REVIEW ARTICLE
Risk of Vancomycin-induced Nephrotoxicity in the
Population With Chronic Kidney Disease
Bhupesh Panwar, MD, Victoria A. Johnson, MD, Mukesh Patel, MD and Daniel F. Balkovetz, MD, PhD
Abstract: The antibiotic vancomycin has been available since the
1950s but has been used more commonly since the early 1980s because
of the widespread appearance of methicillin-resistant Staphylococcus
aureus. Infectious Diseases Society of America guidelines recommend
achieving vancomycin trough levels of 10 to 20 mg/mL. Usage of
vancomycin in high dosages especially $4 g/d has led to an increase
in the incidence of vancomycin-induced nephrotoxicity, particularly in
patients with chronic kidney disease (CKD). This review focuses on the
impact of vancomycin-induced nephrotoxicity in patients with CKD.
Patients with CKD are at increased risk of developing acute kidney
injury and subsequently requiring renal replacement therapy. There is
substantial need for vancomycin pharmacokinetic studies to be per-
formed in the population with CKD to develop an optimum vancomycin
nomogram in these patients. At present, tight monitoring of vancomycin
trough levels in the population with CKD is recommended to help
prevent acute kidney injury and its associated high morbidity, mortality
and health care costs.
Key Indexing Terms: Acute kidney injury; Acute renal failure; Dialysis;
Antibiotics; MRSA. [Am J Med Sci 2013;345(5):396–399.]
I ndividuals with chronic kidney disease (CKD) are inherently at
a higher risk of developing acute kidney injury (AKI) as com-
pared with persons with normal renal function.1,2 Studies have
demonstrated CKD to be a strong predictor for developing AKI
in patients receiving radiocontrast3 or after a major surgery.4
Even a modest decline in the glomerular filtration rate (GFR)
from .60 mL/min to 45 to 59 mL/min can lead to a 2-fold
increase in risk of developing AKI.1 However, it is not clear
whether the presence of poor functional reserve because of mor-
phological and biochemical alterations in the diseased kidney or
merely the presence of other comorbidities with CKD leads to
this increased incidence.5 AKI is associated with a higher mor-
bidity, mortality and health care costs.2 The largest prospective
study to date found severe AKI-associated overall hospital mor-
tality to be 60.3%, and underlying CKD in patients developing
AKI increases the risk of dependence on renal replacement ther-
apy.6 The mortality for critically ill patients receiving renal re-
placement therapy for AKI remains high, with two thirds of
deaths occurring before hospital discharge.7
Over the past several decades, the glycopeptide antibac-
terial vancomycin has been used effectively to treat several
methicillin-resistant Staphylococcus aureus (MRSA) and other
gram-positive bacterial infections. Vancomycin was first
From the Department of Medicine (BP, VAJ, MP, DFB), Division of Nephrol-
ogy, School of Medicine, University of Alabama at Birmingham, Birmingham,
Alabama; and Department of Veterans Affairs Medical Center (VAJ, MP, DFB),
Birmingham, Alabama.
Submitted May 04, 2012; accepted in revised form July 03, 2012.
The authors have no financial or other conflicts of interest to disclose.
Correspondence: Daniel F. Balkovetz, MD, PhD, Department of
Medicine, Division of Nephrology, School of Medicine, University of Alabama
at Birmingham, 668 Lyons-Harrison Research Building, 701 South 19th
Street, Birmingham, AL 35294-0007 (E-mail: balkovet@uab.edu).
396 The American Journal of the Medical Sciences
manufactured in 1952 by Eli Lilly and Company from a chem-
ical derived from Streptomyces orientalis.8 Vancomycin-
induced nephrotoxicity (VIN) was described soon after its first
clinical use in 1956.9 It was soon realized that impurities in
vancomycin preparation contributed to the nephrotoxicity.10
In fact, early vancomycin formulations had a brown color
because of the impurities and was often dubbed “Mississippi
mud.” Occurrence of VIN decreased significantly with
improved purification methods and vancomycin was approved
for clinical use by the U.S. Food and Drug Administration
(FDA) in 1958.8 The FDA recently released a bulletin address-
ing possible quality issues associated with parenteral vancomy-
cin products.11 The FDA evaluated the quality of 6 parenteral
vancomycin products and found the purity to surpass the U.S.
