ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2007, p. 2582–2586
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Vol. 51, No. 7
Vancomycin In Vitro Bactericidal Activity and Its Relationship to
Efficacy in Clearance of Methicillin-Resistant
Staphylococcus aureus Bacteremia?
Pamela A. Moise,1* George Sakoulas,2Alan Forrest,3and Jerome J. Schentag3,4
University of the Pacific School of Pharmacy and San Diego VA Medical Center, San Diego, California 921611;
Westchester Medical Center and Division of Infectious Diseases, New York Medical College, Valhalla,
New York 105952; SUNY Buffalo School of Pharmacy, Buffalo, New York 142603; and
CPL Associates, LLC, Buffalo, New York 142264
Received 29 July 2006/Returned for modification 13 October 2006/Accepted 12 April 2007
We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus
(MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of
vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene
regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom
clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve
peak plasma concentrations of 28 to 32 ?g/ml and trough concentrations of 8 to 12 ?g/ml. Bactericidal assays were
performed over 24 h with ?107to 108CFU/ml in broth containing 16 ?g/ml vancomycin. The median time to
clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating >2.5 reductions in log10
CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log10CFU/ml by 24 h (P ?
0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0
?g/ml compared to that with MRSA isolates with MICs of <1.0 ?g/ml (P ? 0.019). The bacteremia caused by
MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia
(10 days and 6.5 days, respectively; P ? 0.27) and had a decreased probability of eradication (44% and 78%,
respectively; P ? 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased
vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia
while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression
may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies
that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.
The efficacy of vancomycin against methicillin-resistant Staph-
ylococcus aureus (MRSA) has come under increased scrutiny in
data demonstrating a suboptimal clinical response of patients
treated with vancomycin (7–9, 11), worse outcomes in patients
with MRSA infections compared to those in patients with methi-
cillin-susceptible S. aureus infections (3, 4, 6), and the availability
of other antibiotics with activities against MRSA. MRSA strain-
specific characteristics, such as a polymorphism at the accessory
gene regulator (agr) locus (13), vancomycin susceptibility, and
bactericidal activity (18), may also contribute to the response to
Bactericidal antimicrobial regimens are considered to be supe-
stream infections, particularly in the case of infective endocarditis
(5, 14, 15). In our recent study in which we evaluated the rela-
tionship of MIC and bactericidal activity to the efficacy of vanco-
mycin, a superior clinical response of MRSA infections to vanco-
mycin therapy correlated with a lower vancomycin MIC and
increased in vitro killing by vancomycin (18). In light of the vari-
ability in the activity of vancomycin against different MRSA
strains and the continued controversy on the importance of anti-
microbial bactericidal activity in the treatment of bacteremia,
further evaluation of the clinical and microbiological relationship
of the activity of vancomycin against MRSA is anticipated by
clinicians. The primary objective of this study was to determine
the relationship between the time to clearance of MRSA bacter-
emia while patients were receiving vancomycin therapy and the in
vitro bactericidal activity of vancomycin. The secondary objectives
were to evaluate the vancomycin MIC as it related to (i) agr
function, (ii) time to clearance of MRSA bacteremia, (iii) the
probability of MRSA eradication, and (iv) 30-day all-cause mor-
(This study was previously presented in part at the 43rd Infec-
tious Diseases Society of America Annual Meeting, 7 October
2005, San Francisco, CA, and at the 15th International Society of
Interscience Conference on Antimicrobial Agents and Chemo-
therapy], 19 December 2005, Washington, DC.)
MATERIALS AND METHODS
Patients. From a pool of prospectively collected MRSA isolates, 17 agr group
II (agr-II) MRSA isolates were randomly selected from 17 different patients who
had received vancomycin monotherapy for the treatment of MRSA bacteremia
and were matched with 17 non-agr-II MRSA isolates. The analysis focused on all
34 strains from 34 unique patients. The matching was done to determine the
effect of agr. The strains were matched on the basis of the date of culture
* Corresponding author. Mailing address: San Diego VA Medical
Center (119), 3350 La Jolla Village Drive, San Diego, CA 92161.
