Comparative Effectiveness of Cefazolin versus Nafcillin or Oxacillin for Treatment of

Methicillin-Susceptible Staphylococcus aureus Infections Complicated by Bacteremia: A

Nationwide Cohort Study

Jennifer S. McDanel, MS, PhDa,b,c, Mary-Claire Roghmann, MD, MSd,e, Eli N. Perencevich,

MD, MSa,b,c, Michael E. Ohl, MD, MSPHa,b, Michihiko Goto, MD, MSCIa,b, Daniel J. Livorsi,

MD, MSa,b, Makoto Jones, MD, MSf,g , Justin P. Albertson, MSb, Rajeshwari Nair, MBBS,

PhDa,b, Amy M.J. O’Shea, PhDa,b, Marin L. Schweizer, PhDa,b,c

Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City,

Iowaa; Iowa City Veterans Affairs Health Care System, Iowa City, Iowab; Department of

Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowac; Department of

Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore,

Marylandd; Veterans Affairs Maryland Health Care System, Baltimore, Marylande; Department

of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utahf; Veterans

Affairs Salt Lake City Health Care System, Salt Lake City, Utahg

Corresponding Author: Jennifer McDanel, PhD

200 Hawkins Drive

C52-J GH

Iowa City, IA 52242

Phone: (319) 467-5202

Fax: (319) 887-4932

Email: jennifer-mcdanel@uiowa.edu

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights
reserved. For permissions, e-mail: journals.permissions@oup.com. 1
Key points: In this large, multi-center study, patients who received cefazolin for definitive

treatment of methicillin-susceptible Staphylococcus aureus infections complicated by bacteremia

had a lower risk of mortality and similar odds of recurrent infections compared with patients who

received nafcillin or oxacillin.

Abbreviated Title: Treatment for MSSA Bacteremia

Presented In Part: IDWeek, San Diego, CA October 7-11, 2015. Abstract 52930.

2
 ABSTRACT

Background: To treat patients with methicillin-susceptible S. aureus (MSSA) infections, beta-

lactams are recommended for definitive therapy; however the comparative effectiveness of

individual beta-lactams is unknown. This study compared definitive therapy with cefazolin

versus nafcillin or oxacillin among patients with MSSA infections complicated by bacteremia.

Methods: This retrospective study included patients admitted to 119 Veterans Administration

hospitals from 2003 to 2010. Patients were included if they had a blood culture positive for

MSSA and received definitive therapy with cefazolin, nafcillin, or oxacillin. Cox proportional

hazards regression and ordinal logistic regression were used to identify associations between

antibiotic therapy and mortality or recurrence. A recurrent infection was defined as a MSSA

blood culture between 45 to 365 days after the first MSSA blood culture.

Results: Of 3,167 patients, 1,163 (37%) patients received definitive therapy with cefazolin.

Patients who received cefazolin had a 37% reduction in 30-day mortality (Hazard ratios (HR):

0.63; 95% Confidence Intervals (CI): 0.51-0.78) and 23% reduction in 90-day mortality (HR:

0.77; 95% CI: 0.66-0.90) compared with patients receiving nafcillin or oxacillin after controlling

for other factors. The odds of recurrence (Odds Ratio: 1.13; 95% CI: 0.94-1.36) were similar

among patients who received cefazolin compared with patients who received nafcillin or

oxacillin, after controlling for other factors.

Conclusion: In this large, multi-center study, patients who received cefazolin had a lower risk of

mortality and similar odds of recurrent infections compared with nafcillin or oxacillin for MSSA

infections complicated by bacteremia. Physicians might consider definitive therapy with

cefazolin for these infections.

3
Key words: MSSA, bacteremia, nafcillin, cefazolin, treatment

4
INTRODUCTION

Infections caused by Staphylococcus aureus are often complicated by bacteremia. For

patients with methicillin-susceptible S. aureus (MSSA) infections, the Infectious Diseases

Society of America recommends definitive therapy with beta-lactams [1]. Penicillinase-stable

penicillins such as nafcillin or oxacillin are the primary choice for treating MSSA infections

complicated by bacteremia while cefazolin is an alternate choice [2-4]. However, nafcillin and

oxacillin cause more adverse events, such as drug-induced fever, cytopenia, rash, renal

dysfunction, and liver function abnormalities compared with cefazolin [5-7]. In addition,

cefazolin is more convenient than nafcillin or oxacillin for patients completing their antibiotic

course following hospital discharge because cefazolin can be dosed at hemodialysis and can be

administered less frequently than nafcillin or oxacillin.

