1. Crit Care Clin 24 (2008) 393–420
Vancomycin Revisited: A Reappraisal
of Clinical Use
Burke A. Cunha, MD, MACPa,b,*
a
Infectious Disease Division, Winthrop-University Hospital,
Mineola, NY 11501, USA
b
State University of New York, School of Medicine, Stony Brook, NY, USA
Over the years, vancomycin has become the mainstay of methicillin-
resistant Staphylococcus aureus (MRSA) therapy. Although vancomycin is
active against a variety of other gram-positive organisms, other antibiotics
are preferred to treat infections due to these organisms (Table 1). In critical
care medicine, vancomycin has been mainly used to treat infections where
MRSA is the presumed cause of infection. These include central intravenous
line infections, soft tissue infections, bone infections, shunt infections in
hemodialysis patients, bacteremia, and acute bacterial endocarditis. The
widespread use of empiric vancomycin has resulted in adverse effects [1–5].
The initial unpurified formulations of vancomycin were associated with
reports of potential nephrotoxicity [6,7]. Subsequently, the purified prepara-
tions of vancomycin have been used and have not been associated with neph-
rotoxicity. There is no evidence for vancomycin monotherapy–associated
nephrotoxicity [8,9]. The few reports of potential vancomycin nephrotoxicity
described patients receiving vancomycin and known nephrotoxic medica-
tions. Vancomycin plus an aminoglycoside does not appear to increase the
nephrotoxic potential of the aminoglycoside [10–15]. Endotoxin or cytokine
release from gram-negative bacilli treated with an aminoglycoside and van-
comycin may be responsible for an increase in creatinine in some cases, which
may have been mistakenly ascribed to vancomycin toxicity [16]. Because van-
comycin monotherapy is not nephrotoxic, the use of vancomycin serum
levels to avoid nephrotoxicity has no basis [3,17,18]. Because vancomycin
is renally eliminated by glomerular filtration, vancomycin dosing in renal in-
sufficiency can be accurately dosed based on the creatinine clearance (CrCl),
(ie, the daily dose of vancomycin should be reduced in proportion to the
* Infectious Disease Division, Winthrop-University Hospital, 259 First Street, Mineola,
NY 11501.
0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2007.12.012 criticalcare.theclinics.com

2. 394 CUNHA
Table 1
Vancomycin: clinically useful microbiologic spectrum
Clinically effective Clinically ineffective
Gram-positive aerobic cocci Gram-negative aerobic cocci
Staphylococci (MSSA/MRSA), Neisseria meningitidis
Nonenterococcal streptococci (Groups A, B, C, G)
Staphylococcus epidermidis (coagulase negative
staphylococci) (MSSE/MRSE)
Penicillin-resistant Streptococcus pneumoniae
Gram-positive anaerobic cocci Gram-negative aerobic bacilli
Peptococcus Escherichia coli
Peptostreptococcus Klebsiella pneumoniae
Pseudomonas aeruginosa
Gram-positive aerobic bacilli Gram-positive aerobic bacilli
Corynebacterium sp Listeria monocytogenes
Lactobacillus sp
Gram-positive anaerobic bacilli Gram-negative anaerobic bacilli
Clostridium sp Bacteroides fragilis
Group D enterococci Group D enterococci
Enterococcus faecalis (VSE)a Enterococcus faecium (VRE)
Abbreviations: MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA, methicillin-
sensitive Staphylococcus aureus; MSSE, methicillin-sensitive Staphylococcus epidermidis; VRE,
vancomycin-resistant enterococci; VSE, vancomycin-sensitive enterococci.
a
Only when combined with an aminoglycoside (eg, gentamicin).
Data from Refs. [1,3,4].
decrease in renal function). In those responding to vancomycin therapy and
in those with a normal volume of distribution (Vd), vancomycin levels are
unhelpful, expensive, and unnecessary for vancomycin dosing [17–21].
The pharmacokinetic and pharmacodynamic characteristics of vancomy-
cin have been well studied. Vancomycin obeys both ‘‘concentration depen-
dent’’ kinetics at concentrations O MIC and ‘‘concentration independent’’
kinetics at concentrations ! MIC [1,3,19,22]. Because nephrotoxicity is not
a consideration, high-dose vancomycin (eg, 2 g intravenously every 12 hours
[60 mg/kg/d]) has been used in special situations, eg, osteomyelitis without
nephrotoxicity [23,24]. After years of clinical experience, vancomycin side
effects have become more fully appreciated. In addition to ‘‘red neck’’ or
‘‘red man’’ syndrome, leukopenia, thrombocytopenia, and, rarely, sudden
death have been ascribed to vancomycin [1,3,25].
Extensive vancomycin use over the years has resulted in two major prob-
lems. Firstly, excessive use of vancomycin has resulted in an increased
prevalence of vancomycin-resistant enterococci (VRE) worldwide. Vanco-
mycin-sensitive enterococci (VSE) represent the main group D enterococcal
component of feces. Vancomycin has sufficient anti-VSE activity to decrease
VSE in the fecal flora, resulting in a commensurate increase VRE in stools
[26–30]. Although the spectrum of infection caused by VSE and VRE are
the same, the number of antimicrobials available to treat VRE is limited,
making the therapy of VRE more difficult than the therapy of VSE [31,32].

3. VANCOMYCIN REVISITED 395
Another negative effect of vancomycin use over the years has been a rel-
ative increase S aureus resistance [33–37]. Vancomycin therapy results in
cell-wall thickening of S aureus strains, of both methicillin-sensitive S aureus
(MSSA) and methicillin-resistant S aureus (MRSA). Vancomycin-mediated
cell-wall thickening results in ‘‘permeability mediated’’ resistance to vanco-
mycin as well as to other anti-MSSA and anti-MRSA antibiotics [38–42].
Vancomycin-induced ‘‘permeability-mediated’’ resistance is manifested mi-
crobiologically by increased minimum inhibitory concentrations (MICs)
and clinically by delayed resolution or therapeutic failure in treating staph-
ylococcal bacteremias or acute bacterial endocarditis [43–48].
To avoid selecting out heteroresistant vancomycin-intermediate S aureus
(hVISA), vancomycin use should be minimized and other MRSA antibiotics
should preferentially be used instead (eg, minocycline, daptomycin, line-
zolid, or tigecycline) [1,31,32].
Vancomycin pharmacokinetics and pharmacodynamics
Although available orally and intravenously, vancomycin is primarily
administered via the intravenous route in the critical care setting. Oral van-
comycin is the preferred therapy for Clostridium difficile diarrhea because it
is not absorbed, is active against C difficile, and achieves high intraluminal
concentrations in the colon [1,3,32]. Because intravenous vancomycin does
not penetrate into the bowel lumen, intravenous vancomycin has no role
in the treatment of C difficile diarrhea or colitis [1,3,5,49].
Vancomycin is usually administered as 1 g (intravenous) every 12 hours.
After a 1-g intravenous dose, vancomycin serum concentrations are predict-
ably R25 mg/mL [1,3,5,50]. High dose of vancomycin (eg, 2 g intravenously
every 12 hours) has been used in the treatment of central nervous system
(CNS) infections to overcome the relatively poor cerebrospinal fluid (CSF)
penetration of vancomycin (CSF penetration with noninflamed meninges is
0% and with inflamed meninges is only 15% of simultaneous serum concen-
trations) and osteomyelitis (achieves serum trough levels R 15 mg/mL
[1,32,51,52]. For cardiopulmonary bypass (CBP) prophylaxis, use 1 g intrave-
nously preoperatively because vancomycin is rapidly removed during CBP
[53,54]. Burn patients have increased Vd and may require higher doses of van-
comycin. Intravenous drug abusers (IVDAs) have higher vancomycin renal
clearances than do non-IVDAs, and may require higher doses (Box 1) [1].
Vancomycin is not removed by hemodialysis [1,3]. In anuric patients
a 1 g (IV) dose results in peak serum concentrations of about 48 mg/mL.
Vancomycin’s mean elimination half-life is 7.5 days (vancomycin serum
concentration is 3.5 mg/mL after 18 days) [1,32,55,56]. In patients using
new ‘‘high flux’’ membranes for hemodialysis, about 40% of vancomycin
is removed. Therefore, a post–‘‘high flux’’ hemodialysis dose (eg, 500 mg
intravenously, which is w50% of the anuric dose) should be administered
post-hemodialysis [57].