Phone: (858) 583-1392. Fax: (858) 552-7582. E-mail: p_moise@yahoo
?Published ahead of print on 23 April 2007.
isolation, patient age, and patient renal function (based on the calculated cre-
atinine clearance). These 34 patients were previously enrolled in prospective
phase III/IV trials between 1998 and 2002 from six hospitals representing six
states (CT, DE, IA, LA, MA, and NY).
Patients with endocarditis, osteomyelitis, and/or a central nervous system
infection were excluded. Therapeutic drug monitoring was performed prospec-
tively to obtain target 1-h peak serum concentrations of 28 to 32 mg/liter and
trough serum concentrations of 8 to 12 mg/liter. Only patients for whom blood
for culture was taken daily were included. The isolates were stored at ?70°C and
were grown and maintained on Trypticase soy agar for subsequent testing.
Microbiological testing. Blinded from the clinical data, we determined the
reduction in the log10CFU/ml at 24 h in Mueller-Hinton broth containing
vancomycin at 16 ?g/ml using an initial bacterial inoculum of approximately 107
to 108CFU/ml. Bacterial colony counts were determined by serial dilution, as
described previously (18). Susceptibility to vancomycin was determined by the
broth microdilution methods of the Clinical and Laboratory Standards Institute
(formerly NCCLS) (2).
A semiquantitative assessment of the function of agr of the clinical MRSA
isolates was performed by determination of the expression of delta-hemolysin on
sheep blood agar plates, as described previously (17). Each isolate’s delta-
hemolysin expression was scored by one investigator (G.S.), who was blinded to
the clinical data, as follows: 0, absent; 1, severely depressed/barely detectable 2,
easily detectable; 3, increased; 4, exceptionally high.
Definitions. The probability of MRSA eradication from the blood was deter-
mined at the end of therapy. The bacteriological response was classified as
eradication of the baseline MRSA pathogen if blood cultures at the end of
therapy were negative for MRSA. The time to bacterial clearance (i.e., the
number of days to eradication) was defined as the time from the initiation of
vancomycin therapy until the first day after the last positive culture on which the
blood culture was negative.
Thirty-day all-cause mortality was defined as the patient’s status 30 days
following the initiation of vancomycin therapy.
Statistics. Continuous variables were compared by using Kruskal-Wallis anal-
ysis of variance. Categorical variables were compared by the chi-square or Fisher
exact test, where appropriate. The median time to eradication was compared by
using Kaplan-Meier survival analysis and the log rank test. Tree-based modeling
was used to determine the breakpoints in the log10decrease in 24 h (LogDec) as
a predictor of bacterial eradication. Iterative nonlinear regression was used to fit
a mathematical function to the relationship between the probability of bacteriolog-
ical success (dependent variable) and the log10decrease at 24 h (independent
variable). Model discrimination was performed by using Akaike’s information cri-
terion. We used the following Hill-type model:
P ? P0??Pmax? P0? ? ?LogDecH?
where P is the probability of coming to the event (eradication), P0is the prob-
ability of success as LogDec approaches 0, Pmaxis the asymptotic maximum
probability of success, H is Hill’s constant (reflects steepness), LogDec is the
log10decrease at 24 h, and LDmis the LogDec giving a half-maximal effect.
Multivariable logistic regression analysis was performed on bacterial eradication
by using forward stepping, with a P value of ?0.10 required for inclusion in the
model. Variables identified as being borderline significant in our univariate
analysis (P ? 0.10) were used for the analysis. All statistical procedures were
performed with Systat 11 software (Systat Software Inc., Point Richmond, CA).
