SUPPLEMENT ARTICLE

The Pharmacokinetic and Pharmacodynamic

Properties of Vancomycin
Michael J. Rybak
Anti-Infective Research Laboratory, Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Wayne State University,
Detroit, Michigan

Vancomycin is a large glycopeptide compound with a

molecular weight of 1450 Da [1]. It is not appreciably
absorbed orally and is eliminated primarily via the renal
route, with 180%90% recovered unchanged in urine
within 24 h after administration of a single dose [2].
The pharmacokinetic profile of vancomycin is complex
and can be characterized by either a 2- or 3-compartment pharmacokinetic profile (figure 1) [36]. The
drug is administered intravenously, with a standard infusion time of at least 1 h, to minimize infusion-related
adverse effects. In patients with normal creatinine clearance, vancomycin has an a-distribution phase of 30
min to 1 h and a b-elimination half-life of 612 h. The
volume of distribution is 0.41 L/kg [2, 47]. The binding of vancomycin to protein has been reported in the
literature to range from 10% to 50% [811]. Factors
that affect the overall activity of vancomycin include
its tissue distribution, inoculum size, and protein-binding effects.
TISSUE DISTRIBUTION
Vancomycin penetrates into most body spaces, although the concentrations obtained are variable and

Reprints or correspondence: Dr. Michael J. Rybak, Anti-Infective Research

Laboratory, Dept. of Pharmacy Practice, College of Pharmacy and Health Sciences,
Wayne State University, 259 Mack Ave., Detroit, MI 48201 (m.rybak@wayne.edu).
Clinical Infectious Diseases 2006; 42:S359
 2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4201S1-0006$15.00

somewhat dependent on the degree of inflammation

present. In studies examining the penetration of vancomycin into the CSF of patients with uninflamed
meninges, fairly low concentrations have been demonstrated (range, 03.45 mg/L), with corresponding
CSF-to-serum ratios of 00.18 [1, 12]. As expected,
inflamed meninges improve penetration of vancomycin
into the CNS, with reported concentrations of 6.411.1
mg/L and CSF-to-serum ratios of 0.360.48 [1, 12].
The penetration of vancomycin into the lung is
highly variable. Cruciani et al. [13] investigated the
penetration of vancomycin into the lung tissue of 36
patients undergoing a partial lobectomy. After intravenous administration of 1 g of vancomycin, concentrations ranged from 0 to 12.2 mg/L, with a mean concentration of 2.8 mg/L and a penetration of 41% [13].
In a recent study investigating the penetration of vancomycin into the epithelial lining fluid of healthy volunteers given 1 g of vancomycin every 12 h, the mean
concentration at 12 h was 2.4 mg/L, which represented
a 52% overall penetration rate [14]. However, in critically injured patients, penetration of vancomycin into
epithelial lining fluid was more variable, ranging from
0 to 8.1 mg/L after several hours, with an overall bloodtoepithelial lining fluid penetration ratio of 6:1 [15].
Craig and Andes [16] recently compared the efficacy
of vancomycin with that of oritavancin (a glycopeptide
derivative similar to vancomycin) in a thigh and lung
mouse infection model. Although the activity of oriVancomycin Pharmacokinetics/Pharmacodynamics CID 2006:42 (Suppl 1) S35

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Vancomycin is one of only a few antibiotics available to treat patients infected with methicillin-resistant
Staphylococcus aureus and methicillin-resistant, coagulase-negative Staphylococcus species. Therefore, understanding the clinical implications of the pharmacokinetic and pharmacodynamic properties of vancomycin is
a necessity for clinicians. Vancomycin is a concentration-independent antibiotic (also referred to as a timedependent antibiotic), and there are factors that affect its clinical activity, including variable tissue distribution,
inoculum size, and emerging resistance. This article reviews the pharmacokinetic and pharmacodynamic data
related to vancomycin and discusses such clinical issues as toxicities and serum concentration monitoring.

