Vancomycin Revisited: A Reappraisal of Clinical Use
Critical Care Clinics - Volume 26, Issue 4( 2008) - Copyright © 2008 W. B. Saunders
Company
MDC Extra Article: This additional article is not currently cited in MEDLINE, but
was found in MD Consult's full-text literature database.
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
*
Infectious Disease Division, Winthrop-University Hospital,
259 First Street, Mineola, NY 11501.
PII S0749-0704(07)00107-8
Vancomycin has been used for decades to treat serious systemic gram positive infections.
Extensive use over time has demonstrated vancomycin is not nephrotoxic even when
used in high dosage, i.e., twice the usual dose. Since vancomycin is not nephrotoxic, there
is no rationale for dosing vancomycin based on serum vancomycin levels. Since
vancomycin is eliminated by GFR, vancomycin dosing should be based on creatinine
clearance. Vancomycin obeys “concentration dependent” kinetics and higher than usual
doses may be useful in some infections (eg, osteomyelitis). Widespread vancomycin use
has resulted in increased VRE prevalence worldwide. Among staphylococci, vancomycin
induced cell wall thickening results in “permeability mediated” resistance to vancomycin,
as well as other anti-staphylococcal antibiotics. “Permeability mediated” resistance
accounts for the common clinical observation that MRSA infections treated with
vancomycin often resolve slowly or not at all. Other effective MRSA antibiotics are
available (eg, linezolid, daptomycin, minocycline, or tigecycline) and are more reliably
effective, do not increase staphylococcal resistance or increase VRE prevalence.
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], [2], [3], [4], [5].
Table 1 -- Vancomycin: clinically useful microbiologic spectrum
Clinically effective
Gram-positive aerobic cocci
• Staphylococci (MSSA/MRSA),
• Nonenterococcal streptococci (Groups A, B, C, G)
• Staphylococcus epidermidis (coagulase negative
staphylococci) (MSSE/MRSE)
• Penicillin-resistant Streptococcus pneumoniae
Gram-positive anaerobic cocci
•
•
Peptococcus
Peptostreptococcus
Gram-positive aerobic bacilli
•
•
Corynebacterium sp
Lactobacillus sp
Gram-positive anaerobic bacilli
•
Clinically ineffective
Gram-negative aerobic
cocci
•
Neisseria meningitidis
Gram-negative aerobic
bacilli
• Escherichia coli
• Klebsiella pneumoniae
• Pseudomonas
aeruginosa
Gram-positive aerobic
bacilli
• Listeria
monocytogenes
Gram-negative anaerobic
bacilli
Clostridium sp
•
Bacteroides fragilis
Group D enterococci
Group D enterococci
•
• Enterococcus faecium
(VRE)
Enterococcus faecalis (VSE)[a]
Abbreviations: MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA,
methicillin-sensitive Staphylococcus aureus; MSSE, methicillin-sensitive
Staphylococcus epidermidis; VRE, vancomycin-resistant enterococci; VSE,
vancomycin-sensitive enterococci.
Data from Refs. [1], [3], [4].
a
Only when combined with an aminoglycoside (eg, gentamicin).
The initial unpurified formulations of vancomycin were associated with reports of potential
nephrotoxicity [6], [7]. Subsequently, the purified preparations of vancomycin have been
used and have not been associated with nephrotoxicity. 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 medications. Vancomycin plus an aminoglycoside does not appear to
increase the nephrotoxic potential of the aminoglycoside [10], [11], [12], [13], [14], [15]. Endotoxin or
cytokine release from gram-negative bacilli treated with an aminoglycoside and
vancomycin may be responsible for an increase in creatinine in some cases, which may
have been mistakenly ascribed to vancomycin toxicity [16]. Because vancomycin
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 insufficiency can be accurately dosed
based on the creatinine clearance (CrCl), (ie, the daily dose of vancomycin should be
reduced in proportion to the 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], [18], [19], [20], [21].
