ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2007, p. 3731–3733
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Vol. 51, No. 10
Impact of Empirical-Therapy Selection on Outcomes of Intravenous
Drug Users with Infective Endocarditis Caused by
Methicillin-Susceptible Staphylococcus aureus?
Thomas P. Lodise, Jr.,1* Peggy S. McKinnon,2Donald P. Levine,3,4and Michael J. Rybak3,4,5
Albany College of Pharmacy, Albany, New York1; Barnes-Jewish Hospital, St. Louis, Missouri2; School of Medicine,
Wayne State University, Detroit, Michigan3; Detroit Receiving Hospital and University Health Center, Detroit,
Michigan4; and Anti-Infective Laboratory, College of Pharmacy & Health Sciences,
Wayne State University, Detroit, Michigan5
Received 24 January 2007/Returned for modification 15 March 2007/Accepted 23 July 2007
This study compares beta-lactam and vancomycin among intravenous drug users with infective endocarditis
caused by methicillin-susceptible Staphylococcus aureus. Patients who received vancomycin had higher infec-
tion-related mortality, even if they were switched to beta-lactam once culture results became available; this
relationship persisted after logistic regression analysis controlling for clinical characteristics.
Many clinicians believe that vancomycin is inferior to beta-
lactam antibiotics for the treatment of serious methicillin-sus-
ceptible Staphylococcus aureus (MSSA) infections. This notion
is largely based on in vitro data demonstrating that vancomycin
does not kill MSSA as effectively as a beta-lactam (2, 18).
Although the results have been consistent, there are limited
clinical data to support this belief (1, 3, 4, 5, 6, 8, 11, 17, 18).
While infective endocarditis (IE) caused by S. aureus (MSSA
IE) occurs frequently in injection drug users (IDUs), treatment
outcome data for MSSA IE are sparse and have been limited
primarily to comparisons among IDUs with right-sided MSSA
IE of small sample sizes (3, 5, 7, 14, 16, 18). Thus, this inves-
tigation provides additional insights as to whether empirical
beta-lactam therapy is superior to empirical vancomycin ther-
apy for this vulnerable population. (This study was presented
in part at the 42nd Interscience Conference on Antimicrobial
Agents and Chemotherapy, San Diego, CA, September 2002.)
Setting. The study was conducted at Detroit Receiving Hos-
pital, a 279-bed urban level I trauma center.
Study population. The study included all confirmed hospi-
talized patients with IE caused by S. aureus among IDUs
treated between 1 January 1997 and 31 July 2001. The study
included only those patients who met the following criteria: (i)
positive MSSA bloodstream infection, (ii) MSSA bloodstream
infection satisfying the modified Duke criteria for IE (13), (iii)
documented recent use of intravenous drugs prior to admission
in the medical record, and (iv) empirical treatment with van-
comycin or a beta-lactam. This study was approved by the
Wayne State University Human Investigation Committee.
Study design. A retrospective population-based cohort anal-
ysis was performed. Data extracted from the medical record
included age, sex, admitting service, classification by Duke
criteria status, the valve involved, microbiological data, human
immunodeficiency virus (HIV) infection status, antibiotic
treatment, metastatic embolic complications (e.g., pulmonary
emboli and splenic emboli, etc.) present at diagnosis, perfor-
mance of surgery, and outcome.
Microbiology. Microbiological data included all positive S.
aureus cultures. Results of susceptibility testing were per-
formed, interpreted, and recorded according to NCCLS guide-
Treatment data. All antimicrobials administered were
noted. Empirical therapy was defined as the antibiotic admin-
istered prior to the identification and determination of the
susceptibility of the infecting organism (10). Empirical antibi-
otic therapy was classified as either a vancomycin regimen or a
beta-lactam-containing regimen. Patients who received both
beta-lactam and vancomycin were classified in the beta-lactam-
containing group. Definitive therapy was classified as the an-
tibiotic regimen administered after the identification and de-
termination of the antibiotic susceptibility of the infecting
organism. During the study, vancomycin was dosed by a no-
mogram that targeted troughs of between 12 and 15 mg/liter,
as described elsewhere (9). As vancomycin levels are not rou-
tinely monitored at our institution, vancomycin trough levels
were available for only five patients, and the median (range)
vancomycin trough was 18.6 mg/liter (14.5 to 29.0).