Pharmacopeia acceptance criteria. At conventional dosages
(eg, 15 mg/kg every 12 hours), vancomycin has minimal neph-
rotoxicity. Nephrotoxicity has been noted to occur when van-
comycin is used concomitantly with known nephrotoxic drugs
or at very high dosages.12–14 Vancomycin trough levels
$15 mg/mL have been shown to increase the risk of nephro-
toxicity.15,16 A recent study showed increased incidence of
nephrotoxicity when high vancomycin doses ($4 g/d) were
used to achieve these higher troughs.13 The initial vancomycin
trough value has been shown to be the best predictor for
developing nephrotoxicity.17 Incidence of VIN is significantly
higher with initial trough levels $10 mg/mL and may be
unacceptable at levels $20 mg/mL.17
In recent years, VIN has become a real concern because
of the use of higher doses to achieve higher trough levels.12–17
Vancomycin dosing nomograms for patients with CKD were
developed in 1980s based on the pharmacokinetic and pharma-
codynamic properties of vancomycin. Trough levels achieved
using these nomograms are likely to fall short of current rec-
ommendations from the Infectious Diseases Society of America
(IDSA).18 Based on the current literature, we will discuss in this
review the mechanisms behind VIN, especially in the popula-
tion with CKD, and then consider the need for adjustment and
revision of vancomycin dosing nomograms in the population
with CKD based on current infectious disease guidelines.
RESURGENCE OF VANCOMYCIN USE
For many years, vancomycin use was usually limited to
patients allergic to methicillin or other beta-lactamase-resistant
penicillin. This was partly due to the reported toxicity from early
vancomycin formulations and the availability of potentially less
toxic alternatives including methicillin and other penicillins
effective against penicillinase-producing Staphylococcus. The
widespread appearance of MRSA and penicillin-resistant pneu-
mococcus in the 1980s led to increased utilization of vancomycin,
making it a commonly prescribed antibiotic in most hospitals.
WHY HIGHER DOSES OF VANCOMYCIN?
In response to the increasing number of staphylococcal
infections due to strains of S aureus with reduced susceptibility
to vancomycin and cases of vancomycin “failure,” many

Volume 345, Number 5, May 2013

clinicians prescribe higher doses of vancomycin than approved
by the FDA (1g every 12 hours).15,19 The IDSA-endorsed clin-
ical practice guidelines and a consensus statement in 2009 rec-
ommend maintaining trough vancomycin levels .10 mg/mL to
avoid the development of resistance and up to 15 to 20 mg/mL
in severe S aureus infections.20 Two recently published retro-
spective studies examining the effects of targeted higher vanco-
mycin trough levels (.15 mg/mL) reported improved treatment
outcomes in patients with complicated MRSA bacteremia.21,22
Kullar et al22 also reported that patients who experienced neph-
rotoxicity had a significantly longer hospital length of stay and
concluded that additional studies evaluating optimal therapy for
MRSA bacteremia in a larger cohort of matched patients are
warranted to determine the effect on total hospital length of stay
and cost. Use of vancomycin in doses higher than what was
previously recommended has led to the apparent increased
incidence of VIN. One prospective and a few observational
studies have shown higher incidence of nephrotoxicity in
patients receiving high doses of vancomycin.13,15
VANCOMYCIN NEPHROTOXICITY
The diagnosis of vancomycin nephrotoxicity is, in
general, a clinical diagnosis. Because vancomycin is mainly
eliminated by renal clearance, a decrease in renal function will
increase the vancomycin serum concentration and confound the
association between vancomycin serum concentrations and
renal dysfunction. Therefore, VIN has been defined as an
increase in serum creatinine level after initiation of vancomycin
therapy (with high initial vancomycin trough levels) in the
absence of other factors known to alter renal function (sepsis,
hypotension, contrast, nephrotoxic drugs, etc). Typically, but
not always, the high initial vancomycin trough levels will
precede the elevation in serum creatinine. Nephrotoxicity
occurs infrequently when purified vancomycin is used at
traditional doses (about 15 mg/kg every 12 hours).23 Previous
studies controlling for other factors that may have contributed
to nephrotoxicity reported the incidence of VIN to be 5% to
7%.12 The concomitant use of aminoglycosides with vancomy-
cin has been associated with an increased incidence of nephro-
toxicity of up to 35%.12 More recent studies have reported
a higher incidence (12%–34%) of VIN when used in the higher
IDSA-recommended dose range.13,15
The exact mechanism of VIN in not fully understood and
several mechanisms of nephrotoxicity have been postulated.