of in vitro assessments that have demonstrated a 18-fold increase in the MIC as a result of the presence of albumin, whereas
the presence of serum has had a more variable effect [1719].
VANCOMYCIN CONCENTRATION AND KILLING
ACTIVITY

tavancin was comparable in both lung and thigh infection

models, vancomycin activity was found to be 23-fold less potent in the lung infection model, compared with the thigh
infection model.
INOCULUM SIZE
The impact of inoculum on the activity of vancomycin has
recently been examined in an in vitro pharmacodynamic model
incorporating simulated endocardial vegetations against methicillin-susceptible and methicillin-resistant Staphylococcus aureus [17]. The activity of vancomycin, nafcillin, daptomycin,
and linezolid was examined at a moderate inoculum of 106 log10
cfu/g and a high inoculum of 109 log10 cfu/g over a 72-h period.
At the lower inoculum of 106 log10 cfu/g, vancomycin, nafcillin,
and daptomycin demonstrated similar bactericidal activity;
however, at the higher inoculum, nafcillin and vancomycin had
little to no impact over the 72-h period, whereas the effectiveness of daptomycin was minimally affected. Although linezolid
is bacteriostatic, it was not affected by the size of the inoculum.
PROTEIN-BINDING EFFECTS
Although most studies have shown that the binding of vancomycin to protein is moderate (50%), there are a number
S36 CID 2006:42 (Suppl 1) Rybak

HUMAN PHARMACODYNAMIC STUDIES

There are very few human studies evaluating the pharmacodynamics of vancomycin, and the findings of most of those
studies have not been conclusive in determining which parameter has the most value in predicting patient outcome. The
majority of studies have involved relatively small patient populations and patients with a variety of infection types. One
prospective evaluation randomized 106 patients with S. aureus
infections, including bacteremia and endocarditis, to achieve 3
different trough concentration targets of 510 mg/L, 1015 mg/
L, and 1525 mg/L. No relationships were found between peak
concentrations, trough concentrations, or pharmacodynamic
parameters (e.g., peak/MIC, time above the MIC, or AUC/MIC)
and organism eradication or overall patient outcome [25].

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Figure 1. Schematic representation of a 2-compartment pharmacokinetic model, wherein C is the concentration, a and b are the respective
elimination constants, e is the base of the natural logarithm, t is time,
A and B are the respective zero time intercepts for a and b, Ko is the
infusion rate constant, Vc is the volume of the central compartment, Vp
is the volume of the peripheral compartment, K12 and K21 are intracompartmental rate constants, and KEL is the elimination rate constant from
the central compartment.

A number of in vitro and animal studies have been performed

to determine the relationship between vancomycin concentration and killing activity. Most in vitro killing curve experiments
evaluating fixed vancomycin exposure concentrations as small
increments of the MIC demonstrate that killing activity does
not change as a function of increasing concentration [20]. Using an in vitro pharmacodynamic model that could mimic the
elimination half-life of vancomycin, Larson et al. [21] evaluated
the effects of concentration and bacterial activity against a strain
of methicillin-resistant S. aureus. The administration of stepwise increasing clinical concentrations (range, 540 mg/L) resulted in no appreciable difference in killing. The postantibiotic
effect of vancomycin is dependent on the concentration. As
drug concentrations exceed the MIC by 24-fold, the postantibiotic effect was been reported to increase from 0.2 to 2 h
for S. aureus and from 4.3 to 6.5 h for Staphylococcus epidermidis
[22]. In vitro and neutropenic mouse thigh infection models
have demonstrated that the area under the concentration curve
(AUC) divided by the MIC (AUC/MIC) is the best predictor
of the activity of vancomycin against methicillin-susceptible S.
aureus (figure 2), methicillin-resistant S. aureus, and glycopeptide-intermediate S. aureus (GISA). However, in a Streptococcus
pneumoniae nonneutropenic mouse peritonitis model, Knudsen et al. [24] demonstrated that the peak serum concentration
divided by the MIC (peak/MIC) was the pharmacodynamic
parameter with the most predictive value. Why peak/MIC has
predictive value is unknown, but the reason may be one of
several factors, including the species of organism, very high
susceptibility to vancomycin, and the contribution of neutrophils to elimination of the pathogen.

