ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2008, p. 3315–3320
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Vol. 52, No. 9
Relationship between Vancomycin MIC and Failure among Patients
with Methicillin-Resistant Staphylococcus aureus Bacteremia
Treated with Vancomycin?
T. P. Lodise,1,2* J. Graves,1A. Evans,3E. Graffunder,4M. Helmecke,4
B. M. Lomaestro,5and K. Stellrecht3
Albany College of Pharmacy, Pharmacy Practice Department, Albany, New York1; Ordway Research Institute, Albany, New York2;
Albany Medical Center Hospital, Department of Pathology and Laboratory Medicine, Albany, New York3; Albany Medical Center Hospital,
Department of Epidemiology, Albany, New York4; and Albany Medical Center Hospital, Department of
Pharmacy, Albany, New York5
Received 25 January 2008/Returned for modification 20 March 2008/Accepted 23 June 2008
There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus
aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this
growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective
cohort study was conducted among patients with MRSA bloodstream infections who were treated with van-
comycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old,
nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received
vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administra-
tion. Failure was defined as 30-day mortality, bacteremia >10 days on vancomycin therapy, or a recurrence of
MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART)
analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During
the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART
analysis was >1.5 mg/liter. The 66 patients with vancomycin MICs of >1.5 mg/liter had a 2.4-fold increase in
failure compared to patients with MICs of <1.0 mg/liter (36.4% and 15.4%, respectively; P ? 0.049). In the
Poisson regression, a vancomycin MIC of >1.5 mg/liter was independently associated with failure (adjusted
risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P ? 0.01). These data strongly suggest that patients with
MRSA bloodstream infections with vancomycin MICs of >1.5 mg/liter respond poorly to vancomycin. Alter-
native anti-MRSA therapies should be considered for these patients.
Despite its sustained in vitro microbiologic inhibitory activ-
ity, clinicians now question the continued utility of vancomycin
for methicillin-resistant Staphylococcus aureus (MRSA) infec-
tions (18, 23). Within the past 5 years, multiple reports have
described MRSA strains with vancomycin MICs at the high
end of the CLSI susceptibility range (MICs of 2 mg/liter) (6,
18, 22). Data suggest that vancomycin has reduced activity
against MRSA infections, with vancomycin MICs at the high
end of the CLSI susceptibility range (6, 11, 16, 19, 20).
At the Albany Medical Center Hospital (AMCH), a large
proportion of the MRSA bloodstream isolates have vancomy-
cin MICs at the high end of the CLSI susceptibility range. The
MIC50and MIC90for the 76 MRSA bloodstream isolates (59
patients) obtained by using the Etest method and recovered
between January 2005 and June 2006 were 1.5 and 2.0 mg/liter,
respectively. To date, the relationship between vancomycin
MICs and outcomes has not been explored at our institution.
The primary goal of this study was to examine the relationship
between vancomycin MICs and outcomes among patients with
MRSA bloodstream infections treated with vancomycin. Spe-
cifically, this study sought to identify the vancomycin MIC
threshold value within the CLSI susceptibility range that is
associated with an increased probability of failure.
(This study was presented in part as a poster presentation at
the 45th Annual Meeting of the Infectious Diseases Society of
America (IDSA), San Diego, CA, October 2007.)
MATERIALS AND METHODS
Study design and population. A retrospective cohort study was conducted at
the AMCH, a 631-bed, tertiary care, academic hospital located in upstate New
York. All patients with MRSA bloodstream infections (4) between January 2005
and May 2007 were eligible. Patients were included in the study if they were (i)
at least 18 years old, (ii) nonneutropenic (an absolute neutrophil count of ?1,000
cells/mm), (iii) with an MRSA culture that met the CDC criteria for bloodstream
infection (4), (iv) had received vancomycin therapy within 48 h of the index blood
culture collection (10), and (v) had survived ?24 h after vancomycin adminis-
tration. If a patient had more than one episode during a study period, only the
first episode was considered. For patients with multiple MRSA blood cultures,
the vancomycin MIC of the index bloodstream isolate was considered in the
Classification and regression tree (CART) analysis was used to identify the
vancomycin MIC breakpoint among MRSA patients associated with an increased
probability of treatment failure (24). With this method, the MIC that maximized
the difference in treatment failure was identified, and MRSA patients were
divided into the following two groups: those who had high likelihood of treat-
ment failure and those who had low risk of experiencing treatment failure. These
two groups were considered the high and low vancomycin MIC groups, respec-
tively, for the outcome analyses.