We evaluated 34 MRSA bacteremia isolates from 34 pa-
tients consisting of 17 agr-II MRSA isolates matched for date
of isolation, patient age, and patient renal function to 17 non-
agr-II strains. The median age of the 34 patients investigated
was 70 years (range, 30 to 87 years), 68% were male, and 50%
were in an intensive care unit at the time of onset of the
infection (Table 1). The median duration of vancomycin ther-
apy was 16 days. The vancomycin MICs of the 34 strains
ranged from 0.5 to 2.0 ?g/ml (Table 2), and the killing ob-
served in vitro ranged from 0.82 log10CFU/ml to 4.92 log10
CFU/ml. The results of analysis of the clinical and the in vitro
data are displayed in Table 3 and demonstrate a relationship
between the reduction in log10CFU/ml in vancomycin killing
assays, the median day to clearance of bacteremia, and the
clearance rate at the end of treatment.
By tree-based modeling, we determined a vancomycin log10
CFU of killing/ml at 24 h of 2.5 to be a categorical breakpoint
for both of these outcomes. At a vancomycin log10CFU of
killing/ml at 24 h of ?2.5, 4 of 13 patients (31%) had bacterial
eradication; at a vancomycin log10CFU of killing/ml at 24 h of
?2.5, 14 of 21 (67%) did (P ? 0.042). In addition, the median
time to clearance of bacteremia for MRSA isolates demon-
strating a ?2.5-log10reduction in CFU/ml at 24 h (n ? 21) was
6.5 days and was in excess of 10.5 days for MRSA isolates
TABLE 1. Patient and organism characteristicsa
CharacteristicAll patients (n ? 34)
Patients infected with:
agr-II isolates (n ? 17)Non-agr-II isolates (n ? 17)
Male sex (no. [%] of patients)
ICUb(no. [%] of patients)
Creatinine clearance (ml/min)
No. (%) of isolates for which the
vancomycin MIC was:
No. of days of vancomycin therapy
66 ? 17 (70)
62 ? 36 (58)
64 ? 18 (70)
61 ? 39 (57)
68 ? 16 (70)
63 ? 33 (61)
19 ? 10 (16)
21 ? 10 (17)17 ? 9 (14)0.184
aThe data represent means ? standard deviations (medians), unless stated otherwise.
bICU, the patient was in an intensive care unit at the time of onset of the infection.
TABLE 2. Vancomycin MIC versus eradication rates
aDTE, day to eradication.
bEOT, end of treatment. The eradication rate data represent the number of
patients from the organism was eradicated/total number of patients in the group
cThe median time to eradication is greater than 15 days, as only 21% of
patients showed clearance of bacteremia.
VOL. 51, 2007 VANCOMYCIN BACTERICIDAL EFFECT AGAINST MRSA2583
demonstrating a ?2.5-log10reduction in CFU/ml at 24 h (n ?
13) (P ? 0.025) (Fig. 1). In these patients, for whom the
vancomycin peak and trough concentrations (and, thus, a
steady-state area under the concentration-time curve at 24 h)
were prospectively adjusted, there was also an association be-
tween vancomycin treatment success, the time to eradication,
and the vancomycin MIC (Table 2). We found only a 21%
treatment success rate of vancomycin treatment of MRSA
bacteremia caused by isolates showing a vancomycin MIC of 2
?g/ml. In addition, the median time to clearance of bacteremia
was significantly longer for patients infected with isolates for
which the MICs were 2.0 ?g/ml than for patients infected with
isolates for which the MICs were ?1.0 ?g/ml (P ? 0.019).
As can be seen in Table 3, it appears that there may be a
continuous relationship between vancomycin log10CFU of kill-
ing/ml at 24 h and the probability of eradication. Nonlinear
regression found the relationship between the percent proba-
bility of bacteriologic eradication (%P) and LogDec to be
86 ? LogDec6
This Hill-type model fit the experimental data well (r2? 0.85;
P ? 0.001) (Fig. 2).
The 30-day all-cause mortality was also related to in vitro
bactericidal activity: 6 of 13 (46%) patients whose isolates
showed ?2.5-log10CFU of killing/ml at 24 h died within 30
days, whereas 3 of 21 (14%) patients whose isolates showed
?2.5-log10CFU of killing/ml at 24 h died within 30 days (odds
ratio ? 5.15; P ? 0.041).