4. 396 CUNHA
Box 1. Vancomycin: pharmacokinetic and pharmacodynamic
characteristics
Pharmacokinetic parameters
Usual adult dose: 1 g intravenously every 12 hours (30 mg/kg/
d); 2 g intravenously every 12 hours (60 mg/kg/d)
Peak serum levels: 63 mg/mL (1-g dose); 120 mg/mL (2-g dose)
Excreted unchanged (urine): 90%
Serum half-life: 6 hours (normal); 180 hours (end-stage renal
disease)
Plasma protein binding: 55%
Vd: 0.7 L/kg
Therapeutic serum levels:
Peak 1 g 25 mg/mL; 2g 50 mg/mL
Trough: 1 g ‚ 7.5 m/mL; 2 g ‚ 15 m/mL
Pharmacodynamic characteristics
‘‘Concentration dependent’’ kinetics
at concentrations MIC
‘‘Concentration independent’’ kinetics
(time dependent) at concentrations MIC
Primary mode of elimination: renal
Dosage adjustments:
CrCl 50–80 mL/min: dose = 500 mg intravenously every
12 hours
CrCl 10–50 mL/min: dose = 500 mg intravenously every
24 hours
CrCl 10 mL/min: dose = 1 g intravenous every week
Post-hemodialysis dose: none
Post–‘‘high flux’’ hemodialysis dose: 500 mg intravenous
every 12 hours
Post–peritoneal dialysis dose: none
CVVH dose: 1 gm intravenous every 24 hours
Data from Cunha BA, editor. Antibiotic essentials, 7th edition. Royal Oak (MI):
Physicians Press; 2008; with permission.
Peritoneal dialysis (PD) removes no vancomycin. Therefore, after an ini-
tial 1-g intravenous dose, vancomycin should be dosed for a CrCl less than
10 mL/min and no post-PD dose is necessary [1,32]. For patients with peri-
tonitis on chronic ambulatory peritoneal dialysis (CAPD), vancomycin may
be added to peritoneal dialysis fluid. A 1-g intravenous loading dose of
vancomycin may be given to such patients after dialysis, followed by the
renally adjusted maintenance anuric dose [1,32]. In addition, to maintain
equilibrium between the dialysate fluid and the serum compartment,

5. VANCOMYCIN REVISITED 397
vancomycin may also be given intraperitoneally (2–30 mg of vancomycin
per liter of dialysis fluid) with each CAPD [1,32]. Vancomycin has been
used to treat CNS infections, but CNS penetration of vancomycin is vari-
able. Vancomycin administered intravenously achieves only about 15% of
simultaneous serum levels in the CSF in patients with meningitis. If high
CSF concentrations are desired for treatment of gram-positive shunt infec-
tions, give 2 g intravenously every 12 hours until shunt removal. Intrave-
nous vancomycin may be supplemented by intrathecal doses (ie,
vancomycin 10–20 mg/d intrathecally), preferably administered via Om-
maya reservoir [1,3,32,58].
With normal renal function, about 90% of intravenous vancomycin is
eliminated unchanged in the urine during the first 24 hours. After a single
1-g intravenous dose of vancomycin, urine concentrations are w500 mg/mL,
which are maintained for 24 hours [1,3]. Intravenously administered van-
comycin does not concentrate well into, bile (30%), synovial fluid, pleural
fluid, or lung parenchyma [1,58–62].
Intravenous vancomycin diffuses well into most other body compart-
ments except feces, aqueous humor, and CSF [1,60]. While vancomycin pen-
etrates poorly into CSF, it penetrates well into brain tissue (Box 2)
[1,6,32,51,52,58].
Vancomycin levels
Vancomycin is eliminated by glomerular filtration. The serum half-life of
IV vancomycin is 6 hours with normal renal function, and 7 days in anuria
[1,6,56,62]. Many approaches to vancomycin dosing for various degrees of
renal insufficiency have been devised and all are based on CrCl [1,6,21].
Formerly, vancomycin was administered as 500 mg intravenously every
6 hours. Today vancomycin is usually administered as 1 g intravenously
every 12 hours (for adults with a normal Vd and CrCl) [22,63,64]. For seri-
ous systemic infections due to susceptible organisms, is to administer vanco-
mycin 1 g intravenously every 12 hours (15 mg/kg/d) or 2 g intravenously
every 12 hours (30 mg/kg/d) [1,3,32]. Even when used in prolonged high
doses for special situations, such as for MRSA osteomyelitis (2 g intrave-
nously every 12 hours [30 mg/kg/d]), there has been no nephrotoxicity
[23,24].
Since vancomycin was thought to be nephrotoxic, vancomycin dosing
was based on vancomycin levels [65,66]. However, vancomycin has no neph-
rotoxic potential. Thus, there is no rationale for using routine vancomycin
levels to dose patients to avoid nephrotoxicity. Accurate vancomycin dosing
is readily achieved more quickly, simply, less expensively, and without risk
of nephrotoxicity by dosing vancomycin based on CrCl rather then by van-
comycin levels [67–72]. It has been shown that vancomycin levels do not re-
duce nonexistent toxicity but vancomycin levels often result in unnecessary
vancomycin dosing changes [73–78].

6. 398 CUNHA
Box 2. Vancomycin tissue concentrations*
Bone concentrations
Cortical bone
Uninfected: w5%
Infected: w10%
Cancellous bone
Uninfected: w5%
Infected: 5%
Synovial fluid concentrations
Uninflamed synovial fluid: w20%
Urine Concentrations
Uninfected urine: 100% (normal renal function)
Stool concentrations
Feces:
Intravenous: 0%
Orally: 1000%
CSF concentrations
Uninflamed meninges: 0% (prophylaxis of CSF seeding)
Inflamed meninges: 15% (therapy of acute bacterial
meningitis)
Heart concentrations
Cardiac valves: 20%
Lung concentrations
Lung parenchyma: 10%
Bile concentrations
Unobstructed bile: w50%
Ascitic fluid concentrations
Ascites: 10%
* Relative to simultaneous serum levels
There is often considerable delay between the time vancomycin peaks
and troughs are reported [70,74–76]. Two or more days have usually
elapsed when dosing adjustments are made, which means adjustments in
vancomycin dosing are based on previous, but no longer relevant estimates
of, renal function (CrCl) [70,76]. The other practical difficulty with vanco-
mycin serum peak and trough levels is in the timing of the samples which
influences interpretation of the levels. This, in addition, causes unnecessar-
ily frequent changes in vancomycin dosing, which serve no clinical purpose
[1,6,32,70–78].
In anuria, on chronic hemodialysis, vancomycin peak serum concentra-
tions are predictable and vancomycin serum levels are unnecessary. In

7. VANCOMYCIN REVISITED 399
patients receiving vancomycin on ‘‘high flux’’ hemodialysis, a posthemodial-
ysis dose should be given to replace the vancomycin removed. Since about
40% of vancomycin is removed by ‘‘high flux’’ hemodialysis, a 500-mg in-
travenous posthemodialysis dose should be given [57].
Vancomycin serum concentrations may be used to assess adequacy of
therapy in patients with unusual Vd, such as burn patients, or in those
patients not responding to appropriately dosed vancomycin (ie, patients
showing vancomycin ‘‘tolerance’’ or resistance). For these purposes, vanco-
mycin serum levels should be obtained. Except to assess therapeutic efficacy
or ‘‘apparent therapeutic failure’’ there is no rationale for obtaining vanco-
mycin serum levels [69–78].
Vancomycin microbiologic activity and efficacy
Antistaphylococcal activity
Staphylococcus epidermidis
The main use of parenteral vancomycin over the years has been in the
treatment of Staphylococci epidermidis, (ie, coagulase-negative staphylococci
(CoNS) infections, methicillin-sensitive S epidermidis (MSSE), and methicil-
lin-resistant S epidermidis (MRSE) infections). CoNS infections are usually
related to prosthetic implant materials (ie, infections involving prosthetic
joints, prosthetic heart valves, and CNS shunts). These infections are diffi-
cult to eradicate with antimicrobial therapy alone because antibiotics are
unable to eradicate these organisms in the glycocalyx on prosthetic
materials.
Methicillin-resistant Staphylococcus aureus
Vancomycin has been used to treat serious staphylococcal infections,
especially MRSA. The prevalence of MRSA has increased during the past
several decades with three clinical variants recognized. Two of these are
hospital-acquired MRSA (HA-MRSA) and community-onset MRSA
(CO-MRSA). CO-MRSA strains originate in the hospital, circulate in the
community, and subsequently have their onset in the community before be-
ing readmitted to the hospital. A third is community-acquired (CA-MRSA),
a term often mistakenly applied to CO-MRSA because both come from the
community.
However, CA-MRSA infections have two distinctive clinical presentations
readily differentiating them from CO-MRSA strains, which represent the
majority of MRSA admitted from the community (community onset) to the
hospital. CA-MRSA infections usually present either as severe pyoderma or
as necrotizing/hemorragic CAP. Although still rare, these two clinical CA-
MRSA syndromes are recognizable by their clinical presentations. Strains of
CA-MRSA, particularly those with the Panton-Valentine leukocidin gene
(PVL positive), are unusually virulent with a high degree of cytotoxic