Data. Data were extracted from patients’ medical records by a trained reviewer
using a structured data instrument. Data elements included the following con-
* Corresponding author. Mailing address: Albany College of Phar-
macy, Department of Pharmacy Practice, 106 New Scotland Avenue,
Albany, NY 12208-3492. Phone: (518) 445-7292. Fax: (518) 518-694-
7062. E-mail: email@example.com.
?Published ahead of print on 30 June 2008.
vancomycin for MRSA bloodstream infections with vancomy-
cin MICs of ?1.5 mg/liter. In addition, further studies are
needed to determine if optimization of vancomycin therapy
can improve outcomes without subjecting patients to an in-
creased risk of vancomycin-related toxicities.
This article has greatly benefited from the thoughtful editing of
This study was supported by a grant from Cubist Pharmaceuticals.
T.P.L. was the principal investigator for this grant. Please note that
Cubist provided support only to complete the project and was not
involved in the following: design and conduct of the study; collection,
management, analysis, and interpretation of the data; and preparation
and review of the manuscript. No other conflicts of interest exist for
any of the authors.
1. Clinical and Laboratory Standards Institute. 2006. Performance standards
for antimicrobial susceptibility testing; 16th informational supplement. CLSI
M100-S16. Clinical and Laboratory Standards Institute, Wayne, PA.
2. Cockcroft, D. W., and M. H. Gault. 1976. Prediction of creatinine clearance
from serum creatinine. Nephron 16:31–41.
3. Fowler, V. G., Jr., H. W. Boucher, G. R. Corey, E. Abrutyn, A. W. Karchmer,
M. E. Rupp, D. P. Levine, H. F. Chambers, F. P. Tally, G. A. Vigliani, C. H.
Cabell, A. S. Link, I. DeMeyer, S. G. Filler, M. Zervos, P. Cook, J. Parsonnet,
J. M. Bernstein, C. S. Price, G. N. Forrest, G. Fatkenheuer, M. Gareca, S. J.
Rehm, H. R. Brodt, A. Tice, and S. E. Cosgrove. 2006. Daptomycin versus
standard therapy for bacteremia and endocarditis caused by Staphylococcus
aureus. N. Engl. J. Med. 355:653–665.
4. Garner, J. S., W. R. Jarvis, T. G. Emori, T. C. Horan, and J. M. Hughes.
1988. CDC definitions for nosocomial infections, 1988. Am. J. Infect. Con-
5. Harbarth, S., O. Rutschmann, P. Sudre, and D. Pittet. 1998. Impact of
methicillin resistance on the outcome of patients with bacteremia caused by
Staphylococcus aureus. Arch. Intern. Med. 158:182–189.
6. Hidayat, L. K., D. I. Hsu, R. Quist, K. A. Shriner, and A. Wong-Beringer.
2006. High-dose vancomycin therapy for methicillin-resistant Staphylococcus
aureus infections: efficacy and toxicity. Arch. Intern. Med. 166:2138–2144.
7. Jenkins, T. C., C. S. Price, A. L. Sabel, P. S. Mehler, and W. J. Burman. 2008.
Impact of routine infectious diseases service consultation on the evaluation,
management, and outcomes of Staphylococcus aureus bacteremia. Clin. In-
fect. Dis. 46:1000–1008.
8. Knaus, W. A., E. A. Draper, D. P. Wagner, and J. E. Zimmerman. 1985.
APACHE II: a severity of disease classification system. Crit. Care Med.
9. Li, J. S., D. J. Sexton, N. Mick, R. Nettles, V. G. Fowler, Jr., T. Ryan, T.
Bashore, and G. R. Corey. 2000. Proposed modifications to the Duke criteria
for the diagnosis of infective endocarditis. Clin. Infect. Dis. 30:633–638.
