroquinolone-resistant strain of L. pneumophila
was isolated in a legionellosis patient treated with ciproflox-
acin.44 This patient was treated with 400 mg of ciprofloxacin
intravenously twice daily upon the positive result of urine
antigen test of Legionella. But the clinical condition of this
patient deteriorated, leading to intubation and mechanical
ventilation. A point mutation in the QRDR of the gyrA gene
was identified in the strain isolated from bronchoalveolar
lavage and MIC value of ciprofloxacin of 2 mg/L was found
(MIC of levofloxacin was 0.5 mg/L and moxifloxacin was 1.5
mg/L). Therapy was then switched to 500 mg of clarithromy-
cin orally twice daily and the patient recovered. From a cohort
of 82 patients with legionellosis, Shadoud and colleagues45
isolated two strains of L. pneumophila with gyrA83 mutation
associated with a significant increase in fluoroquinolones
MICs. These two patients required ICU admission and pro-
longed hospitalization, but recovered under combined fluo-
roquinolone and macrolide treatment. Those findings
indicated that fluoroquinolone resistance in L. pneumophila
does emerge and the clinical impact will need to be evaluated
more thoroughly in clinical studies and susceptibility testing.
Chlamydophila pneumoniae Resistance
C. pneumoniae is also an intracellular bacterial pathogen
that accounts for approximately 1.9 to 8.0% of CAP cases.7,32
C. pneumoniae are susceptible to a wide variety of antibiotics
that interfere with DNA and protein synthesis intracellularly,
including tetracyclines, macrolides, quinolones, and
rifamycins.
According to in vitro susceptibility testing,41 the most
active agent was clarithromycin, followed by azithromycin
(►Table 4). Doxycycline and fluoroquinolones were also
Antibiotic Resistance in CAP Pathogens Wunderink, Yin 833
C. pneumoniae (n ¼ 9)
MICs ranges (mg/L)
0.06–0.12

0.008–0.03
0.25–1
0.06–0.25
active against C. pneumoniae. Relatively few clinical C. pneu-
moniae isolates with antimicrobial resistance have been
described. Although in vitro selected C. pneumoniae resistant
to rifampin has been reported, no clinical strains have been
isolated yet.46,47 But due to the difficulty of isolation of C.
pneumoniae and the lack of standardized methods for in vitro
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susceptibility testing, the prevalence of antibiotic resistance
in C. pneumoniae may be underestimated.
Staphylococcus aureus Resistance
S. aureus has typically been the second or third most common
bacterial cause of CAP, particularly in relation to influenza
epidemics and in critically ill patients. This frequency is not
surprising, given that 30% of humans have asymptomatic
nasal colonization with S. aureus.
Penicillin Resistance
When penicillin and sulfa-antibiotics were first introduced
into routine clinical practice in the 1930s and early 1940s, S.
aureus was equally susceptible as S. pneumoniae. By the mid-
1940s, penicillin-resistant strains were emerging in hospital-
acquired infections.48 Once the nosocomial infection resis-
tance rates approached 50%, community-acquired penicillin-
resistant S. aureus infections appeared and gradually in-
creased in frequency.49 This initial resistance mechanism
was plasmid encoded, facilitating the spread of resistance,
although the mechanism was hydrolysis of the β-lactam ring.
This hydrolysis mechanism resulted in very narrow resistance
pattern only for penicillin but not including other β-lactams,
such as cephalosporins. In addition to cephalosporins, devel-
opment of semisynthetic penicillins, such as methicillin and
oxacillin, quickly filled in the antibiotic susceptibility gap
when methicillin-sensitive S. aureus (MSSA) is documented
as the only pathogen.
Thankfully, standard antibiotics for CAP usually cover
MSSA adequately, at least until cultures return and specific
treatment with oxacillin or cefazolin can be substituted.
Quinolones have been associated with selection for methicil-
lin resistance, with less risk from moxifloxacin than other
quinolones.
Methicillin Resistance
The first reports of methicillin-resistant S. aureus (MRSA)
were published in 1961. The mecA gene mutation responsible
encodes for a low affinity PBP2a. Importantly, the mecA gene
resulted in resistance to the entire β-lactam class of
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
834 Antibiotic Resistance in CAP Pathogens
antibiotics, including carbapenems as well as penicillins and
cephalosporins. The frequency of MRSA progressively in-
creased in hospitalized patients until 50 to 70% of isolates
in some institutions were MRSA rather than MSSA.
