Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia
BMC Infectious Diseases
Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia
Marin L Schweizer 0 1 2
Jon P Furuno 0
Anthony D Harris 0
J Kristie Johnson 6
Michelle D Shardell 0
Jessina C McGregor 5
Kerri A Thom 0
Sara E Cosgrove 4
George Sakoulas 3 7
Eli N Perencevich 0 1 2
0 Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine , Baltimore, MD , USA
1 Iowa City VA Health Care System , Iowa City, IA , USA
2 Department of Internal Medicine, University of Iowa Carver College of Medicine , Iowa City, IA , USA
3 Department of Pediatrics, University of San Diego School of Medicine , La Jolla, CA
4 Division of Infectious Diseases, Johns Hopkins University School of Medicine , Baltimore, MD , USA
5 Department of Pharmacy Practice, College of Pharmacy, Oregon Health & Science University , Portland, OR , USA
6 Department of Pathology, University of Maryland School of Medicine , Baltimore, MD , USA
7 Department of Medicine, Sharp Memorial Hospital , San Diego, CA
Background: The high prevalence of methicillin-resistant S. aureus (MRSA) has led clinicians to select antibiotics that have coverage against MRSA, usually vancomycin, for empiric therapy for suspected staphylococcal infections. Clinicians often continue vancomycin started empirically even when methicillin-susceptible S. aureus (MSSA) strains are identified by culture. However, vancomycin has been associated with poor outcomes such as nephrotoxicity, persistent bacteremia and treatment failure. The objective of this study was to compare the effectiveness of vancomycin versus the beta-lactam antibiotics nafcillin and cefazolin among patients with MSSA bacteremia. The outcome of interest for this study was 30-day in-hospital mortality. Methods: This retrospective cohort study included all adult in-patients admitted to a tertiary-care facility between January 1, 2003 and June 30, 2007 who had a positive blood culture for MSSA and received nafcillin, cefazolin or vancomycin. Cox proportional hazard models were used to assess independent mortality hazards comparing nafcillin or cefazolin versus vancomycin. Similar methods were used to estimate the survival benefits of switching from vancomycin to nafcillin or cefazolin versus leaving patients on vancomycin. Each model included statistical adjustment using propensity scores which contained variables associated with an increased propensity to receive vancomycin. Results: 267 patients were included; 14% (38/267) received nafcillin or cefazolin, 51% (135/267) received both vancomycin and either nafcillin or cefazolin, and 35% (94/267) received vancomycin. Thirty (11%) died within 30 days. Those receiving nafcillin or cefazolin had 79% lower mortality hazards compared with those who received vancomycin alone (adjusted hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.09, 0.47). Among the 122 patients who initially received vancomycin empirically, those who were switched to nafcillin or cefazolin (66/122) had 69% lower mortality hazards (adjusted HR: 0.31; 95% CI: 0.10, 0.95) compared to those who remained on vancomycin. Conclusions: Receipt of nafcillin or cefazolin was protective against mortality compared to vancomycin even when therapy was altered after culture results identified MSSA. Convenience of vancomycin dosing may not outweigh the potential benefits of nafcillin or cefazolin in the treatment of MSSA bacteremia.
Through the American Recovery and Reinvestment Act
of 2009, Congress requested that the Institute of
Medicine (IOM) recommend national priorities for research
questions to be addressed by Comparative Effectiveness
Research. The first quartile of the IOMs list included a
call to compare the effectiveness of strategies for
reducing healthcare-associated infections . One such
strategy to reduce antibiotic resistant healthcare-associated
infections would be to optimize antibiotic therapy.
The high prevalence of methicillin-resistant
Staphylococcus aureus (MRSA) has led clinicians to select
antibiotics that have coverage against MRSA, usually
vancomycin, for empiric therapy for suspected
staphylococcal infections [2,3] Patients treated initially with
empiric vancomycin are frequently continued on
vancomycin for dosing convenience even after culture
results identify methicillin-susceptible S. aureus (MSSA),
particularly in patients with renal insufficiency .
However, high vancomycin selective pressure may lead to
decreased susceptibility to vancomycin in both MSSA
and MRSA .
