Advances in Therapeutics and Diagnostics
Vancomycin
David R. McNamara, MD, and James M. Steckelberg, MD
Despite use that spans more than four decades, vanco-
mycin remains one of the most important antibiotics in
orthopaedic practice. It has increased in importance in
the last decade because of the growing resistance of many
gram-positive bacteria to β-lactam antibiotics, such as pen-
icillins and cephalosporins. These gram-positive bacte-
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ria, especially Staphylococcus aureus and coagulase-
negative staphylococci, cause a large proportion of the
infections encountered in orthopaedic surgical practice,
especially those involving implanted hardware.
Structure and Mechanism of Action
Vancomycin is a large, complex, tricyclic glycopeptide mol-
ecule (Fig. 1). It works primarily through disruption of
the biosynthesis of peptidoglycan, the major structural
polymer of the gram-positive bacterial cell walls, through
binding to the D-alanyl-D-alanine terminal of cell wall pre-
cursor units. Penicillins and cephalosporins also inhibit
bacterial cell wall synthesis; however, unlike those drugs,
cross-resistance with vancomycin does not develop be-
cause vancomycin acts against different stages of cell wall
synthesis and different specific targets. Although vanco-
mycin possesses activity against nearly all gram-positive
bacteria, its large molecular weight keeps it from pen-
etrating the outer cell membrane of gram-negative ba-
cilli, and it has no useful activity against these organisms.1
Pharmacokinetics
Vancomycin is poorly absorbed from the gastrointesti-
nal tract and requires IV administration for the treatment
of systemic or orthopaedic infections. (The only role for
oral vancomycin is treatment of Clostridium difficile coli-
tis.) After an IV dose, the first distributive phase has a
half-life of approximately 0.4 hours; the second distrib-
utive phase half-life is approximately 1.6 hours. Clear-
ance is primarily through renal glomerular filtration, with
hepatic metabolism only a minor contributor to drug elim-
ination. In the presence of normal renal function, the elim-
ination half-life is approximately 6 hours. Within 24 hours,
70% to 90% of the dose is excreted unchanged in the
urine.1 Drug dosing requires significant adjustment for
both patient size and renal function.
Vol 13, No 2, March/April 2005
The efficacy of vancomycin in bacterial killing prima-
rily correlates with the duration of exposure of suscep-
tible bacteria to a sufficient concentration of the drug. This
is expressed as the ratio of the area under the plasma con-
centration curve to minimal inhibitory concentration
(AUC:MIC). Antibacterial effects that persist after drug
exposure (postantibiotic effect) also contribute to its an-
tibacterial effect.2 The goal of vancomycin dosing is to
optimize exposure of susceptible bacteria to a sufficient
concentration of the drug while avoiding drug toxicity.
Indications for Use
Vancomycin is active against staphylococci, both S au-
reus and coagulase-negative staphylococci, including iso-
lates resistant to β-lactams (so-called methicillin- or
oxacillin-resistant strains). For many years, vancomycin
was the only substantial therapeutic option for serious
infections caused by these strains. Also in the last few
years, a handful of strains of both S aureus and coagulase-
negative staphylococci with reduced susceptibility to van-
comycin have been reported, an ominous development
given the paucity of options for these strains. In addition
to activity against staphylococci, vancomycin is active in
vitro against most strains of corynebacterium, propioni-
bacterium, streptococcal species, and clostridial species.
A significant number of enterococci are now resistant, and
susceptibility testing is required for this organism.3
Dr. McNamara is Instructor of Medicine, Mayo Clinic College of Medi-
cine, Rochester, MN. Dr. Steckelberg is Professor of Medicine, Mayo Clinic
College of Medicine.
None of the following authors or the departments with which they are af-
filiated has received anything of value from or owns stock in a commercial
company or institution related directly or indirectly to the subject of this
article: Dr. McNamara and Dr. Steckelberg.
Reprint requests: Dr. Steckelberg, Mayo Clinic College of Medicine, 200 First
Street SW, Rochester, MN 55905.
Copyright 2005 by the American Academy of Orthopaedic Surgeons.
