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: firstname.lastname@example.org.
?Published ahead of print on 30 June 2008.
ditions: age, sex, weight, height, medical history and comorbidity, healthcare
institution exposure for greater than 72 h within 180 days of hospital admission,
receipt of antibiotics in the 30 days prior to the index blood culture collection,
length of hospitalization prior to collection of index blood culture, hospital unit
residence at the time of index blood culture collection, creatinine clearance
(CrCl) estimated by the Cockcoft-Gault formula (2) at the time of index blood
culture collection, illness severity, antibiotic treatment data (date, time, dosing
regimen, and duration), vancomycin concentrations (date, time, and temporal
relationship to vancomycin dose), source of MRSA bloodstream infection, pres-
ence of infective endocarditis, microbiologic data, and outcome.
The presence of the following comorbid conditions was documented: diabetes
mellitus, heart failure (New York Heart Association classes I to IV), chronic
obstructive pulmonary disease, hepatic dysfunction, renal failure (as indicated by
the necessity for dialysis), history of cerebrovascular accident, human immuno-
deficiency virus infection, decubitus ulcers (stages II to IV), administration of
immunosuppressive drugs (receipt of ?20 mg/day of prednisone or an equivalent
corticosteroid for ?14 days prior to blood culture collection, or the receipt of any
antineoplastic chemotherapy in the 3 months prior to culture collection), and
surgery requiring ?48 h of hospitalization in the 30 days prior to admission.
Disease severity was calculated with two measures: the Acute Physiological
and Chronic Health Evaluation (APACHE II) (8) and the Chronic Disease
Score-Infectious Diseases (CDS-ID) (12). The APACHE II score was calculated
from the worst physiological score in the 48 h prior to the collection of the index
MRSA blood culture. The CDS-ID was calculated at the time of admission.
Treatment data included those for all antibiotics (date, time, dose, route, and
duration) administered to the patient to treat the MRSA bloodstream infection. All
and the initial trough (within 72 h of initiation of vancomycin therapy) and primary
trough (after 72 h of vancomycin therapy) were documented. Antibiotics adminis-
tered in combination with vancomycin for ?48 h (concomitant antibiotics) were also
The source of the MRSA bloodstream infection was determined from an
assessment of other positive S. aureus cultures at the time of S. aureus bacteremia
and the physician’s clinical description in the medical record. When clinical and
microbiological criteria precluded determination of the source, it was considered
unknown (5). The presence of infective endocarditis was also recorded (9).
Microbiologic data. All clinical MRSA isolates from blood cultures were
collected at AMCH during the study period. The date and time of the MRSA
cultures were recorded, as well as the time of the last MRSA blood culture and
first negative blood culture. All isolates were identified as S. aureus according to
standard methods (1). Initial susceptibility testing for oxacillin resistance was
performed according to CLSI guidelines, using a 30-?g cefoxitin disc and Muel-
ler-Hinton agar (1). Individual isolates were then stored in trypticase soy broth
with 20% glycerol at ?70°C until MIC testing was performed. No thawing or
subculturing of isolates was performed between the initial storage and the MIC
For patients that met the study criteria, Etest methodology was used to de-
termine the vancomycin MIC for the index bloodstream isolate. Prior to MIC
testing, each isolate was subcultured to trypticase soy agar plates supplemented
with 5% sheep blood. The plates were incubated overnight (18 to 24 h) at 35°C
in ambient air, and the subculturing process was repeated a second time. From
these plates, portions of colonies were suspended in 0.45% saline to create a 0.5
McFarland turbidity standard. This standardized suspension was used to streak
the inoculum onto the surface of a 150-mm Mueller-Hinton II agar plate to
create a confluent lawn of microbial growth. The surface of the plate was allowed
to dry for 15 min prior to vancomycin Etest strip application.
