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

S U P P L E M E N T A R T I C L E

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 tissuedistribution,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

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-compart-

ment pharmacokinetic profile (figure 1) [3–6]. The

drug is administered intravenously, with a standard in-

fusion time of at least 1 h, to minimize infusion-related

adverse effects. In patients with normal creatinine clear-

ance, vancomycin has an a-distribution phase of ∼30

min to 1 h and a b-elimination half-life of 6–12 h. The

volume of distribution is 0.4–1 L/kg [2, 4–7]. The bind-

ing of vancomycin to protein has been reported in the

literature to range from 10% to 50% [8–11]. Factors

that affect the overall activity of vancomycin include

its tissue distribution, inoculum size, and protein-bind-

ing effects.

TISSUE DISTRIBUTION

Vancomycin penetrates into most body spaces, al-

though 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 ([email protected]).

Clinical Infectious Diseases 2006;42:S35–9

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 van-

comycin into the CSF of patients with uninflamed

meninges, fairly low concentrations have been dem-

onstrated (range, 0–3.45 mg/L), with corresponding

CSF-to-serum ratios of 0–0.18 [1, 12]. As expected,

inflamed meninges improve penetration of vancomycin

into the CNS, with reported concentrations of 6.4–11.1

mg/L and CSF-to-serum ratios of 0.36–0.48 [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 intra-

venous administration of 1 g of vancomycin, concen-

trations ranged from 0 to 12.2 mg/L, with a mean con-

centration of 2.8 mg/L and a penetration of 41% [13].

In a recent study investigating the penetration of van-

comycin into the epithelial lining fluid of healthy vol-

unteers 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 crit-ically 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 blood-

to–epithelial 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 ori-






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 fromEbert [23].

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 eradi-

cation rate and a higher mortality rate ( ) [26]. A recentP p .005

study examined the relationship between the AUC/MIC value

and a successful outcome in 168 patients with S. aureus bac-

teremia. The MIC50

was 0.5 mg/L (range, 0.25–1.0 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 van-

comycin MIC of 8–16 mg/L. The majority of cases of GISA

infection have occurred among patients receiving peritoneal

dialysis or hemodialysis who had received suboptimal, pro-

longed, and repeated courses of vancomycin [28]. Most cases

of GISA infection have involved serum concentrations of van-

comycin that were consistently 10 mg/L. Although the num-

ber 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., heterores-

istant GISA strains) have also been reported to be associated

with vancomycin therapy failure [30, 31]. These strains typically

have an MIC of 1–4 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 dif-

ficult to detect in the clinical laboratory, and their prevalence

may be underreported [32]. Recent in vitro evaluations havedemonstrated a relationship between exposure to low vanco-

mycin serum concentrations and the development of hetero-

resistant GISA [33]. However, because of the difficulty in de-

tecting 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 toimpurities in the manufacturing process [1]. Although most

animal studies have not found that vancomycin causes ne-

phrotoxicity, there have been a number of studies involving

humans that have attempted to link elevated serum vancomycin

serum concentrations with renal damage [35–39]. Most of these

studies are retrospective, and definitions for nephrotoxicity are

highly variable. In many cases, serum vancomycin concentra-

tions were measured after an elevation in serum creatinine



S38 • CID 2006:42 (Suppl 1) • Rybak

levels, making it uncertain which came first. Despite these draw-

backs, the nephrotoxic potential of vancomycin is reported to

be 5% [37, 39]. In one of the largest investigations to date,

Pestotnik et al. [40] reported that the incidence of nephrotox-

icity among 1750 patients was 1.4%. Of interest, vancomycin

appears to potentiate the nephrotoxicity of aminoglycosides,

when administered in combination with this class of drugs.

Both animal and human studies have concluded that the com-bination may increase the nephrotoxicity of aminoglycosides

by, on average, 3–4-fold [37, 39, 41].

With respect to ototoxicity, the overall incidence appears to

be low [42]. Despite clinical case reports of a relationship be-

tween vancomycin serum concentrations and ototoxicity, there

are no animal models that have demonstrated this relationship.

The majority of experts believe that this drug is not ototoxic

[42–45].

The so-called therapeutic range most often quoted for van-

comycin monitoring is peak and trough serum concentrations

of 30–40 mg/L and 5–10 mg/L, respectively [46, 47]. As stated

earlier, there is little evidence to support a relationship between

specific serum concentrations and efficacy and toxicity. Because

vancomycin is a concentration-independent, or time-depen-

dent, antibiotic and because there are practical issues associated

with determining a precise peak serum concentration with this

multicompartment antibiotic, most clinicians have abandoned

the routine practice of determining peak serum concentrations.

Therefore, most clinicians rely solely on monitoring trough

serum concentrations for this antibiotic.

The overall AUC/MIC value may be the pharmacodynamic

parameter that best correlates with a successful outcome as-

sociated with the use of vancomycin; however, further studiesseem to be warranted. The nephrotoxic and ototoxic effects of

this drug are minimal and are not related to specific serum

concentrations. Prolonged exposure to serum concentrations

close to the MIC are associated with the emergence of resis-

tance; therefore, it is important to maintain adequate serum

concentrations in patients with fast or rapidly changing cre-

atinine clearance. There are several body compartments in

which penetration is poor, such as the lung and the CNS. It

would also seem prudent to keep concentrations from being

suboptimal in patients with pneumonia or meningitis, as well

as in patients receiving vancomycin who are receiving dialysis

for renal failure. The American Thoracic Society recently pub-lished guidelines for hospital-acquired, ventilator-associated,

and health care–associated pneumonia. These guidelines rec-

ommend vancomycin trough concentrations of 15–20 mg/L for

the treatment of methicillin-resistant S. aureus pneumonia. The

recommendations are based on vancomycin susceptibility and

pharmacokinetic/pharmacodynamic properties, as well as re-

ported clinical experience, since no definitive clinical studies

have evaluated the recommended serum concentrations with

respect to patient outcome [48]. Although precise and aggres-

sive pharmacokinetic adjustments via the successive measure-

ment of serum concentrations may not be necessary for most

infections, empirical adjustments made using standard phar-

macokinetic equations or a validated nomogram that maintains

trough serum concentrations at 4–5 times the MIC would seem

to be reasonable. Higher concentrations may be needed for

sequestered infections or in situations where vancomycin pen-etration 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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