The pharmacokinetic and pharmacodynamic characteristics of vancomycin have been well
studied. Vancomycin obeys both “concentration dependent” kinetics at concentrations >
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 problems. Firstly,
excessive use of vancomycin has resulted in an increased prevalence of vancomycinresistant enterococci (VRE) worldwide. Vancomycin-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], [27], [28], [29], [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].
Another negative effect of vancomycin use over the years has been a relative increase S
aureus resistance [33], [34], [35], [36], [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 vancomycin as well as to other anti-MSSA and anti-MRSA
antibiotics [38], [39], [40], [41], [42]. Vancomycin-induced “permeability-mediated” resistance is
manifested microbiologically by increased minimum inhibitory concentrations (MICs) and
clinically by delayed resolution or therapeutic failure in treating staphylococcal bacteremias
or acute bacterial endocarditis [43], [44], [45], [46], [47], [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, linezolid, 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 vancomycin 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 predictably ≥25 μg/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
concentrations) and osteomyelitis (achieves serum trough levels ≥ 15 μg/mL [1], [32], [51], [52].
For cardiopulmonary bypass (CBP) prophylaxis, use 1 g intravenously preoperatively
because vancomycin is rapidly removed during CBP [53], [54]. Burn patients have increased
Vd and may require higher doses of vancomycin. Intravenous drug abusers (IVDAs) have
higher vancomycin renal clearances than do non-IVDAs, and may require higher doses
(Box 1) [1].
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 μg/mL (1-g dose); 120 μg/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 μg/mL; 2g > 50 μg/mL
Trough: 1 g ≥ 7.5 μ/mL; 2 g ≥ 15 μ/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.
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 ∼50% of the anuric dose) should be administered post-hemodialysis [57].
Peritoneal dialysis (PD) removes no vancomycin. Therefore, after an initial 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 peritonitis 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, 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
variable. 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 infections, give 2 g
intravenously every 12 hours until shunt removal. Intravenous vancomycin may be
supplemented by intrathecal doses (ie, vancomycin 10–20 mg/d intrathecally), preferably
administered via Ommaya 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 ∼500 μg/mL, which are maintained for 24 hours [1],
[3]. Intravenously administered vancomycin does not concentrate well into, bile (30%),
synovial fluid, pleural fluid, or lung parenchyma [1], [58], [59], [60], [61], [62].
Intravenous vancomycin diffuses well into most other body compartments except feces,
aqueous humor, and CSF [1], [60]. While vancomycin penetrates poorly into CSF, it
penetrates well into brain tissue (Box 2) [1], [6], [32], [51], [52], [58].
Box 2
Vancomycin tissue concentrations∗
Bone concentrations
Cortical bone
Uninfected: ∼5%
Infected: ∼10%
Cancellous bone
Uninfected: ∼5%
Infected: <5%
Synovial fluid concentrations
Uninflamed synovial fluid: ∼20%
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: ∼50%
Ascitic fluid concentrations
Ascites: <10%
∗
Relative to simultaneous serum levels
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 serious
systemic infections due to susceptible organisms, is to administer vancomycin 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 intravenously 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 nephrotoxic 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
vancomycin levels [67], [68], [69], [70], [71], [72]. It has been shown that vancomycin levels do not
reduce nonexistent toxicity but vancomycin levels often result in unnecessary vancomycin
dosing changes [73], [74], [75], [76], [77], [78].
There is often considerable delay between the time vancomycin peaks and troughs are
reported [70], [74], [75], [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
vancomycin serum peak and trough levels is in the timing of the samples which influences
interpretation of the levels. This, in addition, causes unnecessarily frequent changes in
vancomycin dosing, which serve no clinical purpose [1], [6], [32], [70], [71], [72], [73], [74], [75], [76], [77], [78].