8. 400 CUNHA
activity, which accounts for their extensive tissue destruction and two
unique clinical presentations. While these strains are genetically distinctive
(ie, Staphylococcal chromosome cassette [SCC] mec IV), most hospital
laboratories cannot perform studies to identify PVL positive strains. Clini-
cians must rely on the clinical presentation to identify CA-MRSA strains
versus the great majority of MRSA strains from the community, which are
nearly all CO-MRSA. In spite of the increased virulence of CA-MRSA
PVL positive strains, these organisms are surprisingly sensitive to older
antibiotics, such as doxycycline, clindamycin, and trimethoprim-sulfame-
thoxazole (TMP-SMX), but these antibiotics are not effective against
HA-MRSA strains. Vancomycin, linezolid, daptomycin, minocycline, and
tigecycline are active against HA-MRSA, CO-MRSA, and CA-MRSA
strains. For CA-MRSA necrotizing pyodermas, treat with surgical de-
bridement and a HA-MRSA/CO-MRSA antibiotic, such as vancomycin,
linezolid, daptomycin, or tigecycline. For CA-MRSA CAP with influenza-
like illness, treat with influenza antivirals and linezolid [79,80].
Group D enterococci
Since vancomycin was the initial antibiotic effective against MRSA, its
excessive use over time has resulted in two major clinical problems. Firstly,
extensive intravenous (not oral) vancomycin use has resulted in an increase
in the prevalence of E faecium (VRE), as well as increased vancomycin re-
sistance [81]. The increase in VRE isolates is explained by the activity of
vancomycin against the VSE component in the fecal flora, which is the pre-
dominant enterococcal species in the fecal flora. By decreasing VSE in the
fecal flora, there is a commensurate increase in VRE in feces. There has
been an increase worldwide in VRE prevalence due to vancomycin over
use. Instead, other anti-MRSA antibiotics that do not have this effect should
be used [26,81,82].
Vancomycin tolerance and resistance
Enterococci
Enterococci and, to a lesser extent, staphylococci may develop ‘‘tolerance’’
to vancomycin. ‘‘Tolerance’’ may be defined as a minimum bactericidal
concentration (MBC) of R32 times the MIC of an antibiotic. Vancomycin
‘‘tolerance’’ may account for some cases of delayed or blunted therapeutic re-
sponse with enterococci or staphylococci [1,83–85].
Vancomycin is a heptapeptide and is bactericidal for most gram-positive
organisms, including staphylococci but is bacteriostatic against enterococci.
Resistance to vancomycin is mediated by alterations in the permeability of
outer membrane porins in S aureus. Vancomycin binds rapidly and irrevers-
ibly to cell walls, inhibiting cell-wall synthesis. Interfering with peptidoglycan

9. VANCOMYCIN REVISITED 401
cross-linkages causes defective cell-wall synthesis, resulting in bacterial cell-
wall lysis. Enterococci resistance to vancomycin may be of the high- or low-
grade variety. High-level (Van A) vancomycin resistance (MIC R64 mg/mL)
is mediated by plasmids and is inducible and transferable. Low-level
(Van B) resistance (MIC: 32–64 mg/mL) is nontransferable and chromoso-
mally encoded [1,85].
Staphylococci
Widespread vancomycin use has increased staphylococcal resistance to
vancomycin manifested as increased MICs. Clinically, vancomycin resis-
tance is manifested as delayed resolution of infection or therapeutic failure.
It has long been appreciated that patients with MRSA bacteremia/endocar-
ditis often do not respond to vancomycin therapy [86–92]. This cannot be
ascribed to underdosing vancomycin. Even with optimal vancomycin
dosing, persistent MRSA bacteremias and therapeutic failures are not un-
common in clinical practice. Vancomycin therapy increases staphylococcal
cell-wall thickening, particularly in hVISA strains. Cell-wall thickening re-
sults in ‘‘permeability-mediated’’ resistance to vancomycin as well as to
other antistaphylococcal antibiotics. For these reasons, vancomycin may
no longer be the preferred antibiotic for treatment of serious systemic
MRSA infections. Other effective MRSA antibiotics are available and
may be used in place of vancomycin (eg, minocycline, linezolid, tigecycline,
and daptomycin). The empiric use of vancomycin to treat MRSA-colonized
patients should be minimized to avoid further increases in VRE prevalence
and MRSA resistance [1,6,32,93].
Vancomycin: clinical uses
Methicillin-sensitive Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus bacteremias
The finding of S aureus, either of the MSSA or MRSA variety, is common
in blood culture reports. Because MSSA and MRSA often colonize the skin,
these organisms are frequently introduced into blood cultures during veni-
puncture. S epidermidis, (CoNS), are also common blood culture contami-
nants. Approximately 20% of blood cultures are contaminated by MSSA,
MRSA, or CoNS. Clinicians should not equate-positive blood cultures with
bacteremia.
Some organisms have clinical significance whenever present in blood cul-
tures (ie, Listeria monocytogenes, Brucella sp, Streptococcus pneumoniae).
The clinical significance of gram-positive cocci in blood cultures must be as-
sessed by the degree of blood culture positivity and considered in the appro-
priate clinical context. Ordinarily, four blood cultures should be obtained.
This usually allows the clinician to clearly differentiate between blood

10. 402 CUNHA
culture positivity and bacteremia when dealing with blood culture reports
positive for MSSA, MRSA, or CoNS. One or two out of four positive blood
cultures usually represent blood culture contamination rather than infec-
tion. High-grade blood culture positivitydthree of four or four of fourd
is usually indicative of bacteremia. If it is established that the patient has
bacteremia, the clinician’s next task is to determine whether it is a transient
or sustained bacteremia. Staphylococci bacteremia is said to be persistent
when MSSA or MRSA is present repeatedly in consecutive blood cultures
demonstrating high blood culture positivity (ie, three of four or four of
four). One out of four or two of four blood cultures with CoNS almost al-
ways represents blood culture contamination. Conversely, persistent high-
grade blood culture positivity with CoNS, particularly in the presence of
implanted prosthetic materials, usually indicates a prosthetic material- or
device-associated infection [2,32,94,95].
Much empiric vancomycin is used to ‘‘cover’’ ‘‘gram positive cocci in clus-
ters’’ in preliminary blood culture reports rather than bacteremia. The most
common cause of high-grade MSSA, MRSA, or CoNS bacteremia are central
venous catheter (CVC)–related infections. Empiric vancomycin used to
‘‘cover’’ the staphylococcal bacteremia or the ‘‘catheter’’ should be discour-
aged. If CVC line infection is suspected, the line should be removed and the
diagnosis confirmed by semiquantitative catheter tip cultures. Treatment for
CVC line–associated bacteremia is catheter removal, not just antibiotic ther-
apy. Overuse of empiric vancomycin for suspected or known CVC-line infec-
tions has increased the prevalence of VRE. If CVC access is necessary after
CVC removal for semiquantitative catheter tip culture, another line may be re-
placed over a guide wire without risk of pneumothorax, pending catheter tip
results. If the semiquantitative catheter tip cultures are later reported as neg-
ative, the new catheter placed over a guide wire may remain in place. If catheter
tip cultures are positive (ie, R15 colonies of the same organism as causing the
bacteremia), then the line replaced over the guide wire should be removed and
a new CVC placed in a different anatomic location (Boxes 3 and 4) [96,97].
Continuous Methicillin-sensitive Staphylococcus aureus and
methicillin-resistant Staphylococcus aureus bacteremias
Patients presenting with a sustained or persistent MSSA or MRSA bac-
teremia should be treated empirically with an agent that offers a high degree
of activity against MSSA or MRSA, depending upon the hospital’s predom-
inant S aureus type (ie, MSSA versus MRSA) while a workup to determine
the cause of the persistent bacteremia is undertaken. The most common un-
derlying causes of persistent MSSA or MRSA bacteremia are intravascular
infections (ie, CVC-related infections) or acute bacterial endocarditis or par-
avalvular abscess, and less commonly are due to persistent bacteremias from
non-cardiac staphylococcal abscesses and, even less commonly, bone infec-
tions [47,97–101].

11. VANCOMYCIN REVISITED 403
Box 3. Vancomycin: appropriate prophylactic
and therapeutic uses
Prophylaxis
Prosthetic (orthopaedic/cardiovascular) implant surgery
MSSA/MRSA infections in hemodialysis patients
Subacute bacterial endocarditis for:
Oral and upper respiratory tract procedures
(Streptococcus viridans) (in penicillin allergic patients)
Gastrointestinal and genitourinary procedures
(E faecalis, VSE) procedures in patients with previous
subacute bacterial endocarditis or prosthetic valve
endocarditis (plus gentamicin)
Therapy
MRSA, CoNS CNS shunt (ventriculo-atrial,
ventriculo-peritoneal) infectionsa
MRSA hemodialysis catheter infectionsb
Endocarditisc
Streptococus viridans subacute bacterial endocarditis (in
penicillin-allergic patients)
CoNS prosthetic valve endocarditis due to MSSE or MRSE
VSE subacute bacterial endocarditisd
a
Preferred therapy (eg, linezolid).
b
Preferred therapy (eg, daptomycin or linezolid).
c
Alternative therapy preferred.
d
Combined with gentamicin.
Methicillin-sensitive Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus central intravenous line infections
The majority of intravenous line infections related to CVCs are due to
skin organisms (ie, MSSA, MRSA, MSSE, or MRSE). Because vancomycin
is active against these skin pathogens, it is frequently used as empiric mono-
therapy for presumed CVC line infections. There are two problems with this
approach. In institutions where the predominant pathogen causing CVC
line infections is MSSA, rather than MRSA, other agents should be used
in preference to vancomycin. After MSSA and MRSA, aerobic gram-nega-
tive bacilli are the next most important pathogens in CVC line infections.
The use of vancomycin empirically for CVC infections has two hospital-
wide consequences [96,97,101].
Firstly, vancomycin increases institutional prevalence of VRE. Secondly,
exposure to vancomycin has the effect of increasing cell-wall thickness
among staphylococci. Vancomycin-induced thickened bacterial cell walls