J Am Acad Orthop Surg 2005;13:89-92
89
Vancomycin
Figure 1 Structural formula of vancomycin. From the National
Library of Medicine, accessed January 16, 2005, at http://
www.nlm.nih.gov/pubs/techbull/ma00/ma00_chemid_fig8.html.
Vancomycin should not be used routinely for the treat-
ment of infections caused by gram-positive organisms
known to be sensitive to cephalosporins, penicillins, or
other antimicrobials (eg, clindamycin).
Inappropriate use of vancomycin is a great concern.
The emergence of resistant bacterial pathogens common-
ly encountered in health care settings is associated with
selective pressure from antimicrobial use. In particular,
colonization with vancomycin-resistant enterococci has
been associated with receipt in hospitalized patients of
oral and parenteral vancomycin, cephalosporins, and anti-
anaerobic drugs.3 Among the recommendations issued
by the Centers for Disease Control to prevent the spread
of vancomycin resistance is prudent use of the drug.4 Spe-
cifically discouraged are routine surgical prophylaxis in
patients without life-threatening allergy to β-lactam an-
tibiotics; continued empiric use for presumed infections
in patients whose cultures are negative for β-lactam–re-
sistant microorganisms; and use of vancomycin for dos-
ing convenience in patients with renal insufficiency.
Vancomycin is used for perioperative antimicrobial
prophylaxis in patients with a history of type 1 hyper-
sensitivity reaction (urticaria, laryngeal edema, broncho-
spasm, or anaphylaxis) to penicillins or cephalosporins.
Cefazolin is the preferred agent for patients able to tol-
erate β-lactam antibiotics. Perioperative antimicrobial pro-
phylaxis should be administered not more than 1 hour
before surgery and should continue for less than 24 hours’
total duration (cefazolin 1 to 2 g IV every 8 hours for not
more than three doses, or vancomycin 15 mg/kg IV ev-
ery 12 hours for two doses).5 Allergy skin testing may
be able to reduce the unnecessary use of vancomycin for
perioperative prophylaxis in orthopaedic surgical patients
with a reported history of allergy to penicillins or ceph-
alosporins. A study using targeted penicillin allergy skin
90 Journal of the American Academy of Orthopaedic Surgeons
testing to identify patients at increased risk of a hyper-
sensitivity reaction to β-lactam antibiotics reduced the use
of vancomycin in patients with a reported history of al-
lergy to β-lactam agents from 30% to 11%.6
Randomized controlled prospective clinical trials of
vancomycin compared to other antibiotics for the treat-
ment of orthopaedic infections have not been reported.
Despite this, vancomycin, with penicillins and cepha-
losporins, has been used extensively in the treatment of
osteomyelitis and soft-tissue infections for several de-
cades. As an adjunct to appropriate surgical débridement,
it has an established record as an accepted agent for these
infections when they are caused by susceptible bacteria.
Use of vancomycin for treatment of bone and joint in-
fection is not specifically approved by the Food and Drug
Administration (FDA). However, treatment of serious in-
fection caused by organisms such as methicillin-resistant
S aureus is an approved indication.
Rigorous data are limited on optimal duration of an-
timicrobial therapy of musculoskeletal infections. Because
of the lack of prospective randomized trials and the het-
erogenous nature of bone and joint infections, recommend-
ed duration typically follows expert opinion and data from
case series. Decisions on treatment duration normally in-
volve consideration of factors such as response to initial
medical and surgical therapy, adequacy of débridement
in removing infected bone, systemic and local host fac-
tors, and the identity and antimicrobial susceptibility of
the involved microorganisms. Soft-tissue infections com-
monly are treated for approximately 2 weeks. Osteomy-
elitis typically is treated for 4 to 6 weeks, and intra-articular
infections, for 2 to 4 weeks, with longer treatment for more
virulent organisms, such as S aureus.7
Several authors have measured the penetration of van-
comycin into bone. In a study by Graziani et al,8 14 pa-
tients undergoing total hip arthroplasty received a 15 mg/kg
IV vancomycin dose 1 hour before surgery. Vancomycin
concentration was found to range from 0.5 to 16.0 µg/mL