In anuria, on chronic hemodialysis, vancomycin peak serum concentrations are
predictable and vancomycin serum levels are unnecessary. In patients receiving
vancomycin on “high flux” hemodialysis, a posthemodialysis dose should be given to
replace the vancomycin removed. Since about 40% of vancomycin is removed by “high
flux” hemodialysis, a 500-mg intravenous 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, vancomycin serum levels should be obtained. Except to assess therapeutic
efficacy or “apparent therapeutic failure” there is no rationale for obtaining vancomycin
serum levels [69], [70], [71], [72], [73], [74], [75], [76], [77], [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 methicillin-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 difficult 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 being
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
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. Clinicians must rely on the clinical presentation to identify CAMRSA 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-sulfamethoxazole (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 CAMRSA necrotizing pyodermas, treat with surgical debridement and a HA-MRSA/CO-MRSA
antibiotic, such as vancomycin, linezolid, daptomycin, or tigecycline. For CA-MRSA CAP
with influenzalike 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 resistance [81]. The increase in VRE isolates is explained by the
activity of vancomycin against the VSE component in the fecal flora, which is the
predominant 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 ≥32 times
the MIC of an antibiotic. Vancomycin “tolerance” may account for some cases of
delayed or blunted therapeutic response with enterococci or staphylococci [1], [83], [84], [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 irreversibly to cell walls, inhibiting cell-wall
synthesis. Interfering with peptidoglycan 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 ≥64
μg/mL) is mediated by plasmids and is inducible and transferable. Low-level (Van B)
resistance (MIC: 32–64 μg/mL) is nontransferable and chromosomally encoded [1], [85].
Staphylococci
Widespread vancomycin use has increased staphylococcal resistance to vancomycin
manifested as increased MICs. Clinically, vancomycin resistance is manifested as delayed
resolution of infection or therapeutic failure. It has long been appreciated that patients with
MRSA bacteremia/endocarditis often do not respond to vancomycin therapy [86], [87], [88], [89],
[90], [91], [92]. This cannot be ascribed to underdosing vancomycin. Even with optimal
vancomycin dosing, persistent MRSA bacteremias and therapeutic failures are not
uncommon in clinical practice. Vancomycin therapy increases staphylococcal cell-wall
thickening, particularly in hVISA strains. Cell-wall thickening results in “permeabilitymediated” 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 venipuncture. S epidermidis, (CoNS), are
also common blood culture contaminants. 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 cultures (ie, Listeria
monocytogenes, Brucella sp, Streptococcus pneumoniae). The clinical significance of
gram-positive cocci in blood cultures must be assessed by the degree of blood culture
positivity and considered in the appropriate clinical context. Ordinarily, four blood cultures
should be obtained. This usually allows the clinician to clearly differentiate between blood
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 infection. High-grade blood culture positivity—
three of four or four of four—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 always 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 deviceassociated infection [2], [32], [94], [95].
Much empiric vancomycin is used to “cover” “gram positive cocci in clusters” 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 discouraged. 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 therapy. Overuse of empiric
vancomycin for suspected or known CVC-line infections has increased the prevalence of
VRE. If CVC access is necessary after CVC removal for semiquantitative catheter tip
culture, another line may be replaced over a guide wire without risk of pneumothorax,
pending catheter tip results. If the semiquantitative catheter tip cultures are later reported
as negative, the new catheter placed over a guide wire may remain in place. If catheter tip
cultures are positive (ie, ≥15 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 ( [Box 3] , [Box 4] ) [96], [97].
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.
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
Continuous Methicillin-sensitive Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus bacteremias
Patients presenting with a sustained or persistent MSSA or MRSA bacteremia should be
treated empirically with an agent that offers a high degree of activity against MSSA or
MRSA, depending upon the hospital's predominant S aureus type (ie, MSSA versus
MRSA) while a workup to determine the cause of the persistent bacteremia is undertaken.
The most common underlying causes of persistent MSSA or MRSA bacteremia are
intravascular infections (ie, CVC-related infections) or acute bacterial endocarditis or
paravalvular abscess, and less commonly are due to persistent bacteremias from noncardiac staphylococcal abscesses and, even less commonly, bone infections [47], [97], [98], [99],
[100], [101].