Although the difference was not statistically significant, pa-
tients whose isolates had delta-hemolysin scores of 0 or 1,
corresponding to undetectable or barely detectable expression,
had more prolonged bacteremia and a decreased probability of
clearance of bacteremia. Patients with infections caused by
MRSA isolates whose delta-hemolysin scores were 0 or 1 had
a median time to eradication of ?15 days, whereas the median
time to eradication was 6.5 days for patients with infections
caused by MRSA isolates whose delta-hemolysin scores were
at least 2 (P ? 0.28). In addition, 11 of 25 (44%) patients
whose isolates had delta-hemolysin scores of 0 or 1 achieved
clearance of the bacteremia, whereas 7 of 9 (78%) patients
whose isolates had delta-hemolysin scores of at least 2
achieved clearance of the bacteremia (P ? 0.086).
Multivariate logistic regression identified both a higher van-
comycin MIC and a lower level of bactericidal activity to be
associated with a decreased probability of bacterial eradication
in patients with MRSA bacteremia (Table 4). These are not
the results from the univariate analysis. The odds that vanco-
mycin failed to eradicate MRSA for isolates with a vancomycin
MIC of 2 ?g/ml were approximately 14 times higher than that
for MRSA isolates with vancomycin MICs of ?1 ?g/ml. In
addition, the odds that vancomycin failed to eradicate MRSA
bacteremia for isolates with a vancomycin log10CFU of kill-
ing/ml at 24 h of ?2.5 was approximately seven times more
likely than that for isolates with log10reduction in CFU/ml of
at 24 h ?2.5. Delta-hemolysin expression and the agr group
were also entered into the logistic regression model. This data
FIG. 1. Time to bacterial eradication by reduction in log10CFU/ml.
Upper line, 13 patients with a log10decrease at 24 h of ?2.5; lower
dotted line, 21 patients with a log10decrease at 24 h of ?2.5 (P ?
FIG. 2. Nonlinear relationship between percent probability of bac-
terial eradication and log decrease at 24 h (r2? 85%; P ? 0.001). The
datum points represent the proportions of successes in empirically
selected cells: ?2.0-log decrease, 0% success (n ? 6); 2.0- to 2.2-log
decrease, 50% success (n ? 6); 2.3- to 3.0-log decrease, 60% success
(n ? 10); 3.1- to 3.4-log decrease, 67% success (n ? 6); 3.5- to 4.9-log
decrease, 83% success (n ? 6).
TABLE 3. Outcomes by vancomycin bactericidal activity
aDTE, day to eradication.
bEOT, end of treatment. The eradication rate data represent the number of
patients from the organism was eradicated/total number of patients in the group
cNA, not applicable as no patients showed clearance of bacteremia.
TABLE 4. Odds ratios for failure of vancomycin to eradicate MRSA
Characteristic Odds ratio (95% CIa)
Vancomycin MIC ? 2.0 ?g/ml
Reduction in log10CFU/ml ?2.5
aCI, confidence interval.
2584MOISE ET AL.ANTIMICROB. AGENTS CHEMOTHER.
set found a lack of or severely depressed delta-hemolysin ex-
pression to be highly associated with higher vancomycin MICs
(P ? 0.015).
Until 2000, vancomycin served as the main antimicrobial
agent for the treatment of MRSA infections, a role that has
increased dramatically since the mid-1980s as a result of the
marked increase in the prevalence of this pathogen. This role
is now being challenged with the emergence of several new
antimicrobial agents with activities against MRSA and with the
increased awareness that MRSA infections that were previ-
ously deemed susceptible to vancomycin may not respond to
therapy (10–13, 18). The latter point has been highlighted by
the recent change in the vancomycin MIC breakpoint for sus-
ceptibility from 4 ?g/ml to 2 ?g/ml. These factors have given
rise to controversies in the management of MRSA infections,
with some clinicians ready to replace vancomycin in favor of
newer antimicrobials, while others are not convinced that the
expense of the newer antibiotics is justified. Whether the van-
comycin MIC susceptibility breakpoint was lowered sufficiently
is also seriously questioned in light of prior data showing that
bacteremias caused by MRSA demonstrating vancomycin
MICs of 1 to 2 ?g/ml were treated successfully in less than 10%
of cases (18), as well as the findings of this study, in which we
found only a 21% treatment success rate for cases of MRSA
bacteremia caused by isolates showing a vancomycin MIC of 2
In this study we attempted to offer additional data on the
microbiological phenotype of MRSA with respect to vancomy-
cin susceptibility as it relates to vancomycin treatment efficacy
in MRSA bacteremia. We found that increased vancomycin
killing of MRSA in vitro was significantly associated with a
more rapid clearance of bacteremia with vancomycin therapy
and a lower all-cause patient mortality. We defined a nonlinear
mathematic relationship between killing by vancomycin in vitro
and vancomycin treatment success in MRSA bacteremia.