However, some clinicians are reluctant to use cefazolin to treat serious MSSA infections.

Treatment failure has been observed among patients receiving cefazolin for MSSA infections

complicated by bacteremia, specifically in patients with high-inoculum infections such as

valvular vegetation or an undrained abscess [8, 9]. Treatment failure with cefazolin has been

attributed to the inoculum effect, which correlates with inactivation of cefazolin by type A beta-

lactamases [9]. Furthermore cefazolin has little penetration into the cerebrospinal fluid and thus

may be inferior for infections involving the central nervous system.

The optimal choice of beta-lactam therapy for MSSA infections complicated by

bacteremia is unclear. Previous studies have assessed outcomes such as treatment failure, adverse

events, or mortality among patients receiving cefazolin compared with nafcillin or oxacillin for

MSSA infections complicated by bacteremia [5, 7, 10, 11]. The results varied, and for many

studies, no significant difference in outcomes was observed between the therapy groups,

potentially due to the limited sample size [5, 7, 10, 11]. Large multi-center studies are needed to

5
determine if a significant difference in outcomes exists between patients treated with nafcillin or

oxacillin compared with patients treated with cefazolin. This study compared definitive therapy

with cefazolin versus treatment with nafcillin or oxacillin among patients with MSSA infections

complicated by bacteremia at 119 Veterans Affairs (VA) hospitals.

METHODS

Study Design and Patient Population

This retrospective cohort study included patients with medical or surgical admissions to

119 acute care VA hospitals from 2003 to 2010. Patients were included if they had at least one S.

aureus positive blood culture susceptible to either methicillin or oxacillin by antimicrobial

susceptibility testing, and the patients received cefazolin, nafcillin, or oxacillin for definitive

therapy of their MSSA infections complicated by bacteremia. Patients were included only once

in the study based on their first admission with a positive MSSA blood culture. Patients were

excluded if they were admitted to a VA hospital that had fewer than 25 cases of S. aureus

infections complicated by bacteremia throughout the study period since these hospitals do not

treat patients with S. aureus bacteremia on a regular basis.

Data were extracted from the VA electronic health record using the VA Corporate Data

Warehouse and Patient Care Services databases and accessed through the VA Informatics and

Computing Infrastructure. These data were last updated in February 2014 and validated by the

VA Healthcare System through the VA Information Resource Center [12]. The institutional

review board of the University of Iowa and the Research and Development Committee of the

Iowa City VA Medical Center approved this study. The Strengthening the Reporting of

Observational Studies in Epidemiology criteria were followed when preparing the manuscript

[13].

6
Variable Definitions

The primary outcomes examined were 30-day all-cause mortality and 90-day all-cause

mortality. Thirty-day all-cause mortality was defined as death occurring within 30 days after the

collection of the first positive MSSA blood culture, and 90-day all-cause mortality was defined

as death occurring within 90 days after the collection of the first positive MSSA blood culture.

Deaths that occurred outside of the hospital or on a subsequent admission were included since

the VA uses multiple agencies (VA data, Social Security Administration Death Master File,

Medicare Vital Status, and BIRLS Death File) to collect information regarding patient death. The

VA-National Death Index Mortality Data Merge Project reported a 98% agreement between the

combined sources and the National Death Index [14]. Recurrent MSSA infections complicated

by bacteremia were defined as MSSA positive blood cultures between 45 to 365 days after the

first MSSA positive blood culture. A cutoff of 45 days was selected because the recommended

antibiotic treatment for some MSSA invasive infections such as osteomyelitis is up to 42 days (6

weeks).

