Variability in Pediatric Infectious Disease Consultants’
Recommendations for Management of Community-
Adam L. Hersh1*, Daniel J. Shapiro2, Jason G. Newland3, Philip M. Polgreen4, Susan E. Beekmann4,
Samir S. Shah5,6
1Pediatric Infectious Diseases, University of Utah, Salt Lake City, Utah, United States of America, 2Institute for Health Policy Studies, University of California San Francisco,
San Francisco, California, United States of America, 3Children’s Mercy Hospital and Clinics, Kansas City, Missouri, United States of America, 4University of Iowa Carver
College of Medicine, Iowa City, Iowa, United States of America, 5Departments of Pediatrics and Biostatistics and Epidemiology, and the Center for Clinical Epidemiology
and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 6Division of Infectious Diseases, Center for Pediatric
Clinical Effectiveness, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Background: Community-acquired pneumonia (CAP) is a common childhood infection. CAP complications, such as
parapneumonic empyema (PPE), are increasing and are frequently caused by antibiotic-resistant organisms. No clinical
guidelines currently exist for management of pediatric CAP and no published data exist about variations in antibiotic
prescribing patterns. Our objectives were to describe variation in CAP clinical management for hospitalized children by
pediatric infectious disease consultants and to examine associations between recommended antibiotic regimens and local
antibiotic resistance levels.
Methods: We surveyed pediatric members of the Emerging Infections Network, which consists of 259 pediatric infectious
disease physicians. Participants responded regarding their recommended empiric antibiotic regimens for hospitalized
children with CAP with and without PPE and their recommendations for duration of therapy. Participants also provided
information about the prevalence of penicillin non-susceptible S. pneumoniae and methicillin-resistant S. aureus (MRSA) in
Results: We received 148 responses (57%). For uncomplicated CAP, respondents were divided between recommending
beta-lactams alone (55%) versus beta-lactams in combination with another class (40%). For PPE, most recommended a
combination of a beta-lactam plus an anti-MRSA agent, however, they were divided between clindamycin (44%) and
vancomycin (57%). The relationship between reported antibiotic resistance and empiric regimen was mixed. We found no
relationship between aminopenicillin use and prevalence of penicillin non-suscepetible S. pneumoniae or clindamycin use
and clindamycin resistance, however, respondents were more likely to recommend an anti-MRSA agent when MRSA
Conclusions: Substantial variability exists in recommendations for CAP management. Development of clinical guidelines via
antimicrobial stewardship programs and dissemination of data about local antibiotic resistance patterns represent
opportunities to improve care.
Citation: Hersh AL, Shapiro DJ, Newland JG, Polgreen PM, Beekmann SE, et al. (2011) Variability in Pediatric Infectious Disease Consultants’ Recommendations for
Management of Community-Acquired Pneumonia. PLoS ONE 6(5): e20325. doi:10.1371/journal.pone.0020325
Editor: Brad Spellberg, Los Angeles Biomedical Research Institute, United States of America
Received March 21, 2011; Accepted April 21, 2011; Published May 31, 2011
Copyright: ? 2011 Hersh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by grant/cooperative agreement number U50 CCU112346 from the Centers for Disease Control and Prevention (CDC). The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Community acquired pneumonia (CAP) is a common serious
infection in childhood, accounting for over 150,000 hospitaliza-
tions each year in the US . Despite its importance, no national
clinical guidelines currently exist for the management of pediatric
CAP. Recent evidence indicates that overall antibiotic utilization
for hospitalized children varies widely across hospitals ,
although the extent to which this variation exists for individual
conditions, such as CAP, remains unknown.
CAP-associated complications, such parapneumonic empyema
(PPE), have increased in recent years [1,3,4]. Antibiotic-resistant
organisms, especially Staphylococcus aureus and Streptococcus pneumoniae
are important causes of CAP and PPE. Resistance patterns
for these organisms vary widely throughout the United States
[5,6,7,8]. The extent to which antibiotic recommendations for
pneumonia reflect local resistance patterns for these organisms is
unknown. For instance, it is unknown whether clindamycin and
vancomycin, which have activity against methicillin-resistant S.
aureus (MRSA), are recommended more frequently for PPE in
PLoS ONE | www.plosone.org1 May 2011 | Volume 6 | Issue 5 | e20325
communities where MRSA prevalence is higher. Delays in
matching the antibiotic spectrum to the causative bacteria is
clinically relevant for CAP [9,10].