Outcome assessment. The following outcome was assessed:
death related to MSSA IE (infection-related mortality). Death
was attributed to MSSA IE (infection-related mortality) when
at least one of the following indications was present: (i) blood
cultures were positive for MSSA at the time of death; (ii) death
occurred before the resolution of IE symptoms; (iii) death
occurred during hospitalization without an unrelated, alterna-
tive cause; and (iv) autopsy found S. aureus infection as a cause
of death (13).
* Corresponding author. Mailing address: Albany College of Phar-
macy, 106 New Scotland Avenue, Albany, NY 12208-3492. Phone:
(518) 445-7292. Fax: (518) 445-7302. E-mail: email@example.com.
?Published ahead of print on 30 July 2007.
Statistical analysis. Bivariate associations between empiri-
cal treatment selection and outcome were assessed using Pear-
son ?2or Fisher’s exact test (categorical variables) and Stu-
dent’s t or the Mann-Whitney U test (continuous variables).
Logistic regression was used to estimate the independent as-
sociation of empirical treatment selection with infection-re-
lated mortality while adjusting for baseline clinical character-
istics. All calculations were performed with SPSS software,
version 10.0 (SPSS, Chicago, IL).
During the 5-year study period, there were 98 episodes of IE
caused by S. aureus among IDUs. Of the 84 MSSA cases, 72
received either vancomycin (n ? 28) or beta-lactam (n ? 44).
Of the 44 beta-lactam patients, 36 received semisynthetic pen-
icillin and 8 received ceftriaxone. Twelve additional patients
were enrolled in an investigational antibiotic study and are
excluded from this analysis. Of the 72 patients, 16 died, and all
cases of mortality were considered infection related.
Bivariate comparison of baseline clinical features for 72
MSSA patients between treatment groups detected no statis-
tical differences (Table 1). The groups were similar with re-
spect to age, sex, HIV infection status, the valve involved, the
presence of metastatic embolic complications at diagnosis,
concomitant aminoglycoside usage, once-daily versus tradi-
tional aminoglycoside dosing, concomitant usage of rifampin,
and performance of surgical intervention. The median dura-
tion of concomitant aminoglycoside usage was longer for beta-
lactam patients than for vancomycin patients (5.5 days versus
3.0 days; P ? 0.07). Compared to vancomycin patients, those
receiving beta-lactams were more often HIV positive (10.7%
and 25.0%, respectively; P ? 0.1) and less likely to have defi-
nite IE (96.4% and 81.8%, respectively; P ? 0.07).
The outcome analysis detected significantly high infection-
related mortality in the vancomycin group compared to that for
the beta-lactam group (39.4% versus 11.4%; P ? 0.005) (Table
1). Among beta-lactam patients, the infection-related mortality
rate was higher for patients that received ceftriaxone than for
the semisynthetic penicillin patients, but the difference was not
significant (25.0% versus 8.3%; P ? 0.2). Vancomycin use
remained highly predictive of infection-related mortality after
logistic regression analysis adjusted for age, sex, HIV infection
status, Duke criteria status, the valve involved, the presence of
metastatic embolic complications at diagnosis, concomitant
aminoglycoside usage, and the duration of aminoglycoside use
(adjusted odds ratio, 6.5; 95% confidence interval, 1.4 to 29.4).
Among patients with left-side/bilateral involvement, infection-
related mortality was higher among vancomycin patients than
among beta-lactam patients (66.7% versus 27.3%) but the dif-
ference was not significant (P ? 0.08). For patients with right-
sided disease only, infection-related mortality was significantly
higher among vancomycin patients (26.3% versus 6.1%; P ?