Definitive therapy was defined as starting a definitive antimicrobial or continuing an

empiric antimicrobial between days 4 to 14 after the first positive blood culture was collected

[15]. Patients were excluded if they received definitive therapy with both cefazolin and nafcillin

or cefazolin and oxacillin. Comorbid conditions were evaluated using the Charlson Comorbidity

Index, which is based on the International Classification of Diseases, 9th Revision, Clinical

Modification (ICD-9-CM) codes [16]. The modified Acute Physiology and Chronic Health

Evaluation (APACHE) III score was used to measure patients’ severity of illness on hospital

admission [17-18]. A modified APACHE III score was used since not all of the included patients

were admitted to the ICU, and therefore, not all tests were performed on the patients such as the

7
Glasgow Coma score. ICD-9-CM codes were used to identify concurrent infections including

skin and soft tissue infections, endocarditis, and osteomyelitis, chronic conditions such as

hepatitis C, the stages of renal disease, and intravenous drug user [19-21]. APACHE III score

was dichotomized on the median while age was categorized on quartiles.

Dialysis and/or end stage renal disease (ESRD) was defined as receipt of outpatient

dialysis, receipt of dialysis during the index hospital admission, or having ESRD [15]. Facilities

were categorized based on complexity scores provided by the VA Healthcare Analysis and

Information Group [15]. Empiric vancomycin therapy was defined as vancomycin started

between 2 days before the first MSSA positive blood culture was collected through 4 days after

the blood culture was collected [15]. Hospital-onset MSSA infections complicated by bacteremia

were defined as collection of the first MSSA positive blood cultures from a patient more than 48

hours after hospital admission. Post-infection length of stay was defined as the number of days

from collection of the first positive MSSA culture until hospital discharge or in-hospital death.

Prior hospitalization was defined as admission to a VA hospital within the 12 months before the

index admission.

Statistical Analysis

Bivariate analyses examined associations between patient characteristics and therapy,

mortality, or recurrence using the chi-square or Fisher’s exact test for categorical variables and

Student’s t-test or the Wilcoxon Rank-Sum test for continuous variables.

Cox proportional hazards regression was used to examine the association between

antibiotic therapy (cefazolin versus nafcillin or oxacillin) and mortality, where patients were

censored if death occurred within 30 days or 90 days after the first positive blood culture was

collected. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated based on

8
multivariate modeling. Modified APACHE III score, Charlson Comorbidity Index, and

additional concurrent infections (skin and soft tissue infections, endocarditis, and osteomyelitis)

were incorporated in all models since these variables are strong predictors of mortality and may

impact therapy selection. Additionally, the variables included in Table 1 were examined for

inclusion in the multivariate models and selected based on a manual stepwise selection process.

This selection method entered variables individually into the model if P < 0.05 in the bivariate

analysis. Variables were then retained in the model if P < 0.05 even after subsequent variables

were added to the model. A variable was a confounder if the regression coefficient for therapy

was changed by more than 20%. Effect modification was examined by assessing the interaction

of therapy with the potential effect modifier. The proportional hazards assumption was evaluated

by assessing the interaction of therapy with the log of survival time, and the final model was

examined using multiple time points to identify any significant changes in effect over time.

Ordinal logistic regression was used to examine the association between therapy and

recurrence of MSSA infections complicated by bacteremia. Odds ratios (OR) and 95% CI were

calculated. Patients were categorized by outcome: no recurrent MSSA infections complicated by

bacteremia, 45-90 days until a MSSA infection complicated by bacteremia, 91-365 days until a

MSSA infection complicated by bacteremia, and death occurred within 45 to 365 days after the

first MSSA positive blood culture but no MSSA infections complicated by bacteremia during

this time period. The reference group for the analysis was no recurrent MSSA infections

complicated by bacteremia. Patients were excluded from the analysis if they died before 45 days

from the day the first MSSA positive blood cultures were collected. The same set of model

variables were assessed, entered, and included using the same stepwise method and criteria

described above. The modified APACHE III score and Charlson Comorbidity Index were

9
retained in all models regardless of statistical significance, since these variables are strong

predictors of therapy type and recurrent MSSA infections complicated by bacteremia. The

proportional odds assumption was examined for treatment type. All data analysis was completed

using SAS 9.4 (SAS Institute, Cary, NC). A sub-analysis was performed that examined dialysis

and/or had ESRD since these patients may be more likely to receive cefazolin due to the ease of

dosing cefazolin for dialysis.