12. 404 CUNHA
Box 4. Clinical situations in which vancomycin
should be avoided
Prophylaxis
General surgical procedures
MSSA/MRSA neurosurgical shunts
MSSA/MRSA chest tubes
MSSA/MRSA intravenous lines
MSSA/MRSA in febrile leukopenia
Therapy
MRSA colonization of respiratory secretions, wounds, or
urine (avoid treating colonization; treat only infection)
Most serious systemic MRSA infections
Preferentially use other anti-MRSA antibiotics
Intravenous MRSA antibiotics: linezolid, daptomycin,
tigecycline, minocycline
Oral MRSA antibiotics: linezolid, minocycline
are manifested as an increase in MICs, delayed resolution of infection, or
therapeutic failure. Staphylococci with thickened cell walls represent a per-
meability barrier to vancomycin as well as to other antibiotics. This is man-
ifested clinically in the microbiology laboratory as ‘‘MIC drift.’’ The
increase in MICs, often observed during vancomycin therapy, is reflective
of cell-wall thickening. A preferred approach to the empiric treatment to
CVC line infections pending CVC removal is to use meropenem in institu-
tions where CVC infections are more frequently due to MSSA/GNBs than
to MRSA. In institutions where the reverse is true, and MRSA is an
important CVC pathogen, empiric therapy with tigecycline is preferable
to combination therapy with vancomycin plus an anti–GNB antibiotic
(Box 5).
Methicillin-sensitive Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus hemodialysis catheter infections
The treatment of hemodialysis catheter infections in hemodialysis pa-
tients has been a major area of vancomycin usage because vancomycin is
eliminated by glomerular filtration. The increased half-life of vancomycin
in anuria may be used to a therapeutic advantage in patients with MSSA/
MRSA infections in end stage renal disease on hemodialysis. As with other
foreign body infections due to gram-positive organisms, shunt removal is
usually necessary for elimination the infection. Vancomycin has been used
prophylactically and therapeutically in hemodialysis patients to treat dialy-
sis catheter infections due to MSSA and MRSA [32,102–104].

13. VANCOMYCIN REVISITED 405
Box 5. Diagnostic clinical pathway: persistent S aureus
(MSSA, MRSA) bacteremias
Differentiate S aureus blood culture positivity (1/4 or 1/2) from
bacteremia.
With S aureus bacteremia, differentiate low-intensity intermittent
bacteremia (1/2 or 2/4 positive blood cultures) from continuous
high-intensity bacteremia (3/4–4/4 positive blood cultures).
Determine the source of S aureus bacteremia.
Abscesses
Central intravenous lines
Implanted prosthetic devices/materials
Acute bacterial endocarditis
Soft tissue and bone infections
Review antibiotic-related factors.
Determine drug dose/dosing interval.
Determine MIC/MBCs.
Evaluate in vivo versus in vitro effectiveness.
Evaluate potential of permeability-related resistance due
to vancomycin cell-wall thickening.
With high-intensity continuous S aureus bacteremia, obtain
a transthoracic or transesophageal echocardiogram to
diagnose or rule out acute bacterial endocarditis.
Data from Cunha BA. Persistent S aureus bacteremia: clinical pathway
for diagnosis treatment. Antibiotics for Clinicians 2006;10(S1):39–46; with
permission.
Methicillin-sensitive Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus acute bacterial endocarditis
The diagnostic approach to persistent S aureus bacteremia is relatively
straightforward. First, in patients with CVCs, this source of infection should
be ruled out first because since CVC infections are readily diagnosable and
easily treated by CVC removal. If there is no CVC in place, or if the
removed CVC semiquantitative catheter tip cultures are negative, then
endocarditis should be the next diagnostic consideration. MSSA or
MRSA endocarditis presents as acute bacterial endocarditis (ABE). Except
for IVDAs, patients presenting with MSSA or MRSA acute bacterial endo-
carditis, usually present with fever of 102 F or higher. In addition, MSSA or
MRSA acute bacterial endocarditis usually presents without a heart mur-
mur early in the infectious process. Later, when there is valvular destruction,
a new or rapidly changing murmur becomes apparent.

14. 406 CUNHA
In patients with subacute bacterial endocarditis and positive blood cultures
due to subacute bacterial endocarditis pathogens, cardiac echocardiography
is indicated in patients who have a heart murmur. Cardiac echocardiography
may be the transthoracic (TTE) or the transesophageal (TEE) variety. For
screening purposes, TTE is preferred to TEE. For detection of prosthetic
valve endocarditis and myocardial abscess TEE is preferred. In patients
with subacute bacterial endocarditis, the indication for a TTE or a TEE is
the presence of continuous bacteremia due to a known subacute bacterial
endocarditis pathogen plus fever and a heart murmur [105–107].
In contrast, in patients with possible acute bacterial endocarditis, the indi-
cations for a TTE or TEE are fever and a sustained high-grade MSSA or
MRSA bacteremia. A heart murmur is not usually present in acutely in pa-
tients presenting with acute bacterial endocarditis. If cardiac echocardiogra-
phy is negative for vegetations, acute bacterial endocarditis is effectively
eliminated from further consideration. If the high-grade continuous MSSA
or MRSA bacteremia continues, the echocardiography should be reviewed
for a potential paravalvular myocardial abscess. If a myocardial abscess is sus-
pected, TEE, is the preferred echocardiographic modality to demonstrate
a perivalvular septal, or myocardial abscess. In patients with potential staph-
ylococcal prosthetic valve endocarditis (PVE), a TEE is preferred to demon-
strate vegetations. Patients with prosthetic valve(s) should be suspected of
having prosthetic valve endocarditis if there is fever and a continuous high-
grade bacteremia with a known endocarditis pathogen. Fever is usually pres-
ent, but murmurs are difficult to appreciate because of the sounds generated by
the prosthetics valve. Subacute bacterial endocarditis, acute bacterial endo-
carditis, and prosthetic valve endocarditis may be accompanied by peripheral
findings associated with endocarditis (Box 6; Tables 2 and 3) [97,101,106,107].
Staphylococcal central nervous system infections
Vancomycin has been used to treat CNS shunt infections, which are
usually due to CoNS of the MSSE or MRSE variety. CNS shunt infections
usually require shunt removal. If suppression is desired, vancomycin may
be given parenterally and, if necessary, CSF concentrations may be further
increased by intraventricular administration. Usually the best way to admin-
ister intrathecal vancomycin is via an Ommaya reservoir. Vancomycin CSF
levels may be obtained in patients to assure adequate CSF levels, but resolu-
tion of shunt infections almost always requires shunt removal. It is preferable
to use an antibiotic with good CSF penetration (eg, linezolid) [1,31,32].
Febrile neutropenia
Recently, some clinicians have added vancomycin to regimens to treat
febrile neutropenia in compromised hosts receiving chemotherapy. The
increased incidence of gram-positive infections in febrile neutropenia are
not due to neutropenia per se, but are due to central line catheters or

15. VANCOMYCIN REVISITED 407
Box 6. Diagnostic clinical pathway: MSSA/MRSA
acute bacterial endocarditis
Differentiate S aureus blood culture positivity (1/2 or 1/4 positive
blood cultures) from bacteremia (3/4–4/4 positive blood
cultures).
With S aureus bacteremia, differentiate low-intensity intermittent
bacteremia (1/2 or 2/4 positive blood cultures) from continuous
high-intensity bacteremia (3/4–4/4 positive blood cultures).
Acute bacterial endocarditis is not a complication of low-
intensity/intermittent S aureus bacteremia. TTE/TEE
unnecessary, but will verify no vegetations.
If continuous high-grade MSSA/MRSA bacteremia, obtain a TTE
or TEE to document cardiac vegetations and/or paravalvular
abscess and confirm diagnosis of acute bacterial endocarditis.
Diagnostic criteria for MSSA/MRSA acute bacterial endocarditis
Essential features
Continuous high-grade MSSA/MRSA bacteremia
Cardiac vegetations on TTE/TEE
No other source
Nonessential features
Fever ‚102 F (non-IVDAs)
Cardiac murmura
a
With early MSSA/MRSA, a murmur is not present. Later, a new murmur in
acute bacterial endocarditis indicates a vegetation or valvular destruction.
Data from Cunha BA: MSSA/MRSA acute bacterial endocarditis (ABE): clinical
pathway for diagnosis treatment. Antibiotics for Clinicians 2006;10(S1):29–34.
chemotherapy infusion devices in these patients. Depending upon the ge-
ography/epidemiology of the balance between MSSA versus MRSA strains
in patients in the community, empiric treatment with an anti-MSSA or an
anti-MRSA agent may be desired until the temporary or semipermanent
catheter is removed or replaced. For patients presenting with febrile neutro-
penia treated with an antibiotic effective against Pseudomonas aeruginosa
with good anti-MSSA activity, additional antistaphylococcal therapy is
usually unnecessary. Antibiotics commonly used empirically in febrile neu-
tropenia (eg, levofloxacin, meropenem) have anti-MSSA activity. In febrile
neutropencia, fungal infections usually present after 10 to 14 days of antibi-
otic therapy and are clinically manifested as an otherwise unexplained recru-
descence of fever in patients who have responded to empiric anti-P aeruginosa
therapy. If fungal infection can be ruled out, a temporary or semipermanent
central line infection should be suspected. If blood cultures are persistently
positive (high-grade positivity) with MRSA, then anti-MRSA therapy should