Vancomycin has been associated with poor outcomes
such as nephrotoxicity, persistent bacteremia and
treatment failure among MSSA patients [3,5-9]. Higher
mortality in patients with MRSA bacteremia compared to
patients with MSSA bacteremia has been attributable to
differences in host viability, differences in microbial
pathogenicity, and differences in antimicrobial potency,
particularly the inferior anti-staphylococcal killing of
glycopeptides when compared to the beta-lactam antibiotics
nafcillin or cefazolin [7,8,10,11].
Comparative effectiveness research methods are an ideal
methodology to compare treatments for S. aureus
infections because these methods aim to determine
effectiveness in the real-world setting. This study aimed to assess
differences in 30-day in-hospital mortality in patients with
MSSA bacteremia treated with nafcillin or cefazolin
compared to those treated with vancomycin. Additionally, we
assessed whether those treated empirically with
vancomycin would benefit if switched to nafcillin or cefazolin once
MSSA was microbiologically identified.
Study design and patient population
This retrospective cohort study included adult patients
admitted to the University of Maryland Medical Center, a
656-bed tertiary care facility, between January 1, 2003 and
June 30, 2007. Patients were included in the study if they
had a positive blood culture for MSSA and received
vancomycin, nafcillin or cefazolin. Patients with polymicrobial
infections were excluded in order to only assess the
antibiotics and outcomes associated with S. aureus infection.
Patients who only received antibiotics other than
vancomycin, nafcillin, or cefazolin were excluded from the
study. However, if a patient received vancomycin, nafcillin
or cefazolin and another antibiotic (e.g. vancomycin and
piperacillin/tazobactam) they were included in the
Each admission was handled as an independent event
and therefore patients could be included in the study
more than once. Eligible patients were identified using a
relational database that contains medical, pharmaceutical
and microbiologic data. These data have been validated in
previous studies and have positive and negative predictive
values in excess of 99 percent when compared to paper
medical records [12,13]. Additional variables (e.g.
components of the modified Acute Physiology Score [APS]) that
were not available in the relational database were collected
by a research nurse via chart review. This study was
approved by the institutional review board of the
University of Maryland, Baltimore.
The primary outcome of interest was 30-day in-hospital
mortality, which was defined as mortality occurring
during the index hospital admission in the time period
from culture collection to 30 days after culture
collection. The outcome was censored if the patient survived
longer than 30 days after culture collection or if the
patient was discharged alive within 30 days after culture
Severity of illness was measured 24 hours before the
time the culture was obtained using the modified APS. If
the blood culture was obtained within 24 hours of hospital
admission, APS at the time of admission was calculated.
The modified APS is based on the Acute Physiology and
Chronic Health Evaluation (APACHE) III score [14-16].
Since the APACHE III was designed for use among
intensive care unit (ICU) patients, the score has been modified
by excluding variables that are not applicable to this study
population [12-17]. The modified APS includes age,
chronic health (AIDS, hepatic failure, lymphoma,
metastatic cancer, leukemia/multiple myeloma,
immunosupression, cirrhosis), and acute physiologic abnormalities
including pulse rate, mean blood pressure, temperature,
respiratory rate, hematocrit, white blood cell count,
creatinine, pH, blood urea nitrogen, sodium, albumin, bilirubin,
and glucose [12-17]. The Charlson Comorbidity Index, an
aggregate comorbidity score, was calculated using
charge International Classification of Diseases, 9th Revi
sion, Clinical Modification (ICD-9-CM) codes for
comorbid conditions . Blood cultures collected within
48 hours of admission were designated as
communityassociated infections. Time to receipt of nafcillin or
cefazolin was measured from the time the blood culture was
collected to the time the patient first received nafcillin or
cefazolin. Similarly, time to receipt of appropriate therapy
was measured from the time the blood culture was
collected to the time the patient first received an antibiotic in
which the S. aureus isolate from the blood culture was
susceptible in vitro .
Antimicrobial susceptibility profiles were determined
according to Clinical and Laboratory Standards Institute
guidelines . Endocarditis was defined as presence of
an ICD-9-CM code for endocarditis or
echocardiographic findings of vegetation on the index admission.
Hemodialysis was defined as presence of an ICD-9-CM
code for hemodialysis or chronic renal disease on the
index admission. Pneumonia and osteomyelitis were
defined by ICD-9-CM codes on the index admission.