Moise-Broder et al. [26] examined the relationship between the

vancomycin AUC/MIC and the outcomes of 108 patients with
methicillin-resistant S. aureus pneumonia. An AUC/MIC value
of 400 was associated with a successful outcome, whereas an
AUC/MIC value of !400 was associated with a lower eradication rate and a higher mortality rate (P p .005 ) [26]. A recent
study examined the relationship between the AUC/MIC value
and a successful outcome in 168 patients with S. aureus bacteremia. The MIC50 was 0.5 mg/L (range, 0.251.0 mg/L), and
the median AUC/MIC value was 1072. Overall, in this study,
no relationship was found between successful outcome and a
specific AUC/MIC value [27].
The development of staphylococcal resistance to vancomycin
has been associated with prolonged exposure to low serum
concentrations of the drug. GISA infection and subsequent
failure of vancomycin therapy have been reported since the
middle of the 1990s. By definition, these strains have a vancomycin MIC of 816 mg/L. The majority of cases of GISA
infection have occurred among patients receiving peritoneal
dialysis or hemodialysis who had received suboptimal, prolonged, and repeated courses of vancomycin [28]. Most cases
of GISA infection have involved serum concentrations of vancomycin that were consistently 10 mg/L. Although the number of cases of GISA infection has remained low, there appears
to be some evidence that this type of resistance has occurred
in the past but may have been underreported because of our
inability to detect these strains in the clinical laboratory [29].
The Centers for Disease Control and Prevention recommends
the use of vancomycin screening plates of 6 mg/L, which may
increase our ability to detect these strains [30]. S. aureus strains

that display heteroresistance to glycopeptides (i.e., heteroresistant GISA strains) have also been reported to be associated
with vancomycin therapy failure [30, 31]. These strains typically
have an MIC of 14 mg/L but contain a subpopulation of cells
that exhibit higher MIC values when plated onto agar plates
containing vancomycin or when tested with a heavy inocula
by use of the Etest (AB BIODISK) methods for antimicrobial
susceptibility. Similar to GISA strains, these organisms are difficult to detect in the clinical laboratory, and their prevalence
may be underreported [32]. Recent in vitro evaluations have
demonstrated a relationship between exposure to low vancomycin serum concentrations and the development of heteroresistant GISA [33]. However, because of the difficulty in detecting these strains clinically, the overall prevalence and clinical
significance of heteroresistant GISA have not been established
[32, 34].
TOXICITY
In recent years, there appears to be less controversy with regard
to the relationship between serum vancomycin concentrations
and toxicity. Historically, vancomycin toxicities were related to
impurities in the manufacturing process [1]. Although most
animal studies have not found that vancomycin causes nephrotoxicity, there have been a number of studies involving
humans that have attempted to link elevated serum vancomycin
serum concentrations with renal damage [3539]. Most of these
studies are retrospective, and definitions for nephrotoxicity are
highly variable. In many cases, serum vancomycin concentrations were measured after an elevation in serum creatinine

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Figure 2. Relationship between pharmacokinetic/pharmacodynamic indices for vancomycin and bacteriologic efficacy against methicillin-susceptible
Staphylococcus aureus. This plot, which delineates the change in colony-forming units (cfu) in an experimental mouse infection model 3 different
ways, suggests that the area under the curve divided by the MIC (AUC/MIC) is the most valuable pharmacokinetic/pharmacodynamic parameter for
predicting the activity of vancomycin against methicillin-susceptible S. aureus. Peak/MIC, peak serum concentration divided by the MIC. Data are from
Ebert [23].

S38 CID 2006:42 (Suppl 1) Rybak

respect to patient outcome [48]. Although precise and aggressive pharmacokinetic adjustments via the successive measurement of serum concentrations may not be necessary for most
infections, empirical adjustments made using standard pharmacokinetic equations or a validated nomogram that maintains
trough serum concentrations at 45 times the MIC would seem
to be reasonable. Higher concentrations may be needed for
sequestered infections or in situations where vancomycin penetration has been documented to be poor. Further research
examining the outcome of patients as it relates to vancomycin
serum concentrations is warranted.
Acknowledgments
Potential conflicts of interest. M.J.R. receives grant and/or research
support from Advancis, Bayer, Cubist, and Oscient, is a consultant for
Advancis, Bayer, Cubist, and Oscient, and is on speakers bureaus of Aventis,
Bayer, and Cubist.

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