Vancomycin-increased oxidative stress to the renal proximal
tubule has been demonstrated in several animal studies.24–27
Exposure to vancomycin leads to proliferation of proximal
tubular cells because of increased oxygen consumption and
ATP concentration by altering mitochondrial function.26 Neph-
rotoxicity from glycopeptides such as vancomycin is not only
limited to proximal tubular toxicity but also may involve the
medullary region (loop of Henle and collecting duct) of the
nephron.28 Celik et al25 demonstrated a protective effect of
amrinone and other antioxidants against VIN, which is likely
because of inhibition of oxygen-free radical production. Van-
comycin-induced glomerular damage secondary to oxidative
stress has also been demonstrated in rats.27 A recent gene
expression study on high-dose vancomycin in mice showed
increased transcription of complement pathway proteins, sug-
gesting a link between VIN and complement activation.24
PHARMACOKINETICS OF VANCOMYCIN
Vancomycin binds to the peptidoglycan precursors
during bacterial cell wall synthesis preventing the proper
Ó 2012 Lippincott Williams & Wilkins
Vancomycin Nephrotoxicity in CKD
formation of cell wall.29 Vancomycin excretion is almost
exclusively renal, accounting for 70% to 90% of the total clear-
ance.30,31 Renal clearance of vancomycin is a fixed ratio of
creatinine clearance (CrCl) and is not concentration-dependent.
This ratio has been calculated to be about 79% in one study.31
Vancomycin renal clearance is tightly correlated with CrCl in
a linear fashion.32
Glomerular filtration plays a major role in vancomycin
renal excretion. If vancomycin is about 20% protein-bound,
then, based on the above ratio, vancomycin should be entirely
filtered and tubular secretion and reabsorption would play no
role in vancomycin renal clearance. In various studies, vanco-
mycin protein binding has been reported to be about 10% to
30%, which support vancomycin being almost entirely fil-
tered.33,34 Two studies have reported protein binding to be as
high as 50%, suggesting substantial tubular secretion of vanco-
mycin.30,35 High renal parenchymal levels of vancomycin and
substantial tubular uptake support the possibility of tubular
secretion of vancomycin.36
Nonrenal clearance of vancomycin does occur and is
concentration-dependent. In anephric patients, this mechanism
plays a significant role in total vancomycin clearance.30 How-
ever, some studies have reported that nonrenal vancomycin
clearance, which usually accounts for approximately 30% (40
mL/min) of total clearance in patients with normal renal func-
tion, is reduced to as low as 5 to 6 mL/min in patients with
terminal renal insufficiency.32,37 A probable explanation is
reduced vancomycin metabolism in uremic patients.38 Measur-
able vancomycin concentrations have been found in bile and
stool. Hepatic conjugation of vancomycin would seem the most
likely nonrenal route of excretion.39
Vancomycin’s volume of distribution is 0.4 to 1.0 L/kg.
The initial distributive phase can be 30 to 60 minutes with
elimination half-life ranging between 6 and 12 hours.31,32,39,40
The initial distributive phase and volume of distribution do not
change with varying degrees of renal function.40 As discussed
previously, the renal clearance of vancomycin decreases linearly
with decreasing CrCl. In one study, the mean half-life of vanco-
mycin approached 20 hours for a mean CrCl of 23.9 mL/min.40
Taken collectively, the pharmacokinetics of vancomycin clear-
ance are primarily dependent on renal clearance mechanisms.