The vancomycin MIC was determined by using Etest (0.016 to 256 mg/liter)
(AB Biodisk, Solna, Sweden) according to the manufacturer’s instructions. Ref-
erence strain ATCC 29213 was used for quality control. MIC testing of the
organisms was performed over a period of 4 weeks in a single laboratory. All
MICs were read by a single observer (A. Evans) who was blinded to the out-
Outcomes. Due to the retrospective, observational nature of the study, an
objective, easily reproducible assessment of treatment failure that included only
readily measurable study end points was used in the study (13, 17). Treatment
failure was defined as any of the following: (i) death within 30 days of index
MRSA blood culture (30-day mortality); (ii) microbiological failure, defined as a
blood culture growing MRSA obtained 10 days after the initiation of vancomycin
therapy and before the completion of antimicrobial therapy (7); or (iii) recur-
rence of MRSA bacteremia within 60 days of the discontinuation of vancomycin
therapy. If a patient met more than one criterion, the outcome would be classi-
fied only as a failure one time. If vancomycin was started prior to collection of the
index MRSA blood culture specimen, the index MRSA blood culture date was
considered the first day in calculating days of bacteremia.
We did not attempt to determine if 30-day mortality was attributable to the
MRSA bloodstream infection. Rather than basing microbiological failure on
persistent signs and symptoms of infection, treatment was considered a micro-
biological failure only if the duration of bacteremia was ?10 days and before
therapy was completed, as proposed by Jenkins and colleagues (7). We believed
these aforementioned definitions allowed for an objective assessment of these
end points and minimized any subjective biases that may result from assessing
and interpreting retrospective clinical data. We recorded the length of hospital
stay after the index blood culture was collected. Lastly, the proportion of patients
who were switched to an alternative anti-MRSA antibiotic (e.g., daptomycin,
linezolid, or tigecycline) was calculated.
Statistical analyses. Categorical variables were compared by the Pearson ?2
test or Fisher’s exact test, and continuous variables were compared by Student’s
t test or the Mann-Whitney U test. Breakpoints in the distribution of continuous
variables were determined by CART analysis. This analytical tool identifies
breakpoints within an ordinal or continuous variable where the outcome of
interest is distinctly different between the resulting groups (24). The CART
technique was used to identify significant breakpoints in ordinal and continuous
features (vancomycin MIC, age, weight, length of stay prior to index culture
collection, baseline CrCl, and APACHE II and CDS-ID score) that were asso-
ciated with an increased proportion of treatment failure. For the CART analysis,
node splitting was based on the goodness of split statistic, and optimal tree
selection was performed on the basis of pruning and 10-fold cross-validation.
Due to the large proportion of treatment failures, Poisson regression was used
to determine the independent association of the high vancomycin MIC group
with failure while adjusting for potential confounding variables (14, 21). Poisson
regression was used as a substitute for log-binomial regression because the
log-binomial models did not converge to provide parameter estimates (14, 21).
All covariates that differed between high and low vancomycin MIC groups (P ?
0.2) or were associated with failure (P ? 0.2) in the bivariate analysis were
included at model entry in the Poisson regression model, and a stepwise ap-
proach was used to identify independent predictors of treatment failure. In all
analyses, P ? 0.05 was considered significant for two-tailed tests. All calculations
were performed with SYSTAT for Windows (version 11.0) and SPSS version 11.5
During the study period, 105 nonneutropenic patients at
least 18 years of age had MRSA bloodstream infections. Of
these, 92 patients received vancomycin within 48 h of the first
positive MRSA blood culture and survived ?24 h after admin-
istration of vancomycin. The distribution of vancomycin MICs
is displayed in Fig. 1. The majority of MICs were ?1.5 mg/liter
(n ? 66). The median (interquartile range [IQR]) hospital
length of stay following the index culture was 15.5 (9.0 to 32.5)
FIG. 1. Distribution of vancomycin MICs among patients (n ? 92).