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 monotherapy 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-negative 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 are manifested as an increase in MICs,
delayed resolution of infection, or therapeutic failure. Staphylococci with thickened cell
walls represent a permeability barrier to vancomycin as well as to other antibiotics. This
is manifested 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 institutions 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).
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 hemodialysis catheter infections
The treatment of hemodialysis catheter infections in hemodialysis patients 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 dialysis catheter
infections due to MSSA and MRSA [32], [102], [103], [104].
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 endocarditis, usually present with fever of
102°F or higher. In addition, MSSA or MRSA acute bacterial endocarditis usually presents
without a heart murmur early in the infectious process. Later, when there is valvular
destruction, a new or rapidly changing murmur becomes apparent.
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], [106], [107].
In contrast, in patients with possible acute bacterial endocarditis, the indications 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 patients presenting with acute bacterial endocarditis. If
cardiac echocardiography 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 suspected, TEE, is the
preferred echocardiographic modality to demonstrate a perivalvular septal, or myocardial
abscess. In patients with potential staphylococcal prosthetic valve endocarditis (PVE), a
TEE is preferred to demonstrate vegetations. Patients with prosthetic valve(s) should be
suspected of having prosthetic valve endocarditis if there is fever and a continuous highgrade bacteremia with a known endocarditis pathogen. Fever is usually present, but
murmurs are difficult to appreciate because of the sounds generated by the prosthetics
valve. Subacute bacterial endocarditis, acute bacterial endocarditis, and prosthetic valve
endocarditis may be accompanied by peripheral findings associated with endocarditis (Box
6; [Table 2] , [Table 3] ) [97], [101], [106], [107].
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.
Table 2 -- Delayed resolution or failure of vancomycin therapy of MSSA or MRSA
bacteremia and acute bacterial endocarditis
Failure rates
Duration of
bacteremia
MSSA bacteremia
References
Sande [110]
Nafcillin: 4%
Vancomycin: 20%
Nafcillin: 2 days
Vancomycin: 7 days
(20% >3 days)
(12% >7 days)
Failure rates
MSSA acute bacterial
endocarditis
Duration of
bacteremia
References
Nafcillin: 1.4%–26% Nafcillin: 2 days
Vancomycin: 37%– Vancomycin: 5 days
50%
MRSA acute bacterial
endocarditis
Gentry
[111]
Geraci [112]
Esposito [4]
Chang [98]
Small [115]
Nafcillin: Not
applicable
Vancomycin: >7
days
Table 3 -- Combination therapy for MSSA and MRSA acute bacterial endocarditis
Antibiotic combinations
Comments
References
MSSA acute bacterial
endocarditis
Nafcillin + gentamicin
Outcomes same without
gentamicin
Vancomycin + gentamicin
Cha [116]
Lee [117]
MRSA acute bacterial
endocarditis
Vancomycin
Duration of bacteremia: 7 days
Levine [118]
Vancomycin + rifampin
Duration of bacteremia: 9 days
Shelburne
[119]
(antagonistic; not synergistic)
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 administer intrathecal vancomycin is via an Ommaya reservoir. Vancomycin
CSF levels may be obtained in patients to assure adequate CSF levels, but resolution 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 chemotherapy infusion devices in these patients. Depending upon the
geography/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 neutropenia 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
neutropenia (eg, levofloxacin, meropenem) have anti-MSSA activity. In febrile
neutropencia, fungal infections usually present after 10 to 14 days of antibiotic therapy
and are clinically manifested as an otherwise unexplained recrudescence 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 be given until the device is removed. The routine use of vancomycin in
combination 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 Streptococcus viridans
and enterococcal endocarditis. Vancomycin monotherapy has been used successfully
over the years to treat S viridans subacute bacterial 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
resistance 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 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
cephalosporins 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
primary 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 aminoglycoside or rifampin to antistaphylococcal
antibiotics has no benefit and may have a negative effect on outcomes (see [Table 2] , [Table 3]
) [1], [3], [4], [5], [31], [32], [110].