Infectious disease consultants are frequently involved in the care
of children with CAP and local guideline development for the
management of CAP. Additionally, interventions such as antimi-
crobial stewardship programs (ASPs, hospital-based interventions
where antimicrobial prescribing is monitored and physicians
receive feedback), and unit- or disease-specific antibiograms
provide assistance to physicians in selecting the optimal empiric
antibiotic and are typically led by infectious disease consultants
[11,12,13,14]. The objectives of this study were to describe
variation in the clinical management by pediatric infectious
diseases consultants for hospitalized children with CAP and to
examine the associations between infectious disease consultants’
recommended antibiotic regimens, reported antibiotic resistance
levels in their communities, and the presence of ASPs.
Materials and Methods
This study was determined to be exempt from review by the
University of Iowa Institutional Review Board and is not
considered to be human subjects research.
We conducted a survey of pediatric infectious diseases
consultants during Fall 2009 regarding their management
recommendations for pediatric CAP and the reported prevalence
of antibiotic resistance among S. pneumoniae and S. aureus in their
community. All survey questions related to hospitalized children
ages 1–18 years, with no known underlying medical conditions
predisposing them to severe or recurrent pneumonia. Respondents
completed an electronic or paper data entry form. Non-
respondents received up to 2 follow-up queries.
The data source was the pediatric members of the Emerging
Infections Network which consists of 259 pediatric infectious
diseases physicians throughout North America. Membership is
drawn from the Pediatric Infectious Diseases Society and the
Infectious Diseases Society of America and includes physicians
from 44 states and 3 Canadian Provinces. EIN members represent
over 50% of the children’s hospitals in the United States .
The EIN maintains demographic data on individual members
including years of practice, geographic region and practice setting.
For this survey we ascertained supplementaryinformation including
the type of hospital with which the respondent is primarily affiliated
(freestanding children’shospital,children’shospital withina hospital
and general hospital with pediatric beds) and whether or not the
hospital has housestaff, whether the hospital has an antimicrobial
stewardship program, and whether there is a clinical guideline or
pathway for CAP.
To address the first objective, survey respondents were asked to
select the specific antibiotic agent or combination of agents that
they recommended for children hospitalized for CAP, distinguish-
ing between uncomplicated and PPE cases. We defined uncom-
plicated CAP by the presence of a focal consolidation and PPE by
the presence of a focal consolidation plus empyema. For each case,
respondents selected among one or more of the following
agents: ampicillin, ampicillin/sulbactam, 2nd/3rd
cephalosporins, azithromycin, vancomycin, clindamycin and line-
zolid. For subsequent analyses, we categorized ampicillin,
ampicillin/sulbactam and cephalosporins as beta-lactam antibiot-
ics and vancomycin, clindamycin and linezolid as anti-MRSA
antibiotics. Respondents were also asked to select the duration of
antibiotic therapy they recommend for uncomplicated and PPE
cases. Respondents selected among the following categories: 3–5
days; 6–7 days; 8–10 days; 11–14 days; 15–21 days; .21 days.
To collect data for the second objective, respondents were asked
to estimate the resistance levels among isolates in their hospital for
S. pneumoniae and S. aureus. To characterize S. pneumoniae, they
indicated the percentage of isolates with intermediate susceptibility
to penicillin (defined as mean inhibitory concentration (MIC) of
4 mg/mL) and penicillin resistance (defined as an MIC of $8 mg/
mL). To characterize S. aureus, they indicated the percentage of all
S. aureus isolates that are MRSA and the percentage of MRSA
isolates that are resistant to clindamycin (including by D-test). For
all three estimates, they selected among the following categories:
,10%; 10–25%; 26–50%; and .50%.
We used descriptive statistics to describe variations in the
recommended empiric antibiotic regimens, andrecommended
treatment durations. We performed a chi-square test for linear
trend to determine whether there was an association between
respondents’ recommended antibiotic regimens and their
estimates for resistance levels. Specifically, we hypothesized
that respondents that reported a lower percentage of penicillin
non-susceptible isolates (intermediate plus resistant) would be
more likely to recommend an aminopenicillin-containing
antibiotic (e.g. ampicillin or ampicillin/sulbactam) in their
empiric regimen for uncomplicated CAP. We also hypothesized
that respondents reporting a higher reported percentage of
MRSA among S. aureus isolates would be more likely to include
an anti-MRSA agent in their empiric regimen for PPE.