3316 LODISE ET AL.ANTIMICROB. AGENTS CHEMOTHER.
days. A total of 28 unique patients (30.4%) suffered treatment
failure; 15 patients (16.3%) died within 30 days of an index
MRSA blood culture (30-day mortality), 6 patients (6.5%) had
documented MRSA blood cultures for ?10 days while on
vancomycin therapy (microbiological failure), and 12 patients
(13.0%) had an MRSA bloodstream recurrence within 60 days
of the completion of vancomycin therapy. Of the 28 failures, 21
patients met one failure criterion, 4 met two criteria, and 1 met
all three criteria. A post hoc analysis of patients with microbi-
ological failure (n ? 6) was performed, and all had persistent
or worsening signs and symptoms of infection. Of the six pa-
tients with microbiologic failure, the source of the MRSA
bloodstream infection was an intravenous catheter for five
patients, and the intravenous catheter was removed within 4
days of the index MRSA blood culture in all cases (7, 15).
Furthermore, patients with microbiological failure had a sig-
nificantly longer median (IQR) hospital length of stay post-
index culture collection than patients that did not experience
microbiological failure (34 [30 to 72] days versus 14 [8 to 30]
days, respectively; P ? 0.007). Thirty-day mortality was also
significantly higher among patients that had a microbiological
failure than among those that did not (50% versus 14.0%; P ?
Among these 92 patients, 15 were switched to an alternative
anti-MRSA agent; 10 were switched to linezolid, 4 were
switched to daptomycin, and 1 was switched to tigecycline.
These 15 patients received vancomycin for a median (IQR) of
9 (6 to 22) days before switching to the alternative agent. Six of
the 15 patients (40.0%) that had therapy switched were treat-
ment failures; 3 patients died within 30 days of index blood
culture collection, 2 patients had had documented MRSA
blood cultures for ?10 days while on vancomycin therapy, and
4 patients had a MRSA bloodstream recurrence within 60 days
of the completion of vancomycin therapy. Of these six, three
patients met one failure criterion and three met two criteria.
The vancomycin MIC breakpoint derived by CART analysis
to delineate the risk of overall failure was ?1.5 mg/liter; 66
patients (71.7%) had vancomycin MICs of ?1.5 mg/liter (high
vancomycin MIC group) and 26 patients (28.3%) had vanco-
mycin MICs of ?1.5 mg/liter (low vancomycin MIC group). A
comparison of outcomes between the high and low vancomycin
MIC groups is presented in Table 1. Patients with vancomycin
MICs of ?1.5 mg/liter had over a twofold increase in failure
compared to patients who had MICs of ?1.5 mg/liter (36.4%
and 15.4%, respectively; P ? 0.049). The median hospital
length of stay was longer for the high vancomycin MIC group
than for the low vancomycin MIC group (21 days versus 10.5
days, respectively; P ? 0.02). Although not significantly differ-
ent, a greater proportion of the high vancomycin MIC group
versus the low vancomycin MIC group was switched to an
alternative MRSA agent (13 patients [19.7%] versus 2 patients
[7.7%], respectively; P ? 0.21). Of the 13 patients with vanco-
mycin values of ?1.5 mg/liter who switched therapies, 6
(61.5%) were failures, while the 2 patients with vancomycin
MICs of ?1.5 mg/liter who switched therapies were successes.
A bivariate comparison of clinical characteristics between
failures and successes and between the high and low vancomy-
cin MIC groups is shown in Table 2. Using CART analysis,
significant breakpoints were identified for weight, baseline
CrCl, and APACHE II score; CART analysis was unable to
identify significant breakpoints for the other variables. Vari-
ables that were significantly different between failure and suc-
cess in the bivariate analysis were a weight of ?112 kg, pres-
ence of infective endocarditis, hepatic dysfunction, baseline
CrCl, a CrCl of ?33 ml/min, APACHE II score, and an
APACHE II score of ?20. In the high vancomycin MIC versus
low vancomycin MIC bivariate analysis, intensive care unit
(ICU) residence at the time of index blood culture collection
and concomitant administration of gentamicin were the only
variables that were significantly different between the groups.