In penicillin-allergic patients, the treatment of serious systemic infections due to MSSA (ie,
CVC line infections, acute bacterial endocarditis, prosthetic 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 systemic 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 increased VRE
prevalence [37], [38], [39], [40], [41], [42], [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 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], [99], [100], [111], [112], [113], [114], [115], [116], [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. Recently, 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 activity 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 effective alternative anti-MRSA antibiotics. For the oral therapy of MRSA,
minocycline or linezolid may be used ( [Box 7] , [Box 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
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 pharmacokinetically
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 therapeutic 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, daptomycin, 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 antibiotic. However, because
vancomycin must be administered intravenously, 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 verification of PICC line placement, and the cost of home
intravenous agencies must be added to vancomycin cost. While the cost of administering
parenteral antibiotics via PICC lines for vancomycin is similar to that for other
antibiotics, most infections for which vancomycin is administered parenterally may be
treated equally effectively with oral linezolid which is much less expensive (see [Box 4] , [Box 5] ,
Table 4).
Table 4 -- Vancomycin: clinical use and therapeutic alternatives
Clinical uses
Disadvantages,
problems
Therapeutic
alternatives
Advantages of
alternative antibiotics
• Central IV
catheter (CVC)
infections “that may
be due to MRSA”
• Increased VRE
prevalence
• Increased
permeability-mediated
resistance
• MIC “drift”
• Removal of
CVC
• Daptomycin
(6 mg/kg IV
every 24
hours)
• Linezolid
(600 mg IV
every 12
hours)
• High-degree MRSA
activity
• Also covers MSSA,
VSE
• No increased
resistance/VRE
• MRSA
bacteremias, acute
bacterial
endocarditis
• Increased
permeability-mediated
resistance
• Delayed
therapeutic response
(persistent
bacteremia)
• MIC “drift”
• Daptomycin
(6–12 mg/kg IV
every 24
hours)
• Linezolid
(600 mg IV
every 12
hours)
• Most rapidly
bactericidal MRSA
antibiotic
• Effective in
vancomycin “treatment
failures”
• Also available orally
for prolonged therapy
• No increased
resistance/VRE
• MRSA
osteomyelitis
• Vancomycin: often
delayed response with
30 mg/kg/d; better
results with 60
mg/kg/d
• Increased
permeability-mediated
resistance
• Linezolid
(600 mg
IV/orally every
12 hours)
• Minocycline
(100 mgIV/
orally every 12
• Also available orally
for prolonged therapy
• No increased
resistance/VRE
Monotherapy
Clinical uses
• MRSA
nosocomial and
ventilator associated
pneumonia (rare)
Disadvantages,
problems
Therapeutic
alternatives
• Increased MICs
during therapy
• MIC “drift”
hours)
• Essential to avoid
“covering”
MSSA/MRSA
respiratory secretion
colonization
• Increases
permeability-mediated
resistance
• MIC “drift”
• Linezolid
(600 mg IV
every 12
hours)
Advantages of
alternative antibiotics
• Inexpensive and
also available orally for
prolonged therapy.
• Effective in rare
cases of bona fide
MRSA nosocomial
pneumonia and
ventilator-associated
pneumonia
• Therapeutic
parenchymal lung
concentrations
Combination Therapy
• Vancomycin and
ceftriaxone to
prevent “seeding” of
CSF from
bacteremic S
pneumoniae (PRSP)
CAP
• “Double drug”
• Ceftriaxone
therapy unnecessary. (1–2 g IV every
Vancomycin: relatively 12 hours)
low CSF
concentrations
• Good CSF
penetration prevents
PRSP “seeding” of
CSF
• Ceftriaxone
monotherapy provides
adequate CSF
concentrations if PRSP
seeding of CSF
• Vancomycin plus
gentamicin therapy
of E faecalis (VSE)
subacute bacterial
endocarditis
• Vancomycin alone
“bacteriostatic”
against VSE
• Vancomycin
bactericidal only when
combined with an
aminoglycoside (eg,
gentamicin)
• MICs for VSE/VRE
greater than those for
MSSA/MRSA
• Use 12 mg/kg IV
every 24 hours for VSE
endocarditis
• Available orally for
prolonged therapy of
VSE subacute bacterial
endocarditis
• Bacteriostatic but
• Daptomycin
(6 mg/kg IV
every 24
hours)
• Linezolid
(600 mg IV
every 12
hours)
Clinical uses
Disadvantages,
problems
Therapeutic
alternatives
Advantages of
alternative antibiotics
effective in subacute
bacterial endocarditis
Abbreviations: IV, intravenous; PSRP, penicillin-resistant S pneumoniae.
