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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 one of only a few antibiotics available to treat patients infected with methicillin-resistant
Staphylococcus aureus and methicillin-resistant, coagulase-negative Staphylococcus species. Therefore, under-
standing 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 “time-
dependent” 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.

Vancomycin is a large glycopeptide compound with a somewhat dependent on the degree of inflammation
molecular weight of ∼1450 Da [1]. It is not appreciably present. In studies examining the penetration of van-
absorbed orally and is eliminated primarily via the renal comycin into the CSF of patients with uninflamed
route, with 180%–90% recovered unchanged in urine meninges, fairly low concentrations have been dem-
within 24 h after administration of a single dose [2]. onstrated (range, 0–3.45 mg/L), with corresponding
The pharmacokinetic profile of vancomycin is complex CSF-to-serum ratios of 0–0.18 [1, 12]. As expected,
and can be characterized by either a 2- or 3-compart- inflamed meninges improve penetration of vancomycin
ment pharmacokinetic profile (figure 1) [3–6]. The into the CNS, with reported concentrations of 6.4–11.1
drug is administered intravenously, with a standard in- mg/L and CSF-to-serum ratios of 0.36–0.48 [1, 12].
fusion time of at least 1 h, to minimize infusion-related The penetration of vancomycin into the lung is
adverse effects. In patients with normal creatinine clear- highly variable. Cruciani et al. [13] investigated the
ance, vancomycin has an a-distribution phase of ∼30 penetration of vancomycin into the lung tissue of 36
min to 1 h and a b-elimination half-life of 6–12 h. The patients undergoing a partial lobectomy. After intra-
volume of distribution is 0.4–1 L/kg [2, 4–7]. The bind- venous administration of 1 g of vancomycin, concen-
ing of vancomycin to protein has been reported in the trations ranged from 0 to 12.2 mg/L, with a mean con-
literature to range from 10% to 50% [8–11]. Factors centration of 2.8 mg/L and a penetration of 41% [13].
that affect the overall activity of vancomycin include In a recent study investigating the penetration of van-
its tissue distribution, inoculum size, and protein-bind- comycin into the epithelial lining fluid of healthy vol-
ing effects. unteers given 1 g of vancomycin every 12 h, the mean
concentration at 12 h was 2.4 mg/L, which represented
TISSUE DISTRIBUTION
a 52% overall penetration rate [14]. However, in crit-
Vancomycin penetrates into most body spaces, al- ically injured patients, penetration of vancomycin into
though the concentrations obtained are variable and epithelial lining fluid was more variable, ranging from
0 to 8.1 mg/L after several hours, with an overall blood-
to–epithelial lining fluid penetration ratio of 6:1 [15].
Reprints or correspondence: Dr. Michael J. Rybak, Anti-Infective Research
Laboratory, Dept. of Pharmacy Practice, College of Pharmacy and Health Sciences, Craig and Andes [16] recently compared the efficacy
Wayne State University, 259 Mack Ave., Detroit, MI 48201 (m.rybak@wayne.edu).
of vancomycin with that of oritavancin (a glycopeptide
Clinical Infectious Diseases 2006; 42:S35–9
 2006 by the Infectious Diseases Society of America. All rights reserved.
derivative similar to vancomycin) in a thigh and lung
1058-4838/2006/4201S1-0006$15.00 mouse infection model. Although the activity of ori-

Vancomycin Pharmacokinetics/Pharmacodynamics • CID 2006:42 (Suppl 1) • S35


of in vitro assessments that have demonstrated a 1–8-fold in-
crease in the MIC as a result of the presence of albumin, whereas
the presence of serum has had a more variable effect [17–19].