Neither variable, however, was associated with failure. Given
the overrepresentation of ICU residence for patients with van-
comycin MICs of ?1.5 mg/liter, a stratified analysis was per-
formed to examine the relationship between vancomycin MIC
and treatment failure among non-ICU patients; a stratified
analysis that included only patients in the ICU could not be
performed since only two patients with vancomycin MICs of
?1.0 mg/liter were in the ICU at the time of index culture
collection. Among non-ICU patients, failure was significantly
higher among patients with vancomycin MICs of ?1.5 mg/liter
than among those with vancomycin MICs of ?1.0 mg/liter
(37.8% versus 12.5%; P ? 0.03). These observed failure per-
centages are consistent with the overall failure rates for the
groups, indicating that confounding or effect modification are
Vancomycin trough levels were available for 53 patients.
Among these 53 patients, the median initial and primary van-
comycin trough values were not significantly different between
the vancomycin MIC groups and the failure and success
groups. In addition, the ability to achieve a primary trough of
15 mg/liter was not associated with a higher probability of
success compared to not achieving a primary trough of 15
mg/liter (76.9% versus 77.8%, respectively; P ? 0.9), and this
was irrespective of the vancomycin MIC group.
The Poisson regression analysis included all disparate co-
variates (P ? 0.2) and those associated with treatment failure
(P ? 0.2) in the bivariate analysis. Of these, the following were
independently associated with treatment failure: a vancomycin
MIC of ?1.5 mg/liter (adjusted risk ratio [ARR], 2.6; 95%
confidence interval [CI], 1.3 to 5.4; P ? 0.01), APACHE II
TABLE 1. Comparison of outcomes between high (?1.5 mg/liter)
and low (?1.5 mg/liter) vancomycin MICs
(n ? 66)
(n ? 26)
11 (16.7)1 (3.8) 0.17
Hospital length of stay
21 (9.0–43.0)10.5 (9.0–16.5)0.02
Switched to alternative
13 (19.7)2 (7.7)0.21
aAll data presented are no. (percent) of patients.
VOL. 52, 2008 VANCOMYCIN MIC AND PATIENTS WITH MRSA BACTEREMIA3317
TABLE 2. Bivariate comparison of baseline demographic features between the high and low vancomycin MIC groups and between treatment
failures and successes
CharacteristicHigh MIC (n ? 66) Low MIC (n ? 26)P value Failure (n ? 28) Success (n ? 64)P value
Age in yr, mean (SD)59.3 (16.6) 60.9 (16.0)0.7 60.5 (14.5) 59.4 (17.6)0.8
48 (72.7)17 (65.4)0.5 21 (75.0)44 (68.8)0.6
Wt in kg, mean (SD)80.7 (23.9) 85.4 (26.0)0.4 87.8 (30.1)79.5 (21.2)0.2
Wt of ?112 kga
7 (10.6)5 (19.2)0.3 8 (28.6) 6 (9.4)0.02
Ht in inches, mean (SD)66.3 (4.3) 66.7 (3.3)0.666.1 (4.7)66.6 (3.7)0.5
Healthcare institution exposure45 (68.2) 17 (65.4)0.922 (78.6)40 (62.5)0.13
Surgery in previous 30 daysa
16 (24.2)9 (34.6)0.3 9 (32.1)16 (25.0) 0.5
Antibiotics in previous 30 daysa
34 (51.5)18 (69.2) 0.12 19 (67.9)35 (54.7)0.24
Length of stay in days prior to index culture
collection, median (IQR)
2.5 (0–15) 0 (0–6) 0.081 (0–21.5) 0 (0–12.8)0.4
ICU at onseta
21 (31.8) 2 (7.7)0.028 (28.6)15 (23.4) 0.6
Baseline CrCl in ml/min, median (IQR) 56.3 (28.8–78.3)39.6 (16.3–67.8) 0.1531.9 (11.4–67.1)55.5 (30.5–81.7) 0.04
CrCl of ?33 ml/mina
19 (28.8)12 (46.2) 0.115 (53.6) 16 (25.0) 0.008
APACHE II score, mean (SD) 14.2 (6.6)13.8 (6.0) 0.818.3 (6.5) 12.2 (5.5)
APACHE II score of ?20a
11 (16.7)4 (15.4) 0.911 (39.3) 4 (6.3)
CDS-ID score at admission, mean (SD)3.5 (2.1)3.7 (2.7)0.7 3.8 (2.0) 3.4 (2.4)0.5
Source of bacteremiaa
Skin and soft tissue/bone
7 (10.6) 2 (7.7) 1.06 (21.4)3 (4.7) 0.02
Vancomycin trough within 72 h of therapy