Patients with a positive wound culture before the first
positive blood culture were classified as having a wound
Bivariate associations were assessed using the chi-square
test or Fishers exact test for categorical variables and the
Students t-test or the Wilcoxon Rank Sum test for
continuous variables. Logistic regression models were used to
create two different propensity scores. First, a propensity
score was created using variables that were independently
associated with receipt of nafcillin or cefazolin versus
vancomycin. A separate second propensity score was created
using variables that were independently associated with
switching from vancomycin to nafcillin or cefazolin versus
remaining on vancomycin for use in the model assessing
the clinical benefits of switching to nafcillin or cefazolin if
started on vancomycin.
Cox proportional hazard models were then fit to
measure hazard ratios (HRs) and 95% confidence intervals
(CIs) for the associations of interest. The first Cox
proportional hazard model assessed the association between
receipt of nafcillin or cefazolin versus vancomycin and
mortality controlling for the first propensity score. The
second Cox proportional hazard model assessed the
association between switching from vancomycin to nafcillin or
cefazolin versus remaining on vancomycin and mortality
controlling for the second propensity score. All analyses
were performed using SAS software (SAS Institute, Cary,
NC) version 9.1.
Overall, 326 patients had MSSA bacteremia during the
study period. Thirty-one patients were excluded from the
analysis because they did not receive nafcillin, cefazolin
or vancomycin on the index admission. Of the 31
excluded patients, 14 (45%) did not receive
anti-staphylococcal antibiotic therapy and 17 (55%) did not receive
vancomycin, nafcillin or cefazolin but received other
anti-staphylococcal antibiotics. Twenty-eight patients
with polymicrobial infections were excluded. A total of
267 hospital admissions from 252 individual patients
were included in the final analysis. Fourteen percent (38/
267) received nafcillin or cefazolin alone, 51% (135/267)
received both vancomycin and either nafcillin or
cefazolin and 35% (94/267) received vancomycin alone. Thirty
(11%) patients died within 30 days of culture collection.
All patients in this cohort received vancomycin,
nafcillin, or cefazolin. These patients also could have received
other antibiotics. During the index admission, 40% of the
cohort received piperacillin/tazobactam, 20% received a
third-generation cephalosporin, 12% received
trimethoprim/sulfamethoxazole, 12% received
ampicillin/sulbactam, 10% received clindamycin, 9% received cefepime, 7%
received imipenem, 6% received linezolid, 2% received
daptomycin, and 2% received a second-generation
cephalosporin. Patients who received nafcillin or cefazolin but
not vancomycin were significantly less likely to receive
other anti-staphylococcal antibiotics compared to
patients who received vancomycin (p < 0.01).
Nine percent of patients had a transthoracic
echocardiogram (TTE) then a transesophageal echocardiography
(TEE) performed, 30% had only a TTE and 5% had only
a TEE performed. Of the 40 patients classified as having
endocarditis, 60% were classified by echocardiographic
findings of vegetation and 40% were classified via an
ICD-9-CM code for endocarditis.
Table 1 displays the association between patient and
treatment factors and receipt of antibiotics. Patients who
received nafcillin or cefazolin were less likely to have
renal disease and less likely to undergo hemodialysis,
were less likely to have a central venous catheter, and
had lower median severity of illness and comorbidity
scores compared to patients who received vancomycin
(p < 0.05). Patients who received nafcillin or cefazolin
were more likely to have endocarditis (p < 0.01). Patients
who received nafcillin or cefazolin were not significantly
different than those who received vancomycin in regards
to diagnosis of pneumonia, osteomyelitis, or wound
infections. Patients receiving nafcillin or cefazolin were
somewhat less likely to have their central venous catheter
removed (p = 0.08). However, removal of a central
venous catheter was not associated with mortality (p =
0.83) and it was not a confounder in the association
between receipt of cefazolin or nafcillin and mortality.
When 30-day in-hospital mortality was stratified by
antibiotics received during the index admission, we found
cumulative mortality incidences of 3% (1/38) among
patients who received only nafcillin or cefazolin, 7% (10/
135) among patients who received both vancomycin and
nafcillin or vancomycin and cefazolin, and 20% (19/94)
among patients who only received vancomycin (chi-square
test for trend p < 0.01). When we excluded patients who
received both vancomycin and nafcillin or vancomycin
and cefazolin, those who received nafcillin or cefazolin
only were less likely to die compared to those who
received vancomycin only (unadjusted HR: 0.10; 95% CI:
0.01, 0.76). Those who received nafcillin or cefazolin,
including those who received both vancomycin and
nafcillin or cefazolin, were significantly less likely to die
compared to patients who received only vancomycin, after
statistically adjusting for the propensity score which
included severity of illness, aggregate comorbidity, age,
admission to the ICU prior to culture collection,
hemodialysis, endocarditis, time to receipt of appropriate therapy,
and receipt of other anti-staphylococcal antibiotics
(adjusted HR: 0.21; 95% CI: 0.09, 0.47) (Table 2).