Additionally, we hypothesized that among those who included
an anti-MRSA agent for PPE, those with higher reported
clindamycin resistance would be less likely to select clindamycin
(as opposed to vancomycin or linezolid).
Because any observed relationships between antibiotic regimens
and reported resistance levels could be subject to confounding, we
conducted multivariable analysis using logistic regression to
examine the association of other factors, besides resistance, with
antibiotic recommendations using data from the survey. Specifical-
ly, we developed a model for the relationship between reported
resistance for S. pneumoniae and aminopencillin use for uncomopli-
cated CAP and reported clindamycin resistance and clindamycin
selection for PPE. To identify variables for inclusion in the model,
we first examined the bivariate associations between independent
and dependent variables. The independent variables considered for
inclusion in the models were hospital type (freestanding children’s,
children’s hospital within a hospital or pediatric ward); whether or
not the hospital has housestaff; geographic region; presence of an
ASP; presence of a CAP clinical guideline; and reported resistance
levels for penicillin, MRSA and clindamycin. The dependent
variables for the two models were aminopenicillins for uncompli-
cated CAP and clindamycin for PPE. In the final models we
included variableswith a bivariateassociation ofp ,0.2. Forcertain
variables where we hypothesized that a relationship might exist (e.g.
ASP and CAP clinical guideline) we tested the model outcome by
forcing the variable into the model even if the bivariate association
was below 0.2. All analyses were conducted using STATA 11
(STATA CORP, College Station, TX).
Variability Management of Pediatric Pneumonia
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We received responses from 148 out of 259 members for an
overall response rate of 57%. We found no differences between
respondents and non-respondents in terms of their employment
settings, the region of the country where they practiced, or their
total years of experience. Seven respondents did not provide
inpatient clinical care, leaving 141 respondents for subsequent
analysis. Among these, 48% reported having an ASP at their
institution and 34% reported having a clinical pathway or
guideline for CAP.
Antibiotic regimens for uncomplicated CAP
There was considerable variation in the categories of recom-
mended regimens for uncomplicated CAP (Table 1). Data were
available from all 141 respondents. Most respondents (95%)
recommended a beta-lactam, although they were divided among
thoserecommending a beta-lactam alone and thoserecommending a
beta-lactam in combination with another antibiotic category.
Azithromycin was recommended only in the context of combination
therapy (Table 1). An anti-MRSA regimen was recommended in
20% of cases, typically in combination with beta-lactam therapy.
Antibiotic regimens for PPE
For PPE, there was similar variability in terms of the antibiotic
categories included in the recommended regimens (Table 1); 1
respondent did not include antibiotic recommendations for PPE,
leaving 140 respondents for analysis. Most (90%; 127/140)
recommended including an anti-MRSA antibiotic in their empiric
regimen, typically in combination with a beta-lactam antibiotic
with or without concomitant macrolide therapy. Only 7% (10/
140) recommended a beta-lactam alone and 3% (4/140)
recommended a beta-lactam plus azithromycin.
Antibiotic selection within categories
In addition to variation in the antibiotic categories that were
recommended, there was variation within categories in terms of the
specific agents recommended. For beta-lactams, 74% (105/141) of
respondents recommended a cephalosporin for uncomplicated CAP
while 95% (133/140) recommended a cephalosporin for PPE.
Aminopencillins were recommended for uncomplicated CAP by
25% (35/141) of respondents. For anti-MRSA agents, further
variation was noted. For uncomplicated cases, clindamycin was
recommended by 86% (24/28) of respondents and vancomycin by
14% (4/28) of those recommending this category. For PPE,
clindamycin was included in the recommended anti-MRSA regimen
by 44% (55/126) of respondents, vancomycin by 57% (72/126) and
linezolid by 4% (5/126). This sums to .100% due to 6 respondents
recommending multiple anti-MRSA agents concurrently.