initiation, median (IQR) (mg/liter)
10.5 (8.9–15.6) 9.2 (6.2–13.4) 0.111.9 (9.8–17.2)10.0 (6.3–13.4)0.3
Vancomycin trough concn ?72 h of therapy
initiation, median (IQR) (mg/liter)
14.1 (11.0–19.5)16.75 (12.1–23.2)0.4 15.1 (10.0–20.2) 14.3 (11.4–19.7) 0.9
Concomitant antibiotics administered ?48 ha
aAll data are no. (percent) of patients. COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; TMP-SMX, trimethoprim-sulfa-
3318LODISE ET AL.ANTIMICROB. AGENTS CHEMOTHER.
score (ARR, 1.1; 95% CI, 1.05 to 1.1; P ? 0.001), presence of
infective endocarditis (ARR, 2.5; 95% CI, 1.6 to 4.1; P ?
0.001), and a weight of ?112 kg (ARR, 2.5; 95% CI, 1.4 to 4.3;
P ? 0.001). In a second Poisson regression analysis in which
the APACHE II score of ?20 was substituted for the
APACHE II score at model entry, the following were inde-
pendently associated with treatment failure: a vancomycin
MIC of ?1.5 mg/liter (ARR, 2.5; 95% CI, 1.2 to 5.2; P ? 0.01),
an APACHE II score of ?20 (ARR, 2.8; 95% CI, 1.6 to 5.0;
P ? 0.001), presence of infective endocarditis (ARR, 3.0; 95%
CI, 1.7 to 5.5; P ? 0.001), and a weight of ?112 kg (ARR, 2.6;
95% CI, 1.4 to 4.6; P ? 0.001).
To date, published data that have examined the relationship
between vancomycin MICs and the outcomes of MRSA infec-
tions have been limited to the following studies: two post hoc
examinations of MRSA infections from participants in a larger
multicenter, phase III and IV prospective studies (16, 19), a
retrospective examination of dialysis patients with MRSA
bloodstream infections (11), a retrospective cohort study of
patients with a mixed group of MRSA infections (6), and an
observational cohort study of patients with MRSA blood-
stream infections (20). We are aware of only one published
study that specifically examined the relationship between van-
comycin MICs and treatment outcomes among MRSA bacte-
remic patients treated appropriately with vancomycin, and the
only outcome evaluated in this study was mortality (20).
CART analysis determined that patients with vancomycin
MICs of ?1.5 mg/liter had significantly higher failure rates
than those with vancomycin MICs of ?1.5 mg/liter. It is un-
likely that this observed relationship is due simply to a con-
founded effect. The vancomycin MIC groups were highly com-
parable at the baseline. The only variable that differed between
vancomycin MIC groups at a P value of ?0.2 and that was
predictive of failure was a baseline CrCl of ?33 ml/min, which
was more pronounced in the low vancomycin MIC group. Our
results persisted despite this potential bias toward the null
hypothesis. The Poisson regression analysis that controlled for
potential confounding variables confirmed that a high vanco-
mycin MIC was a robust predictor of failure. A twofold in-
crease in median hospital length of stay postcollection of index
blood culture was observed among high vancomycin MIC pa-
tients. Patients in the high vancomycin MIC group were also
more likely to be switched to an alternative agent. In addition,
there was a higher use of concomitant therapies (e.g., genta-
micin, linezolid, etc.) for the group with vancomycin MICs of
?1.5 mg/liter than for the group with vancomycin MICs of
?1.0 mg/liter. While causality cannot be established because
of the nature of the study design, switching therapy or adding
therapies is typically indicative of treatment failure. Collec-
tively, these data strongly suggest that MRSA bloodstream
infections with higher vancomycin MICs (?1.5 mg/liter) do not
respond as well to vancomycin as MRSA bloodstream infec-
tions with low vancomycin MICs (?1.5 mg/liter).