In order to evaluate the benefit of switching therapy
from vancomycin to nafcillin or cefazolin, we examined
the cohort of patients who received vancomycin
empirically, excluding the 13 patients who received nafcillin or
cefazolin before receipt of vancomycin. Of the 122 patients
Age, mean SD, year
Central venous catheter removed
Table 1 Characteristics of the study population stratified by receipt of nafcillin or cefazolin
Data are no. (%) of admissions, unless otherwise indicated. IQR, interquartile range; ICU, intensive care unit; SD, standard deviation.
in this sub-cohort, 66 (54%) were switched from
vancomycin to nafcillin or cefazolin. The median time from receipt
of vancomycin to the switch to nafcillin or cefazolin was
3.0 days (interquartile range: 2.4, 3.9 days).
Patients who switched from vancomycin to nafcillin or
cefazolin were less likely to die compared to those who
remained on vancomycin (unadjusted HR: 0.33; 95% CI:
0.13, 0.87). This association remained significant after
statistically adjusting for the propensity score which
included severity of illness, aggregate comorbidity,
admission to the ICU prior to culture collection,
communityassociated infection, time to receipt of appropriate
Table 2 Propensity score adjusted associations between receipt of nafcillin or cefazolin versus vancomycin and 30-day
Adjusted hazard ratio and 95%
Switch from vancomycin to nafcillin or cefazolin versus remaining on
vancomycin and 30-day in-hospital mortality
Variables included in the
therapy, endocarditis, hemodialysis, and age (adjusted
HR: 0.31; 95% CI: 0.10, 0.95) (Table 2). The association
remained when the six patients who died or were
discharged within 24 hours of culture collection were
excluded. Similarly, switching from vancomycin to
nafcillin or cefazolin remained protective when this variable
was treated as a time varying covariate in the statistical
Among the subset of 139 patients who had a central
venous catheter, receipt of nafcillin or cefazolin was
protective against mortality after statistically adjusting for
the propensity score (adjusted HR: 0.26; 95% CI: 0.10,
0.69). When the cohort was stratified by severity of illness
(modified APS16 or > 16), the cumulative mortality
incidences in both strata were lowest among patients
who received nafcillin or cefazolin only (0% and 11.1%
respectively), followed by patients who received both
vancomycin and nafcillin or cefazolin (1.4% and 13.9%
respectively) and highest among patients who received
vancomycin only (8.6% and 27.1% respectively).
When only the first admission per patient was
analyzed, the results did not change. Receipt of nafcillin and
cefazolin at anytime (adjusted HR: 0.20; 95% CI: 0.09,
0.44) and switching from vancomycin to nafcillin or
cefazolin (adjusted HR: 0.28; 95% CI: 0.09, 0.86) remained
protective against mortality.
When analyzed separately, both nafcillin and cefazolin
were protective against mortality. These associations
remained after adjusting for propensity scores, although
the association between nafcillin and mortality was not
statistically significant (nafcillin adjusted HR: 0.45; 95%
CI: 0.18, 1.15; cefazolin adjusted HR: 0.25; 95% CI: 0.09,
0.66). Additionally, among the 173 patients who ever
received nafcillin or cefazolin, 6% died within 30 days of
culture collection. Patients who died had a longer time
to receipt of nafcillin or cefazolin (mean = 4.0 days,
standard deviation [SD] = 4.5 days) compared to those
who survived (mean = 2.5 days, SD = 6.6 days).
Clinicians are often faced with therapeutic trade-offs that
balance risk and benefit. When faced with treating
staphylococcal infections, this may include balancing the ease of
administration of vancomycin compared to the more
challenging administration of beta-lactam antibiotics such as
nafcillin with a potential trade-off in efficacy. In this
comparative effectiveness analysis, we found that receipt of
nafcillin or cefazolin in MSSA bacteremic patients was
independently associated with a 79% lower adjusted rate
of mortality compared to vancomycin. In addition,
switching antimicrobial therapy from vancomycin to nafcillin or
cefazolin was also highly protective against mortality.