RESULTS

A total of 11,154 patients with MSSA infections complicated by bacteremia were

identified. Of these patients, 7,718 patients were excluded for not receiving definitive therapy

with cefazolin, nafcillin or oxacillin between 4 to 14 days after the first MSSA positive blood

culture was collected (Figure 1). Of the 3,436 patients that received definitive therapy with

cefazolin, nafcillin, or oxacillin, 269 patients were excluded for receiving definitive therapy with

both cefazolin and penicillinase-stable penicillins. APACHE III score (≥ 34; 55% vs. 53%; P =

0.693), age (≥ 62; 50% vs. 52%; P = 0.40), and mortality rate (10% vs. 13%; P = 0.182) were

similar among patients who received both therapies compared with the patients who received

only one therapy. However, patients who received both therapies were more likely to have

received dialysis and/or have ESRD (17% vs. 11%; P = 0.004). During the definitive period, 187

(70%) patients switched from nafcillin or oxacillin to cefazolin while 59 (22%) patients switched

from cefazolin to nafcillin or oxacillin. Twenty-three (9%) patients started both therapies on the

same day.

Of the 3,167 patients receiving definitive therapy with cefazolin, nafcillin, or oxacillin

37% were treated with cefazolin (Table 1). Compared with the patients who received nafcillin or

oxacillin, patients treated with cefazolin were more likely to have a higher APACHE III score (≥

10
34; 56% vs. 52%; P = 0.027), receive dialysis or have ESRD (15% vs. 8%; P < 0.001), and have

diabetes (40% vs. 33%; P < 0.001). Furthermore, the patients treated with cefazolin were less

likely to have endocarditis (4% vs. 7%; P = 0.002), have a hospital-onset infection (21% vs.

24%; P = 0.018), be hospitalized in a more complex VA facility (P < 0.001), and had a slightly

shorter post-infection length of stay in the hospital (12 days vs 13 days; P < 0.001). Mortality

significantly differed between the two therapy groups (Table 1 and Figure 2). Twenty-five

percent of patients receiving nafcillin or oxacillin died at 90 days while only 20% of patients

who received cefazolin died (P = 0.001).

In the multivariate models, patients treated with cefazolin for their MSSA infections

complicated by bacteremia had a 37% reduction in 30-day mortality risk compared with patients

treated with nafcillin or oxacillin (HR: 0.63; 95% CI: 0.51-0.78; Table 2; Supplementary Figure

1) after adjusting for skin and soft tissue infections, endocarditis, osteomyelitis, ICU admission,

diabetes, as well as APACHE III and Charlson comorbidity scores. Similarly the adjusted risk of

90-day mortality was 23% lower for patients receiving cefazolin compared with patients

receiving nafcillin or oxacillin (HR: 0.77; 95% CI: 0.66-0.90; Table 2; Supplementary Figure 2).

The adjusted odds of having a recurrent MSSA infection complicated by bacteremia did not

significantly differ between cefazolin and nafcillin or oxacillin treatment groups (OR: 1.13; 95%

CI: 0.94-1.36; Table 2; Supplementary Figure 3). Only 2% of patients treated with cefazolin

(n=27) and 3% of patients treated with nafcillin or oxacillin (n=65; P = 0.136) had intracranial

and intraspinal abscesses; there were no statistically significant differences in mortality (30-day:

4% vs. 2%; P = 0.503; 90-day: 11% vs. 6%; P = 0.415) or recurrence (4% vs. 0%; P = 0.176)

comparing the treatment groups in that patient population. Eighty-nine percent of the patients

had information available on whether they received an infectious disease (ID) consult between