VANCOMYCIN CONCENTRATION AND KILLING


ACTIVITY

A number of in vitro and animal studies have been performed


to determine the relationship between vancomycin concentra-
tion 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]. Us-
ing 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 step-
wise increasing clinical concentrations (range, 5–40 mg/L) re-
sulted in no appreciable difference in killing. The postantibiotic
effect of vancomycin is dependent on the concentration. As
Figure 1. Schematic representation of a 2-compartment pharmacoki- drug concentrations exceed the MIC by 2–4-fold, the postan-
netic model, wherein C is the concentration, a and b are the respective tibiotic effect was been reported to increase from 0.2 to 2 h
elimination constants, e is the base of the natural logarithm, t is time, for S. aureus and from 4.3 to 6.5 h for Staphylococcus epidermidis
A and B are the respective zero time intercepts for a and b, Ko is the
[22]. In vitro and neutropenic mouse thigh infection models
infusion rate constant, Vc is the volume of the central compartment, Vp
is the volume of the peripheral compartment, K12 and K21 are intracom- have demonstrated that the area under the concentration curve
partmental rate constants, and KEL is the elimination rate constant from (AUC) divided by the MIC (AUC/MIC) is the best predictor
the central compartment. of the activity of vancomycin against methicillin-susceptible S.
aureus (figure 2), methicillin-resistant S. aureus, and glycopep-
tide-intermediate S. aureus (GISA). However, in a Streptococcus
tavancin was comparable in both lung and thigh infection
pneumoniae nonneutropenic mouse peritonitis model, Knud-
models, vancomycin activity was found to be 2–3-fold less po-
sen et al. [24] demonstrated that the peak serum concentration
tent in the lung infection model, compared with the thigh
divided by the MIC (peak/MIC) was the pharmacodynamic
infection model.
parameter with the most predictive value. Why peak/MIC has
predictive value is unknown, but the reason may be one of
INOCULUM SIZE
several factors, including the species of organism, very high
The impact of inoculum on the activity of vancomycin has susceptibility to vancomycin, and the contribution of neutro-
recently been examined in an in vitro pharmacodynamic model phils to elimination of the pathogen.
incorporating simulated endocardial vegetations against meth-
icillin-susceptible and methicillin-resistant Staphylococcus au- HUMAN PHARMACODYNAMIC STUDIES
reus [17]. The activity of vancomycin, nafcillin, daptomycin,
There are very few human studies evaluating the pharmaco-
and linezolid was examined at a moderate inoculum of 106 log10
dynamics of vancomycin, and the findings of most of those
cfu/g and a high inoculum of 109 log10 cfu/g over a 72-h period.
studies have not been conclusive in determining which param-
At the lower inoculum of 106 log10 cfu/g, vancomycin, nafcillin,
eter has the most value in predicting patient outcome. The
and daptomycin demonstrated similar bactericidal activity;
majority of studies have involved relatively small patient pop-
however, at the higher inoculum, nafcillin and vancomycin had
ulations and patients with a variety of infection types. One
little to no impact over the 72-h period, whereas the effective-
prospective evaluation randomized 106 patients with S. aureus
ness of daptomycin was minimally affected. Although linezolid
infections, including bacteremia and endocarditis, to achieve 3
is bacteriostatic, it was not affected by the size of the inoculum.
different trough concentration targets of 5–10 mg/L, 10–15 mg/
L, and 15–25 mg/L. No relationships were found between peak
PROTEIN-BINDING EFFECTS
concentrations, trough concentrations, or pharmacodynamic
Although most studies have shown that the binding of van- parameters (e.g., peak/MIC, time above the MIC, or AUC/MIC)
comycin to protein is moderate (⭐50%), there are a number and organism eradication or overall patient outcome [25].

S36 • CID 2006:42 (Suppl 1) • Rybak


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].