Duration of therapy
Overall, respondents generally recommended longer duration
for PPE than for uncomplicated cases (Figure 1). For uncompli-
cated cases, 140 respondents provided data for duration and only
10% (14/140) recommended a duration of 7 days or less. The
most common duration was 8–10 days, recommended by 56%
(78/140). For PPE, 138 respondents provided data and 35% (48/
138) recommended 11–14 days, 41% (57/138) recommended 15–
21 days and 17% (24/138) recommended .21 days. We found no
associations between treatment duration and antibiotic regimens,
reported MRSA prevalence, the presence of a clinical guideline or
ASP or years of experience for either uncomplicated CAP or PPE.
Relationship between reported antibiotic resistance and
Aminopenicillins for uncomplicated CAP.
provided data on S. pneumoniae resistance. Among these, 27 (21%)
recommended either ampicillin or ampicillin/sulbactam as the sole
agent for uncomplicated CAP while 100 recommended ano-
ther regimen. The percentage of respondents recommending
aminopenicillins did not increase as the reported prevalence of
penicillin non-susceptible pneumococci decreased. Aminopenicillins
wererecommended in26%ofcaseswherethe reported prevalenceof
penicillin non-susceptible pneumococci was ,10% and 25% of cases
where the prevalence of penicillin non-susceptible pneumococci was
26%–50% (p-value for trend=0.46). Only 4 respondents reported
prevalence .50% for S. pneumoniae non-susceptibility and none
recommended aminopenicillins. In multivariable analysis, based on
bivariate associations, geographic region, reported prevalence of
penicillin non-susceptible pneumococci, presence of ASP and CAP
clinical guideline were included in the model. None of these variables
were independently associated with recommending aminopenicillins.
There were 135 respondents who
provided data on MRSA prevalence and empiric antibiotic
recommendations for uncomplicated CAP and 134 for PPE. In
contrast to penicillin non-susceptible pneumococci, we observed an
agents across the increasing levels of reported MRSA prevalence for
uncomplicated CAP and PPE (Figure 2). For uncomplicated CAP,
Table 1. Empiric antibiotic regimens recommended for
uncomplicated pneumonia and PPE.
Beta-lactam Alone 77 (55)10 (7)
Beta-lactam in combination57 (40) 127 (90)
36 (26) 4 (3)
20 (14) 99 (71)
1 (1) 24 (17)
Anti-mrsa alone 5 (4)1(1)
Anti-mrsa+macrolide2 (1)2 (1)
PPE, parapneumonic empyema.
MRSA, methicillin-resistant S. aureus.
Figure 1. Recommended duration of therapy for uncomplicat-
ed CAP (N=140) and PPE (N=138). CAP, community-acquired
pneumonia; PPE, parapneumonic empyema.
Variability Management of Pediatric Pneumonia
PLoS ONE | www.plosone.org3 May 2011 | Volume 6 | Issue 5 | e20325
the percentage increased from 0% of respondents recommending
anti-MRSA agents who reported MRSA prevalence ,10% to 26%
of thosewho reported MRSA prevalence .50% (p trend=0.14).For
PPE, the percentage increased from 50% of respondents who
reported MRSA prevalence ,10% to 94% of respondents who
reported MRSA prevalence .50% (p trend=0.01).
Selection of clindamycin for an anti-MRSA agent
There were 27 respondents who selected an anti-MRSA agent
for uncomplicated CAP and provided data on clindamycin
resistance and 117 for PPE. Overall, we found no direct
relationship between the selection of clindamycin as an anti-
MRSA agent and the reported level of clindamycin resistance
(Figure 3). For uncomplicated CAP, examining this relationship is
somewhat limited due to the fact that clindamycin was the anti-
MRSA agent recommended by 86% of respondents. There was a
trend towards a decline in the percentage of respondents who
selected clindamycin as reported clindamycin resistance increased,
declining from 100% among those reporting clindamycin
resistance ,10% to 67% among those reporting clindamycin
resistance 25–50% (p trend=0.06), however, selection of clinda-
mycin remained high overall. For PPE, the percentage recom-
mending clindamycin as the anti-MRSA agent was unchanged as
reported clindamycin resistance increased, ranging from 38%–
41% across all levels (p trend=0.86).