11
the collection of the first positive MSSA blood culture until hospital discharge or in-hospital

death. ID consult was not available for all patients since this information was collected for

another study. When only the patients who had information on ID consult were examined, risk

estimates for 30-day mortality, 90-day mortality, and recurrent MSSA infections complicated by

bacteremia were similar to the risk estimates in the adjusted models that did not include ID

consult (data not shown). In a sub-analysis excluding patients who received dialysis or had

ESRD, risk estimates were similar to the full cohort for 30-day mortality (HR: 0.66; 95% CI:

0.52-0.82), 90-day mortality (HR: 0.80; 95% CI: 0.68-0.94), and recurrent MSSA infection

complicated by bacteremia (OR: 1.13; 95% CI: 0.92-1.38). When only patients with dialysis

and/or ESRD were examined, the risk estimates did not substantially change compared with the

full cohort for 30-day mortality (HR: 0.48; 95% CI: 0.24-0.97), 90-day mortality (HR: 0.60; 95%

CI: 0.37-0.98), and recurrent MSSA infection complicated by bacteremia (OR: 1.03; 95% CI:

0.64-1.68).

DISCUSSION

This large observational study identified a reduced risk of mortality among patients

treated with cefazolin compared with patients treated with nafcillin or oxacillin for MSSA

infections complicated by bacteremia. Recurrence of MSSA infections complicated by

bacteremia was similar between the two treatment groups. These results support current

guidelines that list cefazolin as an alternative therapy in the treatment of patients with severe,

invasive MSSA infections.

Previous studies evaluated outcomes associated with cefazolin or penicillinase-stable

penicillin treatment for patients with MSSA infections complicated by bacteremia [5, 7, 10, 11].

These studies reported risk estimates favoring therapy with cefazolin, but did not detect a

12
significant difference between the two treatment groups [5, 7, 10, 11]. Li et al. reported slightly

lower rates of 30-day mortality, 90-day mortality, and recurrent bacteremia among patients

receiving cefazolin versus oxacillin for complicated MSSA bacteremia [7]. When comparing

cefazolin with cloxacillin for MSSA infections complicated by bacteremia, Bai et al. found a

non-significant 42% reduced risk of 90-day mortality for patients treated with cefazolin in a

matched propensity score study while Paul et al. reported non-significant decreased odds of 90-

day mortality for patients receiving cefazolin [10, 11]. Furthermore, Lee et al. found increased

odds of treatment failure which included both mortality and recurrent infections at 4-weeks and

12-weeks for patients receiving nafcillin versus cefazolin for MSSA infections complicated by

bacteremia [5]. The previous studies were much smaller than the current study. Bai et al. had the

largest sample size of 354 patients while this study included 3,167 patients [11]. Therefore,

previous studies potentially did not have statistical power to achieve significance.

Prior studies used a variety of outcome definitions [5, 7, 10, 11]. Unfortunately, no

standardized definition exists for reporting mortality or recurrent MSSA infections. Even though

90-day mortality rates were examined, follow-up periods (e.g. days from admission, culture

collection, or initiating therapy) may have differed among studies. This occurrence may have

been reflected in the varying rates of mortality (ranged from 1% to 34%) [7, 10, 11].

Furthermore, our study captured deaths that occurred outside of the hospital admission while

previous studies may not have had access to this information.

This study had limitations. First, there was potential for confounding by indication.

Patients receiving cefazolin may have differed from patients receiving penicillinase-stable

penicillins in ways that were associated with mortality. We attempted to limit the potential for

unadjusted confounding by including both measures of illness severity based on vital signs and

13
laboratory values at baseline (i.e. APACHE III score) and comorbidities (i.e. Charlson

Comorbidity Index). Similarly, residual confounding may impact the outcome due to the sickest

patients receiving nafcillin instead of cefazolin. Physicians may be less likely to try cefazolin

when the patient has a serious MSSA infection (e.g. endocarditis, sepsis) or a high-inoculum

infection (e.g. valvular vegetation, undrained abscess). Third, information on source control (e.g.

intravenous catheter removal), dose of therapy, cause of death, and adverse events were not

available. In addition, we only studied mortality and recurrence with bacteremia. Our results do

not apply to recurrence without bacteremia or other complications of S. aureus bacteremia. Last,

a large proportion of the patients who had MSSA infections complicated by bacteremia did not

receive definitive therapy with nafcillin, oxacillin, or cefazolin due to receiving empiric or

definitive therapy with another antibiotic, dying, being discharged before receiving therapy, or

only receiving empiric but not definitive therapy with nafcillin, oxacillin, or cefazolin.