Our results are generally consistent with three recent studies
that evaluated the relationship between vancomycin MICs and
outcomes among patients with MRSA infections. The 27%
difference in success rates between the vancomycin MIC
groups observed in our study is comparable to the 23% differ-
ence observed in the study by Hidayat et al. (6), the 25%
difference in the study by Moise-Broder et al. (16), and the
45% difference in the study by Sakoulas et al. (19). The more-
drastic difference in success rates in the last study is most likely
a function of differences between study populations. We
examined all patients treated with vancomycin for MRSA
bloodstream infections at our institution, while Sakoulas
and colleagues examined MRSA bacteremic patients from
vancomycin refractory compassionate use studies (19). The
majority of these patients had unsatisfactory responses to van-
comycin. Another interesting similarity noted between our
study and that of Hidayat et al. (6) was the observed relation-
ship between the vancomycin trough and the outcome. In both
studies, achieving a vancomycin trough in excess of 15 mg/liter
did not improve success rates. Similar to the observations in a
study of MRSA bacteremic dialysis patients by Maclayton et al.
(11), our observations revealed a 1.6-fold increase in mortality
and a doubling of morbidity. For morbidity, we observed a
twofold increase in length of stay in the hospital postcollection
of index blood culture, while Maclayton et al. noted a 1.8-fold
increase in mean hospitalization cost (11). Lastly, mortality
associated with MRSA bacteremia was significantly higher
when vancomycin was used empirically for the treatment of
infection with strains with a high vancomycin MIC (?1 mg/
liter) in the study by Soriano and colleagues, and this is con-
sistent with our findings (20).
The first limitation of our study is that MRSA blood culture
data were collected from a single site; institutional differences
in prescribing patterns, antibiotic formularies, and patient pop-
ulations may affect the applicability of these results to other
institutions. Second, our study excluded neutropenic patients;
therefore, the results may not be generalizable to this patient
group. Third, caution should be exercised in interpreting the P
values shown in Table 2, given the large number of bivariate
tests performed and hence the high likelihood that one or
more of the “significant” results are false positive. Finally,
since most strains in our institution had an MIC of 1.5 mg/liter,
additional molecular studies are needed to determine if one
clone or several clones are driving the observed results be-
tween vancomycin MIC and treatment failure at our institu-
In conclusion, our analyses strongly suggest that MRSA
bloodstream infections with higher vancomycin MICs (?1.5
mg/liter) have a higher likelihood of treatment failure. These
patients had a longer duration of bacteremia, a higher likeli-
hood of recurrence, and a longer hospital length of stay.
Higher vancomycin troughs of ?15 mg/liter were not found to
improve success rates. Based on our findings, we believe that
nonvancomycin anti-MRSA therapies should be considered
for patients with MRSA bloodstream infections with vancomy-
cin MICs of ?1.5 mg/liter and that the CLSI and FDA vanco-
mycin susceptibility breakpoint for MRSA bloodstream infec-
tions should be lowered from ?2.0 mg/liter to ?1.0 mg/liter.
Currently, daptomycin is the only drug approved by the FDA
for MRSA bloodstream infections. However, it was found to
be noninferior to vancomycin for S. aureus bacteremia and
infective endocarditis in its phase III clinical study (3). Data
are needed solely to determine if daptomycin or any other
alternative antibiotic can remedy the outcomes observed with
VOL. 52, 2008 VANCOMYCIN MIC AND PATIENTS WITH MRSA BACTEREMIA3319
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.
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