Thus, while the initiation of empiric vancomycin therapy
in cases of suspected S. aureus bacteremia is reasonable
pending microbiological confirmation of S. aureus and
susceptibilities, this data provides strong evidence for the
importance of switching therapy to nafcillin or cefazolin
once culture results confirm MSSA bacteremia. The
benefit was present in this cohort even though the median time
to switching was three days, suggesting that it is beneficial
to switch away from vancomycin even in settings without
access to rapid diagnostics.
This study found that the probability of survival was
greater among patients who received only nafcillin or
cefazolin compared to those who received both
vancomycin and nafcillin or cefazolin. It could be postulated that
clinicians may prescribe more antibiotics to the patients
with severe underlying conditions, which could lead to
these results. However, this trend remained even after
the cohort was stratified by severity of illness. Another
potential reason for these differences may be due to
betalactam antagonism, perhaps through penicillin-binding
protein substrate competition [21,22]. However, a recent
study found a lack of antagonism between oxacillin and
vancomycin against MSSA .
The differences in mortality among patients who
received vancomycin compared to those who received
nafcillin or cefazolin may also be explained by
pharmacodynamic differences among these agents, particularly with
respect to their interactions with innate host defense
molecules. Not only are nafcillin or cefazolin more potent
bactericidal agents in vitro compared to vancomycin, but
they also act synergistically with innate host defense
cationic antimicrobial peptides such as platelet microbicidal
proteins (PMPs) in killing S. aureus .
The recent clinical practice guidelines by the Infectious
Disease Society of America for the treatment of MRSA
stated that vancomycin is clearly inferior to beta-lactams
for MSSA bacteremia and infective endocarditis and cited
five studies to support this statement . Two of the
cited studies assessed the use of vancomycin among
intravenous drug users with endocarditis [26,27]. The three
other cited studies compared outcomes among patients
with S. aureus bacteremia who received vancomycin and
those who received nafcillin or cefazolin [7-9]. Chang et al.
found that nafcillin was superior to vancomycin in
preventing recurrence of S. aureus bacteremia but that study
was not designed to assess mortality and did not assess
the impact of switching from vancomycin to nafcillin .
In contrast, Stryjewski et al. evaluated a cohort of
hemodialysis-dependent patients with MSSA bacteremia, in
which all patients initially received vancomycin. They
found that treatment failure was more common among
patients who continued on vancomycin compared to those
who were switched to a first-generation cephalosporin
(adjusted Odds Ratio: 3.5; 95% CI: 1.2, 13.5). In that study,
treatment failure was defined as death or recurrent
infection, but it was not sufficiently powered to assess mortality
alone . Kim et al., compared receipt of vancomycin
versus beta-lactams among MSSA bacteremia patients
admitted to two South Korean hospitals. They found that
receipt of vancomycin was associated with increased
mortality (adjusted OR: 3.3; 95% CI: 1.2, 9.5). However, less
than 10% of the patients in that study received
vancomycin. Thus their results may not be generalizable to other
populations in which a higher proportion of S. aureus
bacteremic patients receive vancomycin . Additionally,
three more studies compared vancomycin to beta-lactam
antibiotics among patients with endocarditis or
pneumonia and found that those who received vancomycin had
worse patient outcomes [28-30].
None of the prior studies assessed the benefits of
switching from vancomycin to nafcillin or cefazolin in a general
patient population, as we have shown here. This finding
identifies a potential target for interventions designed to
improve antibiotic prescribing and infectious disease
outcomes. A clinical alert or reminder to switch to nafcillin or
cefazolin in non-allergic patients with MSSA bacteremia
would be expected to improve clinical outcomes with
This current study is a subset of a larger cohort of all
UMMC patient admissions with S. aureus bacteremia,
including both MRSA and MSSA. Similar to our current
findings, in the larger cohort we found that appropriate
definitive antibiotic therapy was protective against
mortality; however, appropriate empiric antibiotic therapy was
not protective against mortality . Thus, a short time to
receipt of antibiotics may not be as important as eventual
receipt of optimal antibiotics.