16. 408 CUNHA
Table 2
Delayed resolution or failure of vancomycin therapy of MSSA or MRSA bacteremia and acute
bacterial endocarditis
Failure rates Duration of bacteremia References
MSSA bacteremia Nafcillin: 4% Nafcillin: 2 days Sande [110]
Vancomycin: 20% Vancomycin: 7 days
(20% O3 days)
(12% O7 days)
MSSA acute bacterial Nafcillin: 1.4%–26% Nafcillin: 2 days Gentry [111]
endocarditis Vancomycin: 37%–50% Vancomycin: 5 days Geraci [112]
Esposito [4]
Chang [98]
MRSA acute bacterial Nafcillin: Not applicable Small [115]
endocarditis Vancomycin: O7 days
be given until the device is removed. The routine use of vancomycin in com-
bination therapy with an anti-P aeruginosa antibiotic for febrile neutropenia
should be discouraged to minimize further increases in VRE prevalence and
permeability-mediated resistance [1,32,108].
Penicillin-allergic patients
Vancomycin has been used in penicillin-allergic patients to treat Strepto-
coccus viridans and enterococcal endocarditis. Vancomycin monotherapy
has been used successfully over the years to treat S viridans subacute bacte-
rial endocarditis. Because vancomycin is bacteristatic against E faecalis,
combination therapy with aminoglycoside (eg, gentamicin) has been used
to treat VSE endocarditis. Strains demonstrating high-level gentamicin resis-
tance may be treated with vancomycin plus ceftriaxone or, alternatively,
another antibiotic with bactericidal antienterococcal activity may be used
(eg, daptomycin) (see Box 4) [32,109].
Vancomycin: therapeutic alternatives
The empiric therapeutic approach to central intravenous line–related
infections has been discussed. Empiric therapy during the workup for
Table 3
Combination therapy for MSSA and MRSA acute bacterial endocarditis
Antibiotic combinations Comments References
MSSA acute bacterial endocarditis
Nafcillin þ gentamicin Outcomes same without gentamicin Cha [116]
Vancomycin þ gentamicin Lee [117]
MRSA acute bacterial endocarditis
Vancomycin Duration of bacteremia: 7 days Levine [118]
Vancomycin þ rifampin Duration of bacteremia: 9 days Shelburne [119]
(antagonistic; not synergistic)

17. VANCOMYCIN REVISITED 409
ABE should consist of antistaphylococcal antibiotic that has a high degree
of activity against the presumed pathogen, does not cause resistance, does
not cause the emergence of other organism (eg, VRE), and has a good safety
profile. In the treatment of MSSA bacteremias, vancomycin has been shown
to be inferior to vancomycin in terms of delayed resolution of bacteremia. If
MSSA is the pathogen in bacteremia or endocarditis, vancomycin should
not be used as therapy in these patients and preferably another agent should
be used. In penicillin-allergic patients, vancomycin is often used empirically
to treat MSSA or MRSA bacteremias. However, there are many alternative
antibiotics available that do not cross-react with penicillins or cephalospo-
rins and that are effective to treat MSSA or MRSA bacteremias.
The treatment of MSSA or MRSA bacteremia is optimal with a single
agent. Clinicians often assume there is benefit in adding a second drug for
enhanced antistaphylococcal activity. It has been shown that vancomycin
plus gentamicin offers no benefit in the treatment of MSSA bacteremias.
Another common misconception is that the addition of rifampin or other
drugs to vancomycin will enhance the antistaphylococcal activity of the pri-
mary anti-MSSA/MRSA agent. It has been shown the rifampin is likely to
be antagonistic, not synergistic, against S aureus [110]. While rifampin has
a high degree of in vitro activity against S aureus, rifampin monotherapy
should not be used because of resistance. The practice of adding an amino-
glycoside or rifampin to antistaphylococcal antibiotics has no benefit and
may have a negative effect on outcomes (see Tables 2 and 3) [1,3–
5,31,32,110].
In penicillin-allergic patients, the treatment of serious systemic infections
due to MSSA (ie, CVC line infections, acute bacterial endocarditis, pros-
thetic valve endocarditis, and so on), may be treated with antibiotics other
than vancomycin (ie, meropenem, TMP-SMX, daptomycin). As with
MSSA, there are numerous therapeutic alternatives to vancomycin for the
treatment of serious MRSA infections. Useful antibiotics to treat all
MRSA types (HA-MRSA, CO-MRSA, CA-MRSA) include daptomycin
linezolid, tigecycline, and minocycline [1,32].
If possible, vancomycin should be avoided in therapy of most serious sys-
temic infections due to MSSA/MRSA for two principal reasons. Prolonged
vancomycin exposure selects out heteroresistant strains (hVISA). These
strains are the ones that have thickened cell walls as the result of
vancomycin exposure. Thickened cell walls are manifested as an increase
in MICs and decreased cell-wall permeability to vancomycin as well as to
other antibiotics. The other untoward side effect of vancomycin use is in-
creased VRE prevalence [37–43].
In conclusion, vancomycin should be used selectively for the parenteral
treatment of serious systemic infections due to MSSA, MRSA, or CoNS.
Available therapeutic alternatives do not increase the prevalence of VRE
and do not result in cell-wall thickening and permeability-mediated
resistance. Alternative agents more quickly resolve MSSA/MRSA

18. 410 CUNHA
bacteremias than vancomycin. The addition of gentamicin or rifampin to
vancomycin does not enhance antistaphylococcal activity and may have
a negative effect (ie, antagonism) [47,98–100,111–117].
Vancomycin: reassessment of use
The main role of vancomycin has been in the therapy of serious systemic
MRSA infections [1,118]. The widespread use of vancomycin over the years
has resulted in increased prevalence of VRE in institutions worldwide. Re-
cently, it has been shown that vancomycin induces cell-wall thickening among
staphylococci, resulting in ‘‘permeability-mediated’’ resistance. To avoid
these problems associated with vancomycin, it is preferable to use other
anti-MRSA antibiotics in place of vancomycin. Fortunately, several other
anti-MRSA agents are available. Antibiotics with excellent anti-MRSA activ-
ity include minocycline, linezolid, daptomycin, and tigecycline. Although
vancomycin is available as an oral formulation for C difficile infections, it is
ineffective to treat systemic infections. For the parenteral treatment of serious
systemic MRSA infections, minocycline, daptomycin, and linezolid are effec-
tive alternative anti-MRSA antibiotics. For the oral therapy of MRSA, min-
ocycline or linezolid may be used (Boxes 7 and 8) [1,32,119,120].
Box 7. Vancomycin: use in serious systemic infection
Clinical advantages
Extensive clinical experience
Not nephrotoxic
Clinical disadvantages
Adverse side effects
Red neck (red man) syndrome
Thrombocytopenia
Leukopenia
Sudden death
Increased VRE prevalence
Related to volume of intravenous (not oral) use
S. aureus infections: delayed resolution, therapeutic failures
MSSA/MRSA bacteremias
MSSA/MRSA acute bacterial endocarditis
S. aureus infections: permeability-mediated resistance
(increased MICs)
Cell-wall thickening; decreased S. aureus penetration of
antibiotics (vancomycin and other anti-S aureus
antibiotics)
Not inexpensive

19. VANCOMYCIN REVISITED 411
Box 8. Suboptimal uses of vancomycin
Empiric treatment of central intravenous line infections
In locations where MSSA/GNBs MRSA CVC pathogens
Remove intravenous line as soon as possible
Therapy of MRSA bacteremia/acute bacterial endocarditis
Delayed clinical responses
Therapeutic failures
Intraperitoneal therapy of S aureus/CoNS CAPD peritonitis
Intravenous therapy achieves therapeutic concentration in
ascitic fluid. Requires another antibiotic for
anti–gram-negative bacillary coverage.
Monotherapy of VSE
Bacteriostatic if monotherapy used.
Adequate anti-VSE activity only if given with an
aminoglycoside (eg, gentamicin)
S aureus chronic osteomyelitis
Prevention of S pneumoniae CSF ‘‘seeding’’
(2 to CAP pneumococcal bacteremia)
Unnecessary when using antibiotics that achieve therapeutic
CSF concentrations (eg, ceftriaxone)
Data from Cunha BA, editor. Infections in critical care medicine. 2nd edition.
New York: Informa Health Care USA, Inc.; 2007.
For the therapy of gram-positive CNS infections, other agents are phar-
macokinetically preferable to vancomycin. Linezolid, available orally and
intravenously, achieves high CSF levels when given in the usual dose (ie,
600 mg intravenously or orally every 12 hours). Minocycline using the usual
dose (100 mg intravenously or orally every 12 hours) also achieves therapeu-
tic CSF levels. No data are available regarding treatment of CNS infections
with or tigecycline [1,32].
In access catheter graft infections in chronic hemodialysis patients, dap-
tomycin, linezolid, or tigecycline may be used. Vancomycin can be used to
treat S viridans subacute bacterial endocarditis in penicillin-allergic patients,
but other agents are preferable to vancomycin for this use. Vancomycin
monotherapy is ‘‘bacteristatic’’ against VSE. Therefore, for VSE subacute
bacterial endocarditis, an aminoglycoside should be added to vancomycin
to achieve bactericidal anti-VSE activity alternate therapy for VSE subacute
bacterial endocarditis (eg, meropenem, linezolid, or daptomycin) is available
[3,32,119,120].
Aside from increased prevalence of VRE and increasing resistance among
staphylococci, there are other reasons to avoid or minimize vancomycin use.
Because vancomycin is an older drug, it is often thought of as an inexpensive