(average, 2.3 µg/mL) in cancellous bone, and the drug
was detectable in 10 of 14 cortical bone specimens (av-
erage concentration, 1.1 µg/mL). Vancomycin was de-
tectable in only two of five cortical bone specimens from
patients undergoing débridement for osteomyelitis.8 An-
other study measured a mean vancomycin concentration
of 9.3 µg/mL in healthy sternal bone samples from 10
patients undergoing sternotomy for cardiac surgery.9 In
an experimental S aureus osteomyelitis model, vancomy-
cin had a concentration in infected bone of 5.3 ± 0.8 µg/
mL. By comparison, clindamycin had a concentration of
11.9 ± 1.9 µg/mL after a 70 mg/kg dose; cefazolin, a con-
centration of 4.1 ± 0.7 µg/mL after a 15 mg/kg dose; and
nafcillin, a concentration of 2.1 ± 0.3 µg/mL after a 40
mg/kg dose.10 The clinical significance of animal studies
evaluating bone concentrations of antimicrobials and the

bone-to-serum concentration ratio is less clear because
of differences in methods between studies, limitations in
extrapolating data from animal models using S aureus as
the infecting agent, and the lack of long-term follow-up
inherent in experimental animal models.11
In addition to systemic parenteral vancomycin ther-
apy, local delivery of antibiotics via impregnated poly-
methylmethacrylate (PMMA) beads is commonly used
in the treatment of chronic osteomyelitis or prosthetic joint
infection. The heat stability of vancomycin, in contrast
to that of β-lactam antibiotics (which are degraded dur-
ing the PMMA polymerization process), makes it a use-
ful drug for this application.10
Vancomycin-impregnated PMMA beads have not been
approved by the FDA and are not commercially avail-
able in the United States. For use in the treatment of in-
fected bone as antibiotic-impregnated cement beads or
spacer, in which structural strength of the cement is not
of primary importance, up to 4 g vancomycin into 40 g
PMMA cement can be used, often in combination with
an aminoglycoside antibiotic. Increasing concentrations
of vancomycin may have a negative effect on the mechan-
ical strength and stability of the cement. For use in which
the structural integrity of the cement is important (eg,
prosthesis fixation), only 0.5 to 1 g of powdered antibi-
otic per 40 g of PMMA cement is recommended to avoid
weakening the bone cement.5 Also, the use of vancomycin-
impregnated bone cement should be avoided in prophy-
lactic applications and limited to the treatment of estab-
lished infection.5 An in vitro evaluation of drug release
from PMMA beads in a continuous flow chamber showed
that vancomycin-impregnated PMMA beads had a sim-
ilar percentage of antibiotic release to that of gentamicin-
and tobramycin-impregnated PMMA beads.12
Various commercially available PMMA products may
differ in their vancomycin elution characteristics. The in
vivo significance of in vitro findings in studies compar-
ing different PMMA products is unclear. In addition, elu-
tion characteristics for vancomycin may change in com-
bination with other antibiotics. One study found the in
vitro elution of vancomycin in combination with tobra-
mycin via Palacos R cement (Biomet, Warsaw, IN) to be
greater than that of CMW 1 or CMW 3 cement (DePuy,
Warsaw, IN).13 Another study evaluating the in vitro elu-
tion of vancomycin in Palacos R, CMW, and Simplex P
cement (Stryker, Kalamazoo, MI) found that the addition
of imipenem-cilastatin significantly (P < 0.5) increased
the elution of vancomycin from all three cements.14
Drug Interactions and Adverse Effects
Common adverse effects include infusion-related pruri-
tis and erythema as well as phlebitis. Red man syndrome
Vol 13, No 2, March/April 2005
David R. McNamara, MD, and James M. Steckelberg, MD
involves a pruritic, erythematous rash on the upper trunk,
neck, and face associated with rapid vancomycin infu-
sion causing histamine release. Vancomycin should be
infused at a rate of 1,000 mg over 60 minutes, with larger
doses taking proportionately longer to infuse. Red man
syndrome can be ameliorated with a slower rate of in-
fusion and antihistamine premedication.15 Peripheral vein
phlebitis with vancomycin therapy is common and can
be avoided by infusion via a central venous catheter, such
as a peripherally inserted central catheter (PICC), when
therapy is anticipated to last longer than 10 to 14 days.