10. Lodise, T. P., P. S. McKinnon, L. Swiderski, and M. J. Rybak. 2003. Out-
comes analysis of delayed antibiotic treatment for hospital-acquired Staph-
ylococcus aureus bacteremia. Clin. Infect. Dis. 36:1418–1423.
11. Maclayton, D. O., K. J. Suda, K. A. Coval, C. B. York, and K. W. Garey. 2006.
Case-control study of the relationship between MRSA bacteremia with a
vancomycin MIC of 2 microg/mL and risk factors, costs, and outcomes in
inpatients undergoing hemodialysis. Clin. Ther. 28:1208–1216.
12. McGregor, J. C., E. N. Perencevich, J. P. Furuno, P. Langenberg, K. Flan-
nery, J. Zhu, J. C. Fink, D. D. Bradham, and A. D. Harris. 2006. Comorbidity
risk-adjustment measures were developed and validated for studies of anti-
biotic-resistant infections. J. Clin. Epidemiol. 59:1266–1273.
13. McGregor, J. C., S. E. Rich, A. D. Harris, E. N. Perencevich, R. Osih, T. P.
Lodise, Jr., R. R. Miller, and J. P. Furuno. 2007. A systematic review of the
methods used to assess the association between appropriate antibiotic ther-
apy and mortality in bacteremic patients. Clin. Infect. Dis. 45:329–337.
14. McNutt, L. A., C. Wu, X. Xue, and J. P. Hafner. 2003. Estimating the relative
risk in cohort studies and clinical trials of common outcomes. Am. J. Epi-
15. Mermel, L. A., B. M. Farr, R. J. Sherertz, I. I. Raad, N. O’Grady, J. S.
Harris, and D. E. Craven. 2001. Guidelines for the management of intra-
vascular catheter-related infections. Clin. Infect. Dis. 32:1249–1272.
16. Moise-Broder, P. A., G. Sakoulas, G. M. Eliopoulos, J. J. Schentag, A.
Forrest, and R. C. Moellering, Jr. 2004. Accessory gene regulator group II
polymorphism in methicillin-resistant Staphylococcus aureus is predictive of
failure of vancomycin therapy. Clin. Infect. Dis. 38:1700–1705.
17. Mylotte, J. M., and A. Tayara. 2000. Staphylococcus aureus bacteremia:
predictors of 30-day mortality in a large cohort. Clin. Infect. Dis. 31:1170–
18. Sakoulas, G., R. C. Moellering, Jr., and G. M. Eliopoulos. 2006. Adaptation
of methicillin-resistant Staphylococcus aureus in the face of vancomycin ther-
apy. Clin. Infect. Dis. 42(Suppl. 1):S40–S50.
19. Sakoulas, G., P. A. Moise-Broder, J. Schentag, A. Forrest, R. C. Moellering,
Jr., and G. M. Eliopoulos. 2004. Relationship of MIC and bactericidal
activity to efficacy of vancomycin for treatment of methicillin-resistant Staph-
ylococcus aureus bacteremia. J. Clin. Microbiol. 42:2398–2402.
20. Soriano, A., F. Marco, J. A. Martinez, E. Pisos, M. Almela, V. P. Dimova, D.
Alamo, M. Ortega, J. Lopez, and J. Mensa. 2008. Influence of vancomycin
minimum inhibitory concentration on the treatment of methicillin-resistant
Staphylococcus aureus bacteremia. Clin. Infect. Dis. 46:193–200.
21. Spiegelman, D., and E. Hertzmark. 2005. Easy SAS calculations for risk or
prevalence ratios and differences. Am. J. Epidemiol. 162:199–200.
22. Steinkraus, G., R. White, and L. Friedrich. 2007. Vancomycin MIC creep in
non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-
susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates
from 2001–05. J. Antimicrob. Chemother. 60:788–794.
23. Tenover, F. C., and R. C. Moellering, Jr. 2007. The rationale for revising the
Clinical and Laboratory Standards Institute vancomycin minimal inhibitory
concentration interpretive criteria for Staphylococcus aureus. Clin. Infect.
24. Zhang, H., and S. Burthon. 1999. Recursive partitioning in the health sci-
ences. Springer, New York, NY.
3320 LODISE ET AL.ANTIMICROB. AGENTS CHEMOTHER.