20. 412
Table 4
Vancomycin: clinical use and therapeutic alternatives
Clinical uses Disadvantages, problems Therapeutic alternatives Advantages of alternative antibiotics
Monotherapy
Central IV catheter (CVC) infections Increased VRE prevalence Removal of CVC High-degree MRSA activity
‘‘that may be due to MRSA’’ Increased permeability-mediated Daptomycin (6 mg/kg IV Also covers MSSA, VSE
resistance every 24 hours) No increased resistance/VRE
MIC ‘‘drift’’ Linezolid (600 mg IV
every 12 hours)
MRSA bacteremias, acute bacterial Increased permeability-mediated Daptomycin (6–12 mg/kg Most rapidly bactericidal MRSA
endocarditis resistance IV every 24 hours) antibiotic
Delayed therapeutic response Effective in vancomycin
CUNHA
(persistent bacteremia) ‘‘treatment failures’’
MIC ‘‘drift’’ Linezolid (600 mg Also available orally
IV every 12 hours) for prolonged therapy
No increased resistance/VRE
MRSA osteomyelitis Vancomycin: often delayed Linezolid (600 mg Also available orally
response with 30 mg/kg/d; better IV/orally every 12 hours) for prolonged therapy
results with 60 mg/kg/d Minocycline (100 mgIV/ No increased resistance/VRE
Increased permeability-mediated orally every 12 hours) Inexpensive and also available
resistance orally for prolonged therapy.
Increased MICs during therapy
MIC ‘‘drift’’
MRSA nosocomial and Essential to avoid ‘‘covering’’ Linezolid (600 mg IV Effective in rare cases of bona
ventilator associated pneumonia MSSA/MRSA respiratory every 12 hours) fide MRSA nosocomial
(rare) secretion colonization pneumonia and ventilator-
Increases permeability-mediated associated pneumonia
resistance Therapeutic parenchymal lung
MIC ‘‘drift’’ concentrations

21. Combination Therapy
Vancomycin and ceftriaxone ‘‘Double drug’’ therapy Ceftriaxone (1–2 g IV every Good CSF penetration prevents
to prevent ‘‘seeding’’ of CSF unnecessary. Vancomycin: 12 hours) PRSP ‘‘seeding’’ of CSF
from bacteremic S pneumoniae relatively low CSF concentrations Ceftriaxone monotherapy provides
(PRSP) CAP adequate CSF concentrations if PRSP
seeding of CSF
Vancomycin plus gentamicin therapy Vancomycin alone ‘‘bacteriostatic’’ Daptomycin (6 mg/kg IV MICs for VSE/VRE greater than
of E faecalis (VSE) subacute bacterial against VSE every 24 hours) those for MSSA/MRSA
endocarditis Vancomycin bactericidal only Use 12 mg/kg IV every 24 hours
when combined with an for VSE endocarditis
aminoglycoside (eg, gentamicin) Linezolid (600 mg IV Available orally for prolonged
every 12 hours) therapy of VSE subacute bacterial
endocarditis
VANCOMYCIN REVISITED
Bacteriostatic but effective
in subacute bacterial endocarditis
Abbreviations: IV, intravenous; PSRP, penicillin-resistant S pneumoniae.
413

22. 414 CUNHA
antibiotic. However, because vancomycin must be administered intrave-
nously, the cost of intravenous administration and monitoring must be
added to the actual cost of vancomycin use. If serum vancomycin levels
are used to guide therapy, the cost of such levels plus the cost of serial serum
creatinine levels must also be included in the actual cost of administering
parenteral vancomycin. For patients requiring long-term parenteral therapy
with vancomycin, peripherally inserted central catheters (PICCs) are often
used. The use of a PICC line to administer vancomycin increases antibiotic
cost because other charges related to surgical insertion, radiological verifica-
tion of PICC line placement, and the cost of home intravenous agencies
must be added to vancomycin cost. While the cost of administering paren-
teral antibiotics via PICC lines for vancomycin is similar to that for other
antibiotics, most infections for which vancomycin is administered parenter-
ally may be treated equally effectively with oral linezolid which is much less
expensive (see Boxes 4 and 5, Table 4).
Summary
The reassessment of vancomycin use today is based on an evaluation of
the advantages and disadvantages of vancomycin alternatives for the ther-
apy of MRSA. Other antibiotics exist as alternative therapy for VSE infec-
tions as well as for preventing the ‘‘seeding’’ of the CNS by penicillin-
resistant S pneumoniae from bacteremic pneumococcal CAP. Clinicians
should appreciate the limited role of vancomycin today in MRSA therapy.
Clinicians should also realize vancomycin has limited activity against MSSA
and VSE. Other antibiotics are preferable against MSSA and VSE. Pres-
ently, clinicians should consider alternatives to vancomycin because of the
negative effects of vancomycin therapy (ie, increased VRE prevalence and
increasing resistance among staphylococci), and also because better thera-
peutic alternatives are available with little or no resistance potential, no in-
crease in VRE prevalence, better pharmacokinetics and lower cost (eg,
linezolid) (see Box 6). For the reasons mentioned, clinicians should use van-
comycin sparingly and consider other antibiotic alternatives for MSSA,
MRSA, CoNS, and VSE infections [32,119,120].
References
[1] Kucers A, Crowe SM, Grayson ML, et al. Vancomycin: the use of antibiotics: a clinical
review of antibacterial, antifungal and antiviral drugs. 5th edition. Oxford (United
Kingdom): Butterworth-Heinemann; 1997. p. 763–90.
[2] Louria DB, Kaminski T, Buchman J. Vancomycin in severe staphylococcal infections. Arch
Intern Med 1961;107:225–40.
[3] Cunha BA. Vancomycin. Med Clin North Am 1995;79:817–31.
[4] Esposito AL, Gleckman RA. Vancomcyin: a second look. JAMA 1977;238:1756–7.
[5] Menzies D, Goel K, Cunha BA. Vancomycin. Antibiotics for Clinicians 1998;2:97–9.

23. VANCOMYCIN REVISITED 415
[6] Farber BF, Moellering RC Jr. Retrospective study of the toxicity of preparations of
vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983;23:138–41.
[7] Elting LS, Rubenstein EB, Kurtin D, et al. Mississippi and mud in the 1990s: risks and
outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998;
83:2597–607.
[8] Appel GB, Given DB, Levine LR, et al. Vancomycin and the kidney. Am J Kidney Dis
1986;8:75–80.
[9] Mellor JA, Kingdom J, Cafferkey M, et al. Vancomycin toxicity: a prospective study.
J Antimicrob Chemother 1985;15:773–80.
[10] Nahata MC. Lack of nephrotoxicity in pediatric patients receiving concurrent vancomycin
and aminoglycoside therapy. Chemotherapy 1987;33:302–4.
[11] Goren MP, Baker DK Jr, Shenep JL. Vancomycin does not enhance amikacin-induced
tubular nephrotoxicity in children. Pediatr Infect Dis J 1989;8:278–82.
[12] Goetz MB, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately
and in combination. J Antimicrob Chemother 1993;32:325–34.
[13] Ergur T, Onarlioglu B, Gunay Y, et al. Does vancomycin increase aminoglycoside nephro-
toxicity? Acta Paediatr Jpn 1997;39:422–7.
[14] Pauly DJ, Musa DM, Lestico MR, et al. Risk of nephrotoxicity with combination
vancomycin-aminoglycoside antibiotic therapy. Pharmacotherapy 1990;10:378–82.
[15] Rybak MJ, Albrecht LM, Boike SC, et al. Nephrotoxicity of vancomycin alone and with an
aminoglycoside. J Antimicrob Chemother 1990;25:679–87.
[16] Ngeleka M, Beauchamp D, Tardif D, et al. Endotoxin increases the nephrotoxic potential
of gentamicin and vancomycin plus gentamicin. J Infect Dis 1990;161:721–7.
[17] Rybak MJ, Boike SC. Monitoring vancomycin therapy. Drug Intell Clin Pharm 1986;20:
757–61.
[18] Edwards DJ, Pancorbo S. Routine monitoring of serum vancomycin concentrations:
waiting for proof of its value. Clin Pharm 1987;6:652–4.
[19] Moellering RC Jr. Pharmacokinetics of vancomycin. J Antimicrob Chemother 1984;14:43–52.
[20] Matzke GR, Zhanel GG, Guay DR. Clinical pharmacokinetics of vancomycin. Clin
Pharmacokinet 1986;11:257–82.
[21] Moellering RC Jr, Krogstad DJ, Greenblatt DJ. Vancomycin therapy in patients with
impaired renal function: a nomogram for dosage. Ann Intern Med 1981;94:343–6.
[22] Leader WG, Chandler MH, Castiglia M. Pharmacokinetic optimization of vancomycin
therapy. Clin Pharmacokinet 1995;28:327–42.
[23] Boffi el Amari E, Vuagnat A, Stern R, et al. High versus standard dose vancomycin for
osteomyelitis. Scand J Infect Dis 2004;36:712–7.
[24] Hidayat LK, Hsu DI, Quist R, et al. High dose vancomycin therapy for methicillin-resistant
Staphylococcus aureus infections. Arch Intern Med 2006;166:2138–44.
[25] Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocy-
topenia. N Engl J Med 2007;356:904–10.
[26] Carmeli Y, Samore MH, Huskins C. The association between antecedent vancomycin
treatment and hospital-acquired vancomycin-resistant enterococci: a meta-analysis. Arch
Intern Med 1999;159:2461–8.
[27] Fishbane S, Cunha BA, Shea KW, et al. Vancomycin-resistant enterococcus (VRE) in
hemodialysis patients. Am J Infect Control 1999;20:461–2.
[28] Fridkin SK, Lawton R, Edwards JR, et al. Monitoring antimicrobial use and resistance:
comparison with a national benchmark on reducing vancomycin use and vancomycin-
resistant enterococci. Emerg Infect Dis 2002;8:702–7.
[29] Fridkin SK, Edwards JR, Courval JM, et al. The effect of vancomycin and third-generation
cephalosporins on prevalence of vancomycin-resistant enterococci in 126 U.S. adult
intensive care units. Ann Intern Med 2001;135:175–83.
[30] Kolar M, Urbanek K, Vagnerova I, et al. The influence of antibiotic use on the occurrence
of vancomycin-resistant enterococci. J Clin Pharm Ther 2006;31:67–72.