Summary
The reassessment of vancomycin use today is based on an evaluation of the advantages
and disadvantages of vancomycin alternatives for the therapy of MRSA. Other antibiotics
exist as alternative therapy for VSE infections 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. Presently, 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
therapeutic alternatives are available with little or no resistance potential, no increase in
VRE prevalence, better pharmacokinetics and lower cost (eg, linezolid) (see Box 6). For
the reasons mentioned, clinicians should use vancomycin sparingly and consider other
antibiotic alternatives for MSSA, MRSA, CoNS, and VSE infections [32], [119], [120].
REFERENCES:
[1] Kucers A., Crowe S.M., Grayson M.L., et al: Vancomycin: the use of antibiotics: a clinical
review of antibacterial, antifungal and antiviral drugs. 5th edition Butterworth-HeinemannOxford
(United Kingdom)1997. p. 763–90
[2] Louria D.B., Kaminski T., Buchman J.: Vancomycin in severe staphylococcal infections.
Arch Intern Med 107. 225-240.1961;
[3] Cunha B.A.: Vancomycin. Med Clin North Am 79. 817-831.1995;
[4] Esposito A.L., Gleckman R.A.: Vancomcyin: a second look. JAMA 238. 1977;1756–7
[5] Menzies D., Goel K., Cunha B.A.: Vancomycin. Antibiotics for Clinicians 2. 97-99.1998;
[6] Farber B.F., Moellering , Jr. , Jr.R.C.: Retrospective study of the toxicity of preparations of
vancomycin from 1974 to 1981. Antimicrob Agents Chemother 23. 138-141.1983;
[7] Elting L.S., Rubenstein E.B., Kurtin D., et al: Mississippi and mud in the 1990s: risks and
outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 83. 25972607.1998;
[8] Appel G.B., Given D.B., Levine L.R., et al: Vancomycin and the kidney. Am J Kidney
Dis 8. 75-80.1986;
[9] Mellor J.A., Kingdom J., Cafferkey M., et al: Vancomycin toxicity: a prospective study.
J Antimicrob Chemother 15. 773-780.1985;
[10] Nahata M.C.: Lack of nephrotoxicity in pediatric patients receiving concurrent vancomycin
and aminoglycoside therapy. Chemotherapy 33. 302-304.1987;
[11] Goren M.P., Baker , Jr. , Jr.D.K., Shenep J.L.: Vancomycin does not enhance amikacininduced tubular nephrotoxicity in children. Pediatr Infect Dis J 8. 278-282.1989;
[12] Goetz M.B., Sayers J.: Nephrotoxicity of vancomycin and aminoglycoside therapy
separately and in combination. J Antimicrob Chemother 32. 325-334.1993;
[13] Ergur T., Onarlioglu B., Gunay Y., et al: Does vancomycin increase aminoglycoside
nephrotoxicity?. Acta Paediatr Jpn 39. 422-427.1997;
[14] Pauly D.J., Musa D.M., Lestico M.R., et al: Risk of nephrotoxicity with combination
vancomycin-aminoglycoside antibiotic therapy. Pharmacotherapy 10. 378-382.1990;
[15] Rybak M.J., Albrecht L.M., Boike S.C., et al: Nephrotoxicity of vancomycin alone and with
an aminoglycoside. J Antimicrob Chemother 25. 679-687.1990;
[16] Ngeleka M., Beauchamp D., Tardif D., et al: Endotoxin increases the nephrotoxic potential
of gentamicin and vancomycin plus gentamicin. J Infect Dis 161. 721-727.1990;
[17] Rybak M.J., Boike S.C.: Monitoring vancomycin therapy. Drug Intell Clin Pharm 20. 757761.1986;