More serious adverse effects include ototoxicity and
nephrotoxicity. Cranial eighth nerve damage may result
in permanent equilibrium or hearing loss. Vestibular tox-
icity can be particularly troublesome for patients who al-
ready have gait difficulty as a result of orthopaedic prob-
lems. Concomitant aminoglycoside use has been linked
with increased risk of both ototoxicity and nephrotox-
icity.16 Other potentially serious complications of vanco-
mycin therapy include hypersensitivity rash, reversible
neutropenia, and, rarely, drug fever. Vancomycin does not
significantly interact with other medications, although
concomitant administration of other potentially nephro-
toxic or ototoxic drugs may increase the risk of these com-
plications.
Dosage and Cost
Dosing nomograms use both estimated creatinine clear-
ance and body weight to determine a dose and dosing
frequency (Table 1, available at http://www5.aaos.org/
jaaos/pdf/v13n2a1t1.pdf). Empiric nomograms may not
accurately guide dosing for patients with changing re-
nal function, anuria, or dialysis who will require serum
drug concentration monitoring to adjust doses. The av-
erage wholesale price of daily doses of vancomycin com-
pared with other antibacterials commonly used in ortho-
paedic surgical practice is shown in Table 2.
Patients with end-stage renal failure on dialysis have
often been dosed with once-weekly vancomycin because
of low clearance with traditional dialysis membranes.
Newer dialysis techniques incorporating high-flux mem-
branes, in addition to continuous renal replacement ther-
apies used in hospitalized patients, clear vancomycin
more rapidly and require more frequent dosing and of-
ten larger vancomycin doses. Input from infectious dis-
ease specialists and health-system pharmacists with ex-
pertise in therapeutic drug monitoring and antibiotic
dosing during renal replacement therapy is often valu-
able in achieving accurate dosing of vancomycin in re-
nal impairment.
Measurement of vancomycin concentration in serum
is often performed to guide dosing, especially in patients
91
Vancomycin

Trough serum concentrations of 5 to 10 µg/mL and

Table 2
Dosage and Cost of Vancomycin and Other peak serum concentrations of 20 to 40 µg/mL typically
Antibacterials are desired. In determining treatment outcome, evidence
for monitoring trough concentrations is stronger than for
Dosage Used for monitoring peak concentrations.17 Some institutions rely
Antibacterial Cost Calculation Cost per Day
mainly on trough measurements to guide dosing in pa-
Cefazolin 1 g IV q 8 h $ 8.22 tients who are stable and at steady state. Measurement
Nafcillin 2 g IV q 6 h $14.17 of creatinine level and complete blood count should be
Vancomycin 1 g IV q 12 h $12.12 performed at baseline, several days after beginning van-
Linezolid 600 mg PO q 12 h $123.68 comycin therapy, and generally are repeated weekly.
600 mg IV q 12 h $123.09
Moxifloxacin 400 mg PO daily and $9.80 and 6.28:
and rifampin 600 mg PO BID Total = $16.08 Summary
Average wholesale price (AWP) as published in the Red Book,
ed 108. (Montvale, NJ: Thomson Healthcare, 2004.) Bulk Vancomycin is a glycopeptide antibiotic active against
purchase, generic prices used when available. most gram-positive pathogens encountered in ortho-
paedic surgical practice, with the notable exception of
vancomycin-resistant enterococci. Systemic therapy re-
who will remain on vancomycin therapy for long peri- quires IV administration; the dose used depends on pa-
ods (several weeks or more). This is typically performed tient size and renal function. Patients undergoing pro-
after a pharmacokinetic steady state has been achieved, longed therapy require central venous access for drug
usually after the third empirically determined dose in pa- delivery as well as monitoring of drug levels, blood
tients with a dosing interval of 24 hours or less; it should counts, renal function, and liver tests. Although β-lactam
be repeated weekly in stable patients. Trough concentra- antibiotics are preferable for the treatment of suscepti-
tions are measured on serum obtained immediately be- ble bacterial infections in nonallergic patients, vancomy-
fore administration of a dose of the drug; peak concen- cin remains an essential agent for the treatment of
trations are measured on serum obtained 60 minutes after methicillin-resistant staphylococcal infections encoun-
the end of a dose infusion. tered in orthopaedic surgical practice.

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92 Journal of the American Academy of Orthopaedic Surgeons