Our study had several limitations. The results could be
affected by residual confounding because patients who
received nafcillin or cefazolin were healthier compared to
those who received vancomycin. However, through our
propensity scores we controlled for many factors that may
affect health such as severity of illness, aggregate
comorbidity, endocarditis and receipt of other
anti-staphylococcal antibiotics. In addition, our multivariable analysis
suggested that switching to nafcillin or cefazolin was
associated with a 69% reduction in risk of 30-day mortality. It
would be unlikely that residual confounding, beyond the
numerous factors that we already controlled for, could
explain away such a profound protective effect. The
receipt of other anti-staphylococcal antibiotics may also
have led to residual confounding in this study. Yet,
patients who received nafcillin or cefazolin were
significantly less likely to receive other antibiotics compared to
patients who received vancomycin. Additionally, there was
no significant difference in mortality between patients who
received only vancomycin versus vancomycin plus another
antibiotic other than nafcillin or cefazolin (data not
shown). Thus, the benefits of additional antibiotics would
bias our results toward the null.
Our study was limited by its retrospective observational
design. A randomized control study design would be
preferred to study this association, but some clinicians may
consider it unethical to randomly assign patients with
MSSA to vancomycin given these findings. Due to the
retrospective design of this study, we were not able to
evaluate the duration or drug levels of antibiotic treatment.
Thus under-dosing may be unrecognized, especially
among hemodialysis patients. Additionally, only 19% of
the patients with S. aureus bacteremia had an
echocardiographic evaluation and only 60% of cases classified as
endocarditis had an echocardiography. Thus, our
measurement of endocarditis may be less accurate than
measurements done prospectively.
This study suggests that patients with MSSA bacteremia
should receive nafcillin or cefazolin as soon as the
pathogen is definitively identified by culture since there was a
69% lower risk of death in those patients who were
switched from vancomycin. Thus, these results imply that
clinicians should not continue vancomycin for dosing
scheduling convenience, as any benefits from simplified
dosing schedules would be greatly outweighed by the
survival benefits of switching to nafcillin or cefazolin. An
unmeasured potential implication of this study is that the
choice to switch patients from vancomycin to nafcillin or
cefazolin may decrease vancomycin selection pressure,
thus delaying the emergence of decreased susceptibility to
In summary, receipt of nafcillin or cefazolin was
independently associated with decreased mortality compared to
vancomycin in MSSA bacteremia therapy. This benefit
persists even if receipt is delayed until definitive culture results
are available. Choice of empiric antibiotic therapy must
weigh MRSA coverage against potentially superior
antibiotics. Nafcillin or cefazolin should be considered as the
treatment of choice for definitive therapy for MSSA bacteremia.
Acknowledgements and funding
The authors thank Colleen Reilly, Jingkun Zhu, MS, and Kristen Schratz, for
database maintenance and extraction; Jacqueline Baitch, RN, BSN, and Atlisa
Young, MSW for medical chart review.
Presented in part
49th annual Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC), San Francisco, CA, September 13, 2009.
Financial support and disclosure
AD Harris was supported by the National Institutes of Health grants
1R01A160859-01A1 and 1K24AI079040 - 01A1. JP Furuno was supported by
National Institutes of Health grant 1K01AI071015-03. JK Johnson was
supported by National Institutes of Health grant 1K12RR02350-04. JC
McGregor was supported by National Institutes of Health grant KL2RR024141.
EN Perencevich was supported by US Department of Veterans Affairs Health
Services Research and Develop grants RCD-02-026-2 and IIR-05-123-1. MD
Shardell was supported by National Institutes of Health grant K12HD043489.
MLS and ENP have received research support from Pfizer, Inc. GS is a
consultant for Astellas, Cubist, Pfizer, Ortho-McNeal, has served as a speaker
for Astellas, Cubist, Pfizer and has received research support from Cubist. No
conflict: JPF, ADH, JKJ, MDS, JCM, KAT, SEC.
MLS: participated in the design of the study, performed statistical analysis
and wrote the manuscript; JPF, ADH, JKJ, MDS, JCM, KAT, SEC, GS, ENP:
participated in the design of the study and helped to draft the manuscript.
All authors read and approved the final manuscript.
Financial and non-financial competing interests
This study was funded in part by an investigator-initiated research grant
from Pfizer, Inc (IIR GA5951BG). ML Schweizer had full access to all of the
data in the study and takes responsibility for the integrity of the data and
the accuracy of the data analysis.
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