Because development of VIN is vancomycin dose-dependent,
patients with CKD are at greater risk of having higher serum
concentrations of vancomycin and development of VIN.
VANCOMYCIN DOSING AND MONITORING FOR
VIN IN THE POPULATION WITH CKD
Current dosing and monitoring standards for use of
vancomycin in the population with CKD were established
nearly 3 decades ago targeting much lower trough levels.
Dosing of vancomycin in patients with CKD needs further
study and revision for at least 2 reasons. First, it is unknown if
the current vancomycin dosing guidelines are appropriate for
the population with CKD, particularly when using the higher
trough targets recommended for the treatment of more severe
staphylococcal infections.18 The guidelines recommend main-
taining trough vancomycin levels .10 mg/mL to avoid the
development of resistance and up to 15 to 20 mg/mL in severe
S aureus infections.20 All currently available nomograms for
dosing of vancomycin in the population with CKD have not
been adjusted for attaining higher trough levels. Attaining
trough levels of 10 to 20 mg/mL is challenging in patients with
CKD due in part to impaired clearance rates of vancomycin and
higher risk of developing nephrotoxic serum levels of
397
Panwar et al
vancomycin. Second, there is need for more aggressive moni-
toring of vancomycin levels in the population with CKD due to
increased susceptibility of the population with CKD toward
developing AKI and the rising incidence of VIN with the use
of higher doses of vancomycin.13,15
In 1984, Matzke et al32 determined the pharmacokinetics
of vancomycin for patients with impaired renal function. Using
the Cockroft-Gault equation to determine the CrCl, the authors
determined vancomycin mean half-lives to be 9.1 hours in
patients with CrCl of .60 mL/min, 32.3 hours in patients with
CrCl 60 to 10 mL/min and 146.7 hours in patients with CrCl
,10 mL/min. Using these data, they developed a nomogram for
initial and maintenance dosing of vancomycin to achieve peak
and trough levels of 30 and 7.5 mg/mL, respectively.32
In 1988, Brown and Mauro41 developed a nomogram to
be used for dosing vancomycin in the population with CKD. It
was designed to provide a vancomycin steady-state concentration
mean of 15 mg/mL.41 This was designed to produce theoretical
trough levels between 5 and 13 mg/mL (mean 8.8 mg/mL).
A recent article suggested an extrapolated version of
vancomycin dosing nomogram for use in the population with
CKD.42 The proposed vancomycin dosing schedule in this
article is based on defining the stages of CKD based on the
calculated CrCl (mL/min per 1.73 m2). Using calculated CrCl to
define the CKD stage will underestimate the severity of renal
disease in patients. The current National Kidney Foundation
CKD classification stages 1 to 5 are defined by the estimated
GFR (eGFR), as determined by the modified diet renal disease
(MDRD) equation.43 CrCl estimations are significantly higher
than eGFR calculations. This is because CrCl includes creatinine
clearance by both GFR and tubular secretion, whereas eGFR is
an estimation of only GFR. One potential concern with using
the MDRD equation to dose vancomycin is that at lower levels
of serum creatinine, the MDRD equation underestimates GFR44
and might lead to underdosing vancomycin in patients with
mild degrees of renal dysfunction. Regardless, this newly pro-
posed dosing schedule has not been validated by prospective
randomized controlled clinical trials.
CONCLUSIONS
Vancomycin is still considered indispensable for the
treatment of staphylococcal infections. Reduced susceptibility
of vancomycin in S aureus has prompted the development of
vancomycin dosing guidelines recommending higher doses of
vancomycin to achieve higher trough concentrations in select
situations. Routine use of higher doses of vancomycin has been
associated with increased VIN. Patients with CKD who are
receiving vancomycin are at greater risk of developing VIN. In
patients with CKD, we recommend measuring the initial vanco-
mycin trough concentration and frequent subsequent drug level
monitoring to minimize VIN risk. Alternative anti-staphylococcal
antibacterials should be considered in situations where monitor-
ing of vancomycin trough levels is either unreliable or not pos-
sible, particularly in the population with CKD.
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