24. 416 CUNHA
[31] Cunha BA. Antimicrobial therapy of multi-drug resistant S pneumoniae VRE MRSA.
Med Clin North Am 2006;90:1165–82.
[32] Cunha BA. Antibiotic essentials. 7th edition. Royal Oak (MI): Physicians Press; 2008.
[33] Tenover F, Biddle J, Lancaster M. Increasing resistance to vancomycin and other glycopep-
tides in Staphylococcus aureus. Emerg Infect Dis 2001;7:327–32.
[34] Liu C, Chambers HF. Staphylococcus aureus with heterogeneous resistance to vancomycin:
epidemiology, clinical significance, and critical assessment of diagnostic methods. Antimi-
crob Agents Chemother 2003;47:3040–5.
[35] Cosgrove SE, Carroll KC, Perl TM. Staphylococcus aureus with reduced susceptibility to
vancomycin. Clin Infect Dis 2004;39:539–45.
[36] Fridkin SK, Hageman J, McDougal LK, et al. Epidemiological and microbiological
characterization of infections caused by Staphylococcus aureus with reduced susceptibility
to vancomycin, United States, 1997–2001. Clin Infect Dis 2003;36:429–39.
[37] Wang G, Hindler JF, Ward KW, et al. Increased vancomycin MICs for Staphylococcus
aureus. Clinical isolates from a university hospital during a 5-year period. J Clin Microbiol
2006;44:3883–6.
[38] Cui L, Ma K, Sato K, et al. Cell wall thickening is a common feature of vancomycin
resistance in Staphylococcus aureus. J Clin Microbiol 2003;41:5–14.
[39] Cui L, Tominaga E, Hiramatsu K. Correlation between reduced daptomycin susceptibility
and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob
Agents Chemother 2006;50:1079–82.
[40] Bell JM, Walters LJ, Turnidge JD, et al. Vancomycin hetero-resistance has a small but
significant effect on the daptomycin minimum inhibitory concentration of Staphylococcus
aureus [abstract D-814]. Paper presented at the 46th ICAAC. San Francisco (CA), Septem-
ber 27–30, 2006.
[41] Sakoulas G, Alder J, Thauvin-Eliopoulos C, et al. Induction of daptomycin heterogeneous
susceptibility in Staphylococcus aureus by exposure to vancomycin. Antimicrob Agents
Chemother 2006;50:1581–5.
[42] Patel JB, Jevitt LA, Hageman J, et al. An association between a reduced susceptibility to
daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus. Clin Infect
Dis 2006;42(11):1652–3.
[43] Howden BP, Ward PB, Charles PGP, et al. Treatment outcomes for serious infections
caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibil-
ity. Clin Infect Dis 2004;38:521–8.
[44] Charles PG, Ward PB, Johnson PD, et al. Clinical features associated with bacteremia due
to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004;38:
448–51.
[45] Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure
associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient
with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother
2003;47:1262–6.
[46] Howden BP, Johnson PD, Ward PB, et al. Isolates with low-level vancomycin resistance
associated with persistent methicillin-resistant Staphylococcus aureus bacteremia.
Antimicrob Agents Chemother 2006;50:3049–57.
[47] Wong SS, Ng TK, Yam WC, et al. Bacteremia due to Staphylococcus aureus with reduced
susceptibility to vancomycin. Diagn Microbiol Infect Dis 2000;36:261–8.
[48] Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus aureus: what the
infectious disease specialist needs to know. Clin Infect Dis 2001;32:108–15.
[49] Bouza E, Burillo A, Munoz P. Antimicrobial therapy of Clostridium difficile–associated
diarrhea. Med Clin North Am 2006;90:1141–63.
[50] Cunha BA, Klein NC. Vancomycin. In: Yoshikawa T, editor. Antibiotics in the elderly.
New York: Marcel Dekker; 1994. p. 311–22.

25. VANCOMYCIN REVISITED 417
[51] Gump DW. Vancomycin for treatment of bacterial meningitis. Rev Infect Dis 1981;3:
289–92.
[52] Nagl M, Neher C, Hager J, et al. Bactericidal activity of vancomycin in cerebrospinal fluid.
Antimicrob Agents Chemother 1999;43:1932–4.
[53] Skhirtladze K, Hutschala H, Fleck T, et al. Impaired target site penetration of vancomycin
in diabetic patients following cardiac surgery. Antimicrob Agents Chemother 2006;50:
1372–5.
[54] Massias L, Dubois C, de Lentdecker P, et al. Penetration of vancomycin in uninfected
sternal bone. Antimicrob Agents Chemother 1992;36:2539–41.
[55] Ackerman BH, Vannier AM. Necessity of a loading dose when using vancomycin in
critically ill patients. J Antimicrob Chemother 1992;29:460–1.
[56] Cunha BA, Deglin J, Chow M, et al. Pharmacokinetics of vancomycin in patients undergo-
ing chronic hemodialysis. Rev Infect Dis 1981;3:269–72.
[57] DelDot ME, Lipman J, Tett SE. Vancomycin pharmacokinetics in critically ill patients
receiving continuous venovenous haemodiafiltration. Br J Clin Pharmacol 2004;58:
259–68.
[58] Lutsar I, McCracken GH Jr, Friedland IR. Antibiotic pharmacodynamics in cerebrospinal
fluid. Clin Infect Dis 1998;27:1117–27.
[59] Byl B, Jacobs F, Wallemacq P, et al. Vancomycin penetration of uninfected pleural fluid
exudate after continuous or intermittent infusion. Antimicrob Agents Chemother 2003;
47:2015–7.
[60] Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue.
J Antimicrob Chemother 1996;38:865–9.
[61] Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin in severe staphylococcal
infections: prospective multicenter randomized study. Antimicrob Agents Chemother
1996;38:865–9.
[62] Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin
Infect Dis 1994;18:544–6.
[63] Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentra-
tions with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15:
85–91.
[64] James JK, Palmer SM, Levine DR, et al. Comparison of conventional dosing versus
continuous-infusion vancomycin therapy for patients with suspected or documented
gram-positive infections. Antimicrob Agents Chemother 1996;40:696–700.
[65] Kralovicov K, Spanik S, Halko J, et al. Do vancomycin serum levels predict failures of
vancomycin therapy or nephrotoxicity in cancer patients? J Chemother 1997;9:420–6.
[66] Masur H, Francioli P, Ruddy M, et al. Vancomycin serum levels and toxicity in chronic
haemodialysis patients with Staphylococcus aureus bacteremia. Clin Nephrol 1983;20:85–8.
[67] Andres I, Lopez R, Pou L, et al. Vancomycin monitoring: one or two serum levels? Ther
Drug Monit 1997;19:614–9.
[68] Sayers JF, Shimasaki R. Routine monitoring of serum vancomycin concentrations: The
answer lies in the middle. Clin Pharm 1988;7:18.
[69] Moellering RC Jr. Monitoring serum vancomycin levels: climbing the mountain because it
is there? Clin Infect Dis 1994;18:544–6.
[70] Rodvold KA, Zokufa H, Rotschafer JC. Routine monitoring of serum vancomycin concen-
trations: Can waiting be justified? Clin Pharm 1987;6:655–8.
[71] Freeman CD, Quintiliani R, Nightingale CH. Vancomycin therapeutic drug monitoring: Is
it necessary. Ann Pharmacother 1993;27:594–8.
[72] Saunders NJ. Vancomycin administration and monitoring reappraisal. J Antimicrob
Chemother 1995;36:279–82.
[73] Karam CM, McKinnon PS, Neuhauser MM, et al. Outcome assessment of minimizing
vancomycin monitoring and dosing adjustments. Pharmacotherapy 1999;19:257–66.