MRSA as a cause of CAP began to be increasingly reported,
principally in the context of HCAP.50 Unfortunately, early
studies of HCAP used criteria developed for healthcare-asso-
ciated bacteremia and were based primarily on culture-
positive case of pneumonia. However, increasingly data
have demonstrated that the incidence of MRSA CAP is less
than originally estimated.6 One estimate based on discharge
diagnoses suggests that the incidence is only 3 to 4%.51
Further concern was raised by data that treatment of patients
with HCAP risk factors with usual CAP antibiotics, which do
not include coverage of MRSA, has better outcome in general
than broad-spectrum antibiotics, including MRSA
coverage.1,2,52
A more current study has reassessed risk factors for MRSA
as a cause of CAP.1 The independent risk factors for MRSA CAP
are listed in ►Table 5. These risk factors are slightly different
than those for MDR gram-negative etiologies for CAP. An
important finding is that at least two risk factors are required
for the risk of MRSA to be high enough to warrant empirical
MRSA treatment. The CDC EPIC study essentially indepen-
dently validated these criteria since patients with some of the
most important risk factors—recent hospitalization, nonam-
bulatory status, and enteral feeding—were not included in the
study and the incidence of MRSA was <1%.6 EPIC also
confirmed that chronic hemodialysis is a risk factor for
MRSA CAP.53
Vancomycin-Intermediate Resistance
The MRSA causing CAP in patients at risk for HCAP (►Table 5)
likely reflect resistance patterns occurring in hospital-ac-
quired S. aureus isolates. The spectrum of vancomycin resis-
tance has been shifting to higher minimal inhibitory
concentrations. The mechanism of resistance in these vanco-
mycin intermediate S. aureus (VISA) isolates is alteration in
the cell wall, making the isolate less susceptible to vancomy-
cin. In infections with a large inoculum, such as pneumonia, a
VISA subpopulation may exist concurrently with the suscep-
tible population, termed heteroresistance. Heteroresistant
strains occurred in up to 14% of isolates from some areas.54
The incidence of VISA and heteroresistance in CAP/HCAP
patients is unknown but probably reflects the local ecology.
Table 5 Risk factors for healthcare-associated MRSA CAP
Hospitalization for  2 days during preceding 90 days
Chronic dialysis during preceding 30 d
Congestive heart failure
Use of antibiotics in previous 90 d
Positive MRSA culture in previous 90 d
Use of gastric acid suppressive agents
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
Wunderink, Yin
Community-Acquired MRSA
In the early 1990s, MRSA infections in otherwise healthy
people were increasingly reported. Initially, reports described
skin and soft-tissue/wound infections but increasingly cases
of CAP were reported. Community-acquired MRSA (CA-
MRSA) CAP was associated with significant mortality,55 espe-
cially notable because of the frequent occurrence in an
otherwise normal host.
Analysis demonstrated that the methicillin-resistance
gene in these strains was located on a different chromo-
somal cassette than previous hospital-acquired strains.
Probably equally important, genes encoding various exo-
toxins were also transmitted with this mecA gene cassette.
Panton-Valentine leukocidin (PVL) received the greatest
interest, although other exotoxins, particularly α-hemoly-
sin, are more likely the cause of the serious complications.
PVL-positive stains were associated with different reperto-
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ries of exotoxins from different areas of the world. The
initial North American strain was the USA400 clone: the
more pathogenic USA300 clone now dominates in most
areas of the United States.
The clinical presentation of patients with CA-MRSA CAP is
relatively unique (►Table 6). While now becoming more
common in patients with risk factors for HCAP as well, the
classic is still in patients with no underlying disease or at least
well-controlled chronic diseases such as diabetes mellitus.53
Rapid progression of infiltrates and pleural effusions is also
classic and development of necrosis or even cavitation at the
time of presentation should significantly increase suspicion
for CA-MRSA. Massive hemoptysis (►Fig. 1) is an ominous
sign.56 Influenza coinfection appears to be a risk factor, but
CA-MRSA CAP can occur during all seasons. Expression of
other exotoxins can also cause skin rashes and hypotension,
similar to the toxic-shock syndrome.
Confirmation of CA-MRSA CAP is usually not difficult—
cultures from almost every site are usually positive on Gram
stain and rapidly grow on culture even if a few doses of
antibiotics have been given. Bacteremia is more common than
most other causes of CAP. Thankfully, the single mecA gene
mechanism of resistance in CA-MRSA lends makes it an ideal
target for newer molecular diagnostics based on PCR detec-
tion of the mecA gene.
Because exotoxins play such an important role in the
pathogenesis of CA-MRSA CAP, antibiotics which interfere
with ribosomal synthesis can have a beneficial effect on
blocking toxin production independent of the bactericidal/
bacteriostatic properties.6 Linezolid is probably the most
reliable antibiotic,57 while combining clindamycin with van-
comycin may have equivalent activity.58 Other drugs poten-
tially appropriate for skin infections, such as trimethoprim/
sulfamethoxazole, tetracyclines, and clindamycin alone, are
not appropriate for CA-MRSA CAP. MSSA strains can also
demonstrate prominent exotoxin production and can be as
lethal as CA-MRSA for CAP. However, the rapidly bactericidal
β-lactams minimize exotoxin production. A similar effect
with ceftaroline, a cephalosporin with in vitro MRSA activi-
ty,59 is possible but data on treatment of CA-MRSA CAP are
currently lacking.