With respect to MICs, we found that MRSA strains with
MICs of 2 ?g/ml, which are still considered susceptible by the
new MIC susceptibility breakpoint, were associated with a suc-
cess rate of 21% for vancomycin treatment of MRSA bacter-
emia. Infections with MRSA strains with MICs of 0.5 ?g/ml
showed a 77% treatment success rate with vancomycin. From
these findings, we support the performance by clinical micro-
biology laboratories of additional evaluations of vancomycin
MICs, for instance, by microdilution or Etest, for MRSA
bloodstream isolates beyond the reporting of the categorical
results (e.g., susceptible, intermediate, or resistant) offered by
certain automated systems (e.g., the MicroScan system). Indi-
vidual centers using qualitative susceptibility testing systems
may wish to survey the vancomycin MIC distribution of their
MRSA clinical isolates, and if a high percentage are found to
have MICs of ?2 mg/ml, it may be easier to move to alterna-
tive or combination empirical and directed therapy for MRSA
While this was not a prospective study, data from this inves-
tigation are consistent with those presented in other reports
showing a microbiological correlation with vancomycin treat-
ment success. Such data are providing increasing support for
the fact that S. aureus may develop physiological changes, such
as tolerance to glycopeptides, that influence vancomycin ther-
apy in patients with serious infections, such as bacteremia, with
minimal changes in susceptibility detected by MIC determina-
tion. Furthermore, by the time that the organism develops
increases in vancomycin MICs that approach 2 ?g/ml, the
upper limit of the current range of susceptibility, the efficacy of
vancomycin for the treatment of MRSA bacteremia appears to
be severely compromised.
With the recent approval of daptomycin by the Food and
Drug Administration, this agent may be considered an alter-
native for the treatment of MRSA bacteremia due to organ-
isms with vancomycin MICs of 2 ?g/ml. In fact, the recent
findings of increased daptomycin MICs in S. aureus isolates
exposed to vancomycin in vitro and in vivo, coupled with the
possible cross-resistance to platelet-derived microbicidal pro-
teins induced by vancomycin, draw consideration for daptomy-
cin as a first-line agent in favor of vancomycin for some cases
of MRSA bacteremia (16).
It is possible that MIC and delta-hemolysin expression are
both independent predictors of the efficacy of vancomycin, but
it would take a larger study to state that both are indepen-
dently associated with the outcome. Since the patients in this
study were matched by agr group, it is not surprising that agr
grouping did not come out of the model.
In summary, this study provides additional evidence in favor
of important prognostic information on the efficacy of vanco-
mycin treatment for MRSA bacteremia that can be obtained
by vancomycin MIC determination, the in vitro killing activity
of vancomycin, and the semiquantitative assessment of delta-
hemolysin expression. We provide a nonlinear mathematical
relationship of vancomycin killing in vitro and the success of
treatment with vancomycin in MRSA bacteremia. More data
are necessary to guide clinicians with the optimal incorporation
of newer antibiotics in place of vancomycin for the treatment
of serious MRSA infections.
There were no funding sources for this project.
Author disclosures are as follows: P. A. Moise is a member of the
speakers bureau of Cubist, G. Sakoulas is a member of the speakers
bureaus of Cubist, Pfizer, and Wyeth, and J. J. Schentag received a
research grant from Wyeth.
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