Moise-Broder et al. [26] examined the relationship between the that display heteroresistance to glycopeptides (i.e., heterores-
vancomycin AUC/MIC and the outcomes of 108 patients with istant GISA strains) have also been reported to be associated
methicillin-resistant S. aureus pneumonia. An AUC/MIC value with vancomycin therapy failure [30, 31]. These strains typically
of ⭓400 was associated with a successful outcome, whereas an have an MIC of 1–4 mg/L but contain a subpopulation of cells
AUC/MIC value of !400 was associated with a lower eradi- that exhibit higher MIC values when plated onto agar plates
cation rate and a higher mortality rate (P p .005 ) [26]. A recent containing vancomycin or when tested with a heavy inocula
study examined the relationship between the AUC/MIC value by use of the Etest (AB BIODISK) methods for antimicrobial
and a successful outcome in 168 patients with S. aureus bac- susceptibility. Similar to GISA strains, these organisms are dif-
teremia. The MIC50 was 0.5 mg/L (range, 0.25–1.0 mg/L), and ficult to detect in the clinical laboratory, and their prevalence
the median AUC/MIC value was 1072. Overall, in this study, may be underreported [32]. Recent in vitro evaluations have
no relationship was found between successful outcome and a demonstrated a relationship between exposure to low vanco-
specific AUC/MIC value [27]. mycin serum concentrations and the development of hetero-
The development of staphylococcal resistance to vancomycin resistant GISA [33]. However, because of the difficulty in de-
has been associated with prolonged exposure to low serum tecting these strains clinically, the overall prevalence and clinical
concentrations of the drug. GISA infection and subsequent significance of heteroresistant GISA have not been established
failure of vancomycin therapy have been reported since the [32, 34].
middle of the 1990s. By definition, these strains have a van-
comycin MIC of 8–16 mg/L. The majority of cases of GISA TOXICITY
infection have occurred among patients receiving peritoneal
dialysis or hemodialysis who had received suboptimal, pro- In recent years, there appears to be less controversy with regard
longed, and repeated courses of vancomycin [28]. Most cases to the relationship between serum vancomycin concentrations
of GISA infection have involved serum concentrations of van- and toxicity. Historically, vancomycin toxicities were related to
comycin that were consistently ⭐10 mg/L. Although the num- impurities in the manufacturing process [1]. Although most
ber of cases of GISA infection has remained low, there appears animal studies have not found that vancomycin causes ne-
to be some evidence that this type of resistance has occurred phrotoxicity, there have been a number of studies involving
in the past but may have been underreported because of our humans that have attempted to link elevated serum vancomycin
inability to detect these strains in the clinical laboratory [29]. serum concentrations with renal damage [35–39]. Most of these
The Centers for Disease Control and Prevention recommends studies are retrospective, and definitions for nephrotoxicity are
the use of vancomycin screening plates of 6 mg/L, which may highly variable. In many cases, serum vancomycin concentra-
increase our ability to detect these strains [30]. S. aureus strains tions were measured after an elevation in serum creatinine

Vancomycin Pharmacokinetics/Pharmacodynamics • CID 2006:42 (Suppl 1) • S37


levels, making it uncertain which came first. Despite these draw- respect to patient outcome [48]. Although precise and aggres-
backs, the nephrotoxic potential of vancomycin is reported to sive pharmacokinetic adjustments via the successive measure-
be ⭐5% [37, 39]. In one of the largest investigations to date, ment of serum concentrations may not be necessary for most
Pestotnik et al. [40] reported that the incidence of nephrotox- infections, empirical adjustments made using standard phar-
icity among 1750 patients was 1.4%. Of interest, vancomycin macokinetic equations or a validated nomogram that maintains
appears to potentiate the nephrotoxicity of aminoglycosides, trough serum concentrations at 4–5 times the MIC would seem
when administered in combination with this class of drugs. to be reasonable. Higher concentrations may be needed for
Both animal and human studies have concluded that the com- sequestered infections or in situations where vancomycin pen-
bination may increase the nephrotoxicity of aminoglycosides etration has been documented to be poor. Further research
by, on average, 3–4-fold [37, 39, 41]. examining the outcome of patients as it relates to vancomycin
With respect to ototoxicity, the overall incidence appears to serum concentrations is warranted.
be low [42]. Despite clinical case reports of a relationship be-
Acknowledgments
tween vancomycin serum concentrations and ototoxicity, there
are no animal models that have demonstrated this relationship. Potential conflicts of interest. M.J.R. receives grant and/or research
support from Advancis, Bayer, Cubist, and Oscient, is a consultant for
The majority of experts believe that this drug is not ototoxic
Advancis, Bayer, Cubist, and Oscient, and is on speakers’ bureaus of Aventis,
[42–45]. Bayer, and Cubist.
The so-called therapeutic range most often quoted for van-
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Vancomycin Pharmacokinetics/Pharmacodynamics • CID 2006:42 (Suppl 1) • S39

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