Table 6 Risk factors for community-acquired MRSA CAP
Lung necrosis
Early cavitation
Rapid increase in size of infiltrate
Rapid increase in pleural effusion
Neutropenia
Clindamycin Resistance
Initially, CA-MRSA strains were susceptibility to older oral
agents such as clindamycin and trimethoprim/sulfamethoxa-
zole. The 20% or greater incidence of clindamycin resistance in
both MSSA and MRSA makes it an unreliable agent for
monotherapy of S. aureus CAP. Clindamycin is best reserved
as a combination agent for CA-MRSA or with fluoroquino-
lones in penicillin-allergic patients.
Hemophilus influenzae Resistance
Based on molecular diagnostics, the incidence of H. influenzae
CAP is likely grossly underestimated.60 H. influenzae is equally
or more sensitive to a single dose of antibiotics than pneu-
mococcus. The inability to routinely culture suggests that H.
influenzae resistance is not a big issue. In addition, use of H.
Fig. 1 Autopsy specimen of a previously healthy 43-year-old patient with CA-MRSA who presented with gross hemoptysis.
Antibiotic Resistance in CAP Pathogens Wunderink, Yin 835
Gross hemoptysis
Concomitant influenza
Previously healthy host
Summer month
Erythematous rash
influenzae type b vaccine may be shifting the spectrum to
nontypable strains.61
Ampicillin-resistance occurs in more than 30% of H. influ-
enza isolate in North America; most can still be adequately
treated with ceftriaxone.61,62 Beta-lactam resistance with
mechanisms other than a β-lactamase appear to be increasing
in prevalence.63
Downloaded by: State University of New York at Stony Brook. Copyrighted material.
Data from acute exacerbations of chronic obstructive
pulmonary disease (COPD) suggest that macrolide resistance
may be the main concern for H. influenzae. Macrolide resis-
tance rates may also be as high as 30%.61 Use of cephalosporin
combination therapy or a fluoroquinolone masks the macro-
lide resistance in most hospitalized CAP patients. Fluoroquin-
olone resistance remains very low for H. influenzae.
Solithromycin, a new fluoroketolide, has activity against
resistant strains of H. influenza as well.64
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 6/2016
836 Antibiotic Resistance in CAP Pathogens
Table 7 Risk factors for gram-negative pathogens resistant to
usual therapy
Hospitalization for  2 days during preceding 90 days
Nonambulatory status
Tube feedings
Use of antibiotics in previous 90 d
Immunocompromised status
Use of gastric acid suppressive agents
Enterobacteriaceae Resistance
A variety of Enterobacteriaceae, such as E. coli, Klebsiella, and
Enterobacter, cause CAP, even in patients without healthcare-
associated risk factors. The frequency can be 2 to 5% of
cases,1,6,65,66 even in immunocompromised patients.67 The
majority of these Enterobacteriaceae are very sensitive to
both cephalosporins and fluoroquinolones. Less than 1% of
these have extended spectrum β-lactamases.1
Risk factors for gram-negative pathogens resistant to usual
CAP therapy are seen in ►Table 7.1 Three risk factors are
required before the risk of drug-resistant pathogens warrants
use of broad-spectrum antibiotics.68 Use of narrow-spectrum
antibiotics in this population is associated with higher
mortality.
Pseudomonas aeruginosa Resistance
Pseudomonas aeruginosa is an uncommon yet important
cause of CAP. Risk factors include those listed in ►Table 7,1
as well as a prior history of severe airways disease, either
severe COPD or bronchiectasis.3,66 Because community-ac-
quired Pseudomonas pneumonia occurs disproportionately in
patients with airway disease, the acuity of illness is signifi-
cantly less than in hospital-acquired pneumonia unless the
patient is severely immunocompromised. Most diagnoses are
made by sputum culture, not bacteremia.
Since the common denominator in all of these situations is
prior antibiotic therapy, a high proportion of isolates are
resistant to the usual CAP therapies, including fluoroquino-
lones. Broad-spectrum β-lactams are usually required for
appropriate treatment.3
Conclusion
Compared with hospital-acquired pneumonia, the impact of
antibiotic resistance in CAP is relatively small. Resistance is
usually confined to fairly well-circumscribed clinical scenari-
os, most often associated with exposure to the hospital
environment. Given this resistance incidence, a strong ratio-
nale is needed for use of antibiotics other than the standard β-
lactam/macrolide or fluoroquinolone regimens.
Seminars in Respiratory and Critical Care Medicine Vol. 37
Wunderink, Yin
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