0.04). Among patients with definite IE, infection-related mor-
tality was significantly higher among vancomycin patients
(40.7% versus 13.9%; P ? 0.02). Of the 28 patients who were
started on vancomycin, 22 had vancomycin changed to an al-
ternative primary regimen, 21 were changed to a semisynthetic
penicillin, and 1 was switched to quinupristin-dalfopristin. Pa-
tients received vancomycin for a median of 3 days (interquar-
tile range, 3 to 4 days) prior to being switched. No difference
TABLE 1. Comparison of baseline clinical characteristics and outcomes for patients with MSSA IE who received empirical beta-lactam
therapy and for those who received empirical vancomycin therapy
Baseline clinical feature or overall outcome
Beta-lactam (n ? 44) Vancomycin (n ? 28)
Baseline clinical features
Mean age (SD) (yr)
Status according to Duke criteria
Heart side involvement
Metastatic embolic complications present at diagnosis
Concomitant aminoglycoside usage
Pulse (once-daily) daily dosingb
Intermittent (traditional) daily dosingc
Concomitant rifampin usage
Overall outcome (infection-related mortality) for indicated
Definite IE by Duke criteria (%)
aExcept for the mean age data, all data are presented as numbers of patients (with percentages respective to the total number in the indicated therapy group in
bDose: 3 mg/kg of body weight/day as one daily dose.
cDose: 3 mg/kg of body weight/day in three divided doses.
3732NOTESANTIMICROB. AGENTS CHEMOTHER.
between infection-related mortalities was noted for patients
who received vancomycin as the primary regimen and patients
who had vancomycin switched to beta-lactam therapy (33.3%
versus 40.9%; P ? 0.7).
The results indicate that there are indeed differences in
outcomes for IDUs with MSSA IE who received empirical
beta-lactam therapy and for those who received vancomycin.
Vancomycin patients had higher infection-related mortality by
bivariate analysis, and this relationship persisted in the logistic
regression analysis after controlling for baseline clinical char-
acteristics. These findings support the notion that vancomycin
is inferior to beta-lactam for the treatment of IDUs with
MSSA IE. In addition, vancomycin patients switched to beta-
lactam therapy once susceptibility results became available still
had an infection-related mortality rate higher than that seen
for patients treated with beta-lactam from the initiation of
therapy. Based on these results, our institution advocates the
inclusion of a beta-lactam in the empirical therapy for serious
Several caveats should be noted when interpreting these
results. First, this single-center analysis focused solely on IDUs
with MSSA IE; the results may not be generalizable to other
populations. Second, while the optimal way to compare anti-
biotic dosing regimens is through a randomized clinical trial,
such a study would be difficult to execute for a variety of ethical
and clinical reasons. Although this was a single-center retro-
spective cohort study, the two treatment groups were well
balanced at baseline, and logistic regression was used to adjust
for any lingering differences that may have introduced bias.
Although the groups were well matched at baseline, the po-
tential for selection bias still exists because of the observational
nature of the study. For example, baseline serum creatinine
levels, echocardiographic data, and estimated ejection frac-
tions were not available and thus were not compared between
treatment groups. Third, only two patients had a surgical in-
tervention, and this may have impacted mortality, particularly
in the left-sided disease group. Finally, the study outcomes
were limited to objective endpoints due to the difficulty of
assessing clinical response in the retrospective study design.
In conclusion, this study compared infection-related mortal-
ities for empirical beta-lactam therapy and for vancomycin
therapy among IDUs with MSSA IE. The results support the
findings of other clinical series in suggesting that vancomycin is
inferior to beta-lactam therapy for MSSA and confirms this for
IDUs with MSSA IE. The results also suggest that the empir-
ical therapy window is critical to outcomes, since vancomycin
patients switched to beta-lactam therapy once susceptibility
results became available still had outcomes inferior to those for
patients treated with a beta-lactam from the initiation of ther-
apy. Based on the observed results, empirical therapy with both
a beta-lactam and an anti-methicillin-resistant S. aureus agent
should be considered for serious S. aureus infections, and fur-
ther study of this novel combination empirical regimen in a
randomized, prospective fashion is warranted.
The manuscript benefited greatly from the thoughtful editing of
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