Because reported clindamycin resistance did not seem to have a
strong influence on selection of clindamycin versus another anti-
MRSA agent, especially for PPE, we developed a multivariable
logistic model to assess whether any other factors were associated
specifically with recommending clindamycin for PPE. Based on
bivariate associations, the variables included in the model included
reported MRSA prevalence and clindamycin resistance, practicing
at a teaching hospital, the presence of a clinical pathway for
pneumonia and the number of years of clinical experience in
infectious disease. The only factor that was independently asso-
ciated with recommending clindamycin was years of experience.
Compared with those with .15 years of experience, the odds of
recommending clindamcyin as an anti-MRSA agent for PPE (as
opposed to vancomycin or linezolid) was substantially greater for
those with ,5 years (OR 7.8; 95% CI 1.9–31.3) and 5–15 years
(OR 6.4; 95% CI 1.6–25.3). These results were unchanged when
presence of an ASP was forced into the model.
Our study has two important findings. First, we found evidence
that substantial variation exists in the recommendations for CAP
management from pediatric infectious diseases consultants,
including the empiric antibiotic regimens and duration of therapy.
Second, we found that differences in reported local antibiotic
resistance patterns do not fully account for variations in antibiotic
There are currently no national clinical guidelines for pediatric
CAP, although 33% of our respondents indicated that they had a
guideline established at their hospital. While the existence of a
local guideline could reduce variation within an individual
institution, the lack of association between the presence of a
guideline and any of the practice patterns we examined (e.g.
aminopenicillins for uncomplicated CAP) suggests that existing
CAP guidelines are not uniform. Some of the variation we
observed may reflect local factors that differ between hospitals
including resistance patterns or formulary differences. It is likely,
however, that much of the variation in terms of recommended
antibiotics and treatment duration simply reflects a lack of
consensus, due in part to limited evidence. A recently developed
CAP clinical guideline from the Infectious Diseases Society of
America (IDSA) has the potential to improve clinical practice and
CAP is a model condition for the development of clinical
guidelines and ASP interventions considering that it is a common
condition, has geographic variation in etiology and resistance and
the potential for significant practice pattern variation. Empiric
prescribing practices need to be individualized to account for each
institution’s local antibiotic resistance patterns. Additionally,
treatment of CAP, especially PPE, is made more challenging by
the fact that cultures are frequently negative, although newer
molecular methods are promising . The development and
dissemination of clinical guidelines as well as antibiograms to assist
with clinical decision making are important ASP functions .
Figure 2. Percentage of respondents who recommended an
anti-MRSA agent for uncomplicated CAP (N=135) and PPE
(N=134) across a range of reported MRSA prevalence levels in
their community. MRSA, methicillin-resistant S. aureus; CAP, commu-
nity-acquired pneumonia; PPE, parapneumonic empyema.
Figure 3. Percentage of respondents who recommended
clindamycin as an anti-MRSA agent for uncomplicated CAP
(N=27) and PPE (N=117) across a range of reported clinda-
mycin resistance levels. MRSA, methicillin-resistant S. aureus; CAP,
community-acquired pneumonia; PPE, parapneumonic empyema.
Variability Management of Pediatric Pneumonia
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Although antibiograms that are tailored to specific patient
populations with specific conditions (e.g. pneumonia) have the
potential to improve empiric antibiotic prescribing, they may not
be easily accessible or widely used . Furthermore, ASPs and
guidelines can emphasize the importance of viral testing for
patients with CAP, as certain viral infections such as influenza are
associated with higher rates of CAP complications and differences
in the etiology of bacterial co-infection . Previous studies
indicate that many pediatric institutions do not have ASPs and
that existing ASPs have substantial deficiencies . Improving
the extent to which unit and condition specific antibiograms are
made accessible to providers is a key area for ASP to support front-
line prescribing physicians [11,12]. Our findings that ASPs and
CAP guidelines were not associated with differences in treatment
recommendations suggest that opportunities exist for these
interventions to focus on enhancing the treatment of CAP with
narrower spectrum antibiotic alternatives (e.g. ampicillin) and the
extent to which treatment recommendations match local resis-
We were surprised to find no relationship between recom-
mending clindamycin for PPE and reported clindamycin resis-
tance. In particular, many respondents noted that they would
recommend clindamycin despite noting relatively high levels of
resistance in their community. There are several potential
explanations for this result. A lack of reliable susceptibility data
from antibiograms is one possibility. Another is that other factors
favoring clindamycin relative to vancomycin, such as the
availability of an oral formulation and that therapeutic drug
monitoring is not necessary, are more important drivers for ID
consultants’ recommendations. A previous study suggested that ID
consultants do not rank antibiotic resistance among the most
important factors influencing their prescribing decisions . It
may also be that some respondents who prescribe clindamycin in
settings where resistance was reportedly high feel that S. aureus is an
uncommon cause of complicated CAP and thus the risk of a
susceptibility mismatch is low. We did, however, observe a
relationship between higher reported MRSA prevalence and more
recommendations for anti-MRSA agents, indicating that respon-
dents accounted for it as an important pathogen.