Additionally, 269 patients were excluded for receiving definitive therapy with both cefazolin and

penicillinase-stable penicillins. Therefore, the results of this study may not be generalizable to all

patients who have MSSA infections complicated by bacteremia.

Information was not available regarding intravenous antibiotics received after hospital

discharge. After hospital discharge, many veterans receive additional intravenous antibiotics at

home for their MSSA infection complicated by bacteremia. The antibiotics are frequently

administered by home healthcare services which are not usually VA affiliated. Therefore,

information to inspect duration of therapy and switching therapy due to adverse reactions after

hospital discharge is not incorporated in the VA dataset that was used for this study.

In conclusion, definitive therapy with cefazolin may be superior to nafcillin or oxacillin

when examining mortality among patients with MSSA infections complicated by bacteremia.

14
Clinicians may want to consider prescribing cefazolin for patients with MSSA infections

complicated by bacteremia not involving the central nervous system; however, more research is

needed such as randomized trials comparing the efficacy of cefazolin with nafcillin or oxacillin

in order to optimize MSSA bacteremia treatment outcomes among specific groups of patients.

15
 AKNOWLEDGEMENTS

Financial Support. This study was supported by VA HSR&D Career Development Award [CDA

11-211] (PI: Schweizer). MLS were supported by VA HSR&D Career Development Award

[CDA 11-215].

Role of the Sponser: The VA Office of Research and Development had no role in the design and

conduct of the study; collection, management, analysis, and interpretation of the data; or

preparation of the manuscript.

Disclaimer: The opinions expressed are those of the authors and not necessarily those of the

Department of Veterans Affairs or the United States Government

Conflicts of Interest. MCR, ENP, MEO, MG, DJL, MJ, JPA, RN, AMJO, and MLS report no

conflicts of interest relevant to this article. JSM has received speaker honorarium from

BioMerieux.

16
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Figure 1: Flow diagram of patients with MSSA infections complicated by bacteremia who were
excluded from the study for not receiving definitive treatment with cefazolin, nafcillin, or
oxacillin

Note: a Definitive therapy is defined as starting an antimicrobial or continuing on an empiric

antimicrobial between 4 to 14 days after the first MSSA positive blood culture was collected.
b
Antibiotics examined were cephalosporins, carbapenems, beta-lactamase inhibitors,
aminoglycosides, macrolides, quinolones, vancomycin, clindamycin, and linezolid.
c
Patients received empiric therapy with an antibiotic and therapy with that agent was stopped
before the definitive period.

Figure 2: Kaplan-Meier curve of mortality comparing patients who received cefazolin versus
patients who received nafcillin or oxacillin for MSSA infections complicated by bacteremia

20
Table 1: Characteristics of patients with MSSA infections complicated by bacteremia that
received definitive therapy with cefazolin, nafcillin, or oxacillin (N = 3,167)a