26. 418 CUNHA
[74] Darko W, Medicis JJ, Smith A, et al. Mississippi mud no more: cost-effectiveness of
pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. Pharmaco-
therapy 2003;23:643–50.
[75] Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations:
reappraisal of their clinical value. Clin Infect Dis 1994;18:533–43.
[76] Cunha BA. Vancomycin serum levels: unnecessary, unhelpful, and costly. Antibiotics for
Clinicians 2004;8:273–7.
[77] Cunha BA, Mohan SS, Hamid N, et al. Cost ineffectiveness of serum vancomycin levels.
Eur J Clin Microbiol Infect Dis 2007;13:509–11.
[78] Allegaert K, van den Anker JN. Predictability of vancomycin pharmacokinetics in
neonates. Eur J Clin Microbiol Infect Dis 2007;26:847–8.
[79] Cunha BA. Clinical manifestations and antimicrobial therapy of methicillin resistant
Staphylococcus aureus (MRSA). Clin Microbiol Infect 2005;11:33–42.
[80] Alder JD. Staphylococcus aureus: antibiotic resistance and antibiotic selection. Antibiotics
for Clinicians 2006;10(S1):19–24.
[81] Krol V, Cunha BA, Schoch PE, et al. Empiric gentamicin and vancomycin therapy for
bacteremias in chronic dialysis outpatient units in the era of antibiotic resistance. J Chemo-
ther 2006;18:490–3.
[82] Quale J, Landman D, Saurina G, et al. Manipulation of hospital antimicrobial formulary to
control an outbreak of vancomycin-resistant enterococci. Clin Infect Dis 1996;23:1020–5.
[83] Saribas S, Bagdatli Y. Vancomycin tolerance in enterococci. Chemotherapy 2004;50:
250–4.
[84] Watanakunakorn C. Antibiotic-tolerant Staphylococcus aureus. J Antimicrob Chemother
1978;4:561–8.
[85] Cunha BA, Mickail N, Eisenstein L. E faecalis vancomycin sensitive enterococci (VSE)
bacteremia unresponsive to vancomycin successfully treated with high dose daptomycin.
Heart Lung 2007;36:456–61.
[86] Hussain FM, Boyle-Vavra S, Shete PB, et al. Evidence for a continuum of decreased
vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates. J Infect
Dis 2002;186:661–7.
[87] Sakoulas G, Moise-Broder PA, Schentag JJ, et al. Relationship of MIC and bactericidal
activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus
aureus bacteremia. J Clin Microbiol 2004;42:2398–402.
[88] Schwaber MJ, Wright SB, Carmeli Y, et al. Clinical implications of varying degrees of
vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg
Infect Dis 2003;9:657–64.
[89] Srinivasan A, Dick JD, Perl TM. Vancomcyin resistance in staphylococci. Clin Microbiol
Rev 2002;15:430–8.
[90] Walsh TR, Howe RA. The prevalence and mechanisms of vancomycin resistance in
Staphylococcus aureus. Annu Rev Microbiol 2002;56:657–75.
[91] Wooton M, Walsh TR, Macgowan AP. Evidence for reduction in breakpoints used to
determine vancomycin susceptibility in Staphylococcus aureus. Antimicrob Agents
Cheomther 2005;49:3982–3.
[92] Ward PB, Johnson PD, Grabsch EA, et al. Treatment failure due to methicillin-resistant
Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin. Med J Aust
2001;175:480–3.
[93] Wooten M, MacGowan AP, Walsh TR. Comparative bactericidal activities of daptomycin
and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA) and
Heterogenous GISA isolates. Antimicrob Agents Chemother 2006;50:4195–7.
[94] Burillo A, Bouza E. Epidemiology of MSSA and MRSA: colonization and infection.
Antibiotics for Clinicians 2006;10(S1):3–10.
[95] Kim SH, Park WB, Lee KD, et al. Outcome of Staphylococcus aureus bacteremia in patients
with eradicable foci versus noneradicable foci. Clin Infect Dis 2003;37:794–9.

27. VANCOMYCIN REVISITED 419
[96] Evans M, Finch R. Approach to staphylococcal central IV line infections and bacteremias.
Antibiotics for Clinicians 2006;10(S1):25–8.
[97] Cunha BA. Persistent S aureus bacteremia: clinical pathway for diagnosis treatment.
Antibiotics for Clinicians 2006;10(S1):39–46.
[98] Chang FY, Peacock JE Jr, Musher DM, et al. Staphylococcus aureus bacteremia: recurrence
and the impact of antibiotic treatment in a prospective multicenter study. Medicine
(Baltimore) 2003;82:333–9.
[99] Lodise TP, McKinnon PS, Swiderski L, et al. Outcomes analysis of delayed antibiotic treatment
for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003;36:1418–23.
[100] Rotun SS, Mcmath V, Schoonmaker DJ, et al. Staphylococcus aureus with reduced suscep-
tibility to vancomycin isolated from a patient with fatal bacteremia. Emerg Infect Dis 1999;
5:147–9.
[101] Cunha BA. IV line infections. In: Cunha BA, editor. Infectious diseases in critical care
medicine. 2nd edition. New York: Informa Healthcare; 2007.
[102] Morris AJ, Bilinsky RT. Prevention of staphylococcal shunt infections by continuous
vancomycin prophylaxis. Am J Med Sci 1971;262:87–92.
[103] Eykyn S, Phillips I, Evans J. Vancomycin for staphylococcal shunt site infections in patients
on regular haemodialysis. Br Med J 1970;3:8–82.
[104] Tofte RW, Solliday J, Rotschafer J, et al. Staphylococcus aureus infection of dialysis shunt:
absence of synergy with vancomycin and rifampin. South Med J 1981;74:612–6.
[105] Cunha BA, Gill MV, Lazar J. Acute infective endocarditis. Infect Dis Clin North Am 1996;
10:811–34.
[106] Cunha BA. MSSA/MRSA acute bacterial endocarditis (ABE): clinical pathway for
diagnosis treatment. Antibiotics for Clinicians 2006;10(S1):29–34.
[107] Brusch JL. Infective endocarditis. New York: Informa Healthcare; 2007. p. 143–272.
[108] Picazo JJ. Association for Health Research and Development (ACINDES). Management
of the febrile neutropenic patient. Int J Antimicrob Agents 2005;2(S1):S120–2.
[109] Cunha BA. Clinical approach to antibiotic therapy in the penicillin allergic patient. Med
Clin North Am 2006;90:1257–64.
[110] Bliziotis IA, Ntziora F, Lawrence KR, et al. Rifampin as adjuvant treatment of gram-
positive bacterial infections: a systemic review of comparative clinical trials. Eur J Clin
Microbiol Infect Dis 2007;26:849–56.
[111] Gentry CA, Rodvold KA, Novack RM, et al. Retrospective evaluation of therapies for
Staphylococcus aureus endocarditis. Pharmacotherapy 1977;17:990–7.
[112] Geraci JE, Wilson WR. Vancomycin therapy for infective endocarditis. Rev Infect Dis
1981;3(Suppl):S520–58.
[113] Small PM, Chambers HF. Vancomycin for Staphylococcal aureus endocarditis in intrave-
nous drug users. Antimicrob Agents Chemother 1990;34:1227–31.
[114] Lee DG, Chun HS, Yim DS, et al. Efficacies of vancomycin, arbekacin, and gentamicin
alone or in combination against methicillin-resistant Staphylococcus aureus in an in vitro
infective endocarditis model. Antimicrob Agents Chemother 2003;47:3768–73.
[115] Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus
rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med
1991;115:674–80.
[116] Shelburne SA, Musher DM, Hulten K, et al. In vitro killing of community-associated
methicillin-resistant Staphylococcus aureus with drug combinations. Antimicrob Agents
Chemother 2004;48:4016–9.
[117] Cha R, Brown WJ, Ryback MJ. Bactericidal activities of daptomycin, quinupristin-
dalfopristin, and linezolid against vancomycin-resistant Staphylococcus aureus in an in
vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents
Chemother 2003;47:3960–3.
[118] Kirst HA, Thompson DG, Nicas TI. Historical yearly usage of vancomycin. Antimicrob
Agents Chemother 1998;42:1303–4.

28. 420 CUNHA
[119] Stevens DL. The role of vancomycin in the treatment paradigm. Clin Infect Dis 2006;42:
S51–7.
[120] Pope SD, Roecker A. Vancomycin for treatment of invasive, multi-drug resistant
Staphylococcus aureus infections. Expert Opin Pharmacother 2007;8:1245–61.