Unlike the association between antibiotic selection and MRSA
prevalence, we did not observe a relationship between antibiotic
selection and resistance in the case of aminopenicillins and the
reported prevalence of penicillin non-susceptible S. pneumoniae. As
with selecting clindamycin for MRSA, otherfactorsbesidesresistance
may contribute to physician preferences. In this instance, some
physicians may find aminopenicillins less attractive than cephalospo-
rins because of greater dosing frequency , even with low
prevalence of penicillin non-susceptible S. pneumoniae. At the same
time, evidence supports the use of aminopenicillins for treatment of
CAP, even in the setting of relative resistance [21,22,23], which may
with in this context.
We found that respondents with fewer years of clinical
experience were far more likely to prescribe clindamycin for
PPE than those with more clinical experience. A potential
explanation for this finding is that respondents who completed
training more recently may have more readily adopted practice
patterns reflecting the emergence of the USA300 strain of
community-associated MRSA, which is frequently susceptible to
We are not aware of any other studies that have explicitly
examined the relationship between reported antibiotic resistance and
antibiotic selection. Our findings indicate that many factors
contribute to antibiotic selection, and perceived levels of antibiotic
resistance is not necessarily the primary one. Nonetheless, our
findings with respect to recommendations for clindamycin do raise
some concerns. Use of clindamycin for treatment of pediatric MRSA
infections has increased dramatically nationwide . Because there
may be seasonal, institutional and geographic variation in the
organisms that cause uncomplicated and complicated CAP,
combined with variation in resistance patterns, it is imperative that
physicians have access to updated epidemiologic data for their
community.Indeed, over 80% of our respondents indicated that they
desired more information about local antibiotic resistance rates to
assist in empiric prescribing decisions.
We observed variation in recommendations for macrolides.
Monotherapy with a macrolide was not recommended by any
respondents, even for uncomplicated CAP, presumably as a
reflection of S. pneumoniae resistance. Although IDSA guidelines for
the treatment of adult CAP recommend empiric therapy targeting
atypical pathogens , evidence favoring use of macrolides to
target these organisms (especially Mycoplasma pneumoniae) for
treatment of pediatric CAP is not convincing .
There are several limitations to our study. Because the data are
derived from a survey and not from an administrative database or
chart review, the respondents’ reported practices might not match
their actual practices. Infectious diseases physicians are not usually
the primary prescribers for children with CAP, however, they do
frequently contribute to guidelines and local practice consensus.
Physicians may have different antibiotic prescribing practices for
pediatric CAP for patients in different age groups (e.g. ,1–5 years
and .5 years) which was not captured by this survey. Our analysis
of resistance was based on respondents’ report rather than
antibiogram data and thus may not reflect actual epidemiology.
However, the relationship between what respondents believe the
resistance patterns to be to their and their practice patterns is likely
a more important driver of practice.
We found that substantial variation exists among pediatric
infectious disease consultants in their recommendations for
empiric antibiotic regimens for pneumonia and that this variation
is only partly related to reported local antibiotic resistance
patterns. One area highlighted by our findings is that greater
dissemination improvements to resources about the epidemiology
of local resistance patterns may assist physicians in their selection
of empiric antibiotic regimens for CAP or other conditions where
antibiotic resistance is common.
Conceived and designed the experiments: ALH JGN PMP SEB SSS.
Performed the experiments: ALH JGN PMP SEB SSS. Analyzed the data:
ALH DJS. Wrote the paper: ALH. Critical revision of manuscript: DJS
JGN PMP SEB SSS.
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