Characteristic Cefazolinb Nafcillin or P-value

N=1,163 Oxacillinb
N=2,004
Gender- Male 1,133 (97) 1,974 (99) 0.031
Age: < 56 years 296 (25) 474 (24) 0.715
56-62 267 (23) 479 (24)
62-74 312 (27) 546 (27)
≥75 288 (25) 505 (25)
APACHE III Score: 651 (56) 1,040 (52) 0.027
score ≥ 34
Charlson Comorbidity Index: 2 (1-3) 2 (1-3) 0.013
median (rangec) score
Other infections
Skin and soft tissue infections 287 (25) 460 (23) 0.271
Osteomyelitis 138 (12) 267 (13) 0.236
Endocarditis 52 (4) 145 (7) 0.002
Dialysis and/or End Stage Renal 176 (15) 168 (8) < 0.001
Disease
Hospital-onset infectiond 241 (21) 489 (24) 0.018
Hospitalization in the prior year 670 (58) 1,138 (57) 0.652
Admission to Intensive Care Unit 178 (15) 378 (19) 0.011
Received empiric vancomycin 909 (78) 1,581 (79) 0.628
Renal stage
I 1 (< 1) 0 (0) 0.367
II 4 (< 1) 2 (< 1) 0.201
III 20 (2) 22 (1) 0.140
IV 14 (1) 12 (1) 0.045
V 7 (1) 14 (1) 0.747
Chronic kidney disease, 58 (5) 106 (5) 0.711
Unspecified
HIV infection 18 (2) 34 (2) 0.751
Hepatitis C infection 119 (10) 218 (11) 0.570
Intravenous Drug User 110 (9) 221 (11) 0.164
Diabetes 465 (40) 668 (33) < 0.001
Admission year 0.316
2003 163 (14) 255 (13)
2004 149 (13) 285 (14)
2005 153 (13) 256 (13)
2006 130 (11) 238 (12)
2007 123 (11) 259 (13)
2008 156 (13) 250 (12)
2009 136 (12) 233 (12)
2010 153 (13) 228 (11)
Facility Type < 0.001
1a (most complex) 523 (47) 1,043 (54)
1b 240 (21) 413 (22)

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 1c 204 (18) 232 (12)
2 125 (11) 197 (10)
3 (least complex) 27 (2) 30 (2)
Post-infection length of stay in the 12 (8-18) 13 (9-22) < 0.001
hospital: median (rangec) dayse
30-day mortality 113 (10) 307 (15) < 0.001
45-day mortality 164 (14) 393 (20) < 0.001
90-day mortality 231 (20) 502 (25) 0.001
MSSA Recurrence
45-90 days 20 (2) 28 (1) 0.474
91-365 days 38 (3) 44 (2) 0.067

a
Definitive therapy is defined as starting an antimicrobial or continuing on an empiric
antimicrobial between 4 to 14 days after the first MSSA positive blood culture was collected.
b
The numbers in parentheses are percentages unless otherwise specified.
c
Interquartile range.
d
Positive MSSA culture was collected > 48 hours after admission.
e
Defined as the day the first MSSA blood culture was collected until the patient was either
discharged from the hospital or died.

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Table 2: Multivariate regression models comparing patients with MSSA infections complicated
by bacteremia who received definitive therapy with cefazolin versus nafcillin or oxacillin
(N=3,167)

Model Outcome Regression Analysis Risk Ratio P-value

(95% Confidence
Interval)
Mortality Hazard Ratio
Unadjusted 30-day mortality Cox Proportional Hazards 0.51 (0.49-0.76) < 0.001
Regression
Adjusteda 30-day mortality Cox Proportional Hazards 0.63 (0.51-0.78) < 0.001
Regression

Unadjusted 90-day mortality Cox Proportional Hazards 0.75 (0.65-0.88) < 0.001
Regression
Adjustedb 90-day mortality Cox Proportional Hazards 0.77 (0.66-0.90) 0.001
Regression

Recurrencec Odds Ratiod

Unadjusted Recurrence Ordinal Logistic Regression 1.20 (1.00-1.44) 0.047
e
Adjusted Recurrence Ordinal Logistic Regression 1.13 (0.94-1.36) 0.211

a
Adjusted for skin and soft tissue infections, endocarditis, osteomyelitis, APACHE III score,
Charlson comorbidity index, admission to the ICU, and diabetes.
b
Adjusted for skin and soft tissue infections, endocarditis, osteomyelitis, APACHE III score,
Charlson comorbidity index, hospital-onset infection, admission to the ICU, and diabetes.
c
Recurrence is defined as a MSSA positive blood culture within 45-365 days after first MSSA
positive blood culture.
d
These odds ratios are based on a multivariate ordinal logistic regression. As such the odds ratio
represents the cumulative odds of recurrence and is assumed to be the same across cumulative
probabilities.
e
Adjusted for APACHE III score, Charlson comorbidity index, and hospital-onset infection.

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Figure 1

24
Figure 2

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