[18] Edwards D.J., Pancorbo S.: Routine monitoring of serum vancomycin concentrations:
waiting for proof of its value. Clin Pharm 6. 652-654.1987;
[19] Moellering , Jr. , Jr.R.C.: Pharmacokinetics of vancomycin. J Antimicrob
Chemother 14. 43-52.1984;
[20] Matzke G.R., Zhanel G.G., Guay D.R.: Clinical pharmacokinetics of vancomycin. Clin
Pharmacokinet 11. 257-282.1986;
[21] Moellering , Jr. , Jr.R.C., Krogstad D.J., Greenblatt D.J.: Vancomycin therapy in patients
with impaired renal function: a nomogram for dosage. Ann Intern Med 94. 343-346.1981;
[22] Leader W.G., Chandler M.H., Castiglia M.: Pharmacokinetic optimization of vancomycin
therapy. Clin Pharmacokinet 28. 327-342.1995;
[23] Boffi el Amari E., Vuagnat A., Stern R., et al: High versus standard dose vancomycin for
osteomyelitis. Scand J Infect Dis 36. 712-717.2004;
[24] Hidayat L.K., Hsu D.I., Quist R., et al: High dose vancomycin therapy for methicillinresistant Staphylococcus aureus infections. Arch Intern Med 166. 2138-2144.2006;
[25] Von Drygalski A., Curtis B.R., Bougie D.W., et al: Vancomycin-induced immune
thrombocytopenia. N Engl J Med 356. 904-910.2007;
[26] Carmeli Y., Samore M.H., Huskins C.: The association between antecedent vancomycin
treatment and hospital-acquired vancomycin-resistant enterococci: a meta-analysis. Arch Intern
Med 159. 2461-2468.1999;
[27] Fishbane S., Cunha B.A., Shea K.W., et al: Vancomycin-resistant enterococcus (VRE) in
hemodialysis patients. Am J Infect Control 20. 461-462.1999;
[28] Fridkin S.K., Lawton R., Edwards J.R., et al: Monitoring antimicrobial use and resistance:
comparison with a national benchmark on reducing vancomycin use and vancomycin-resistant
enterococci. Emerg Infect Dis 8. 702-707.2002;
[29] Fridkin S.K., Edwards J.R., Courval J.M., et al: The effect of vancomycin and thirdgeneration cephalosporins on prevalence of vancomycin-resistant enterococci in 126 U.S. adult
intensive care units. Ann Intern Med 135. 175-183.2001;
[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 31. 67-72.2006;
[31] Cunha B.A.: Antimicrobial therapy of multi-drug resistant S pneumoniae VRE & MRSA.
Med Clin North Am 90. 1165-1182.2006;
[32] Cunha B.A.: Antibiotic essentials. 7th edition Physicians PressRoyal Oak (MI)2008.
[33] Tenover F., Biddle J., Lancaster M.: Increasing resistance to vancomycin and other
glycopeptides in Staphylococcus aureus. Emerg Infect Dis 7. 327-332.2001;
[34] Liu C., Chambers H.F.: Staphylococcus aureus with heterogeneous resistance to
vancomycin: epidemiology, clinical significance, and critical assessment of diagnostic methods.
Antimicrob Agents Chemother 47. 3040-3045.2003;
[35] Cosgrove S.E., Carroll K.C., Perl T.M.: Staphylococcus aureus with reduced susceptibility
to vancomycin. Clin Infect Dis 39. 539-545.2004;
[36] Fridkin S.K., Hageman J., McDougal L.K., et al: Epidemiological and microbiological
characterization of infections caused by Staphylococcus aureus with reduced susceptibility to
vancomycin, United States, 1997–2001. Clin Infect Dis 36. 429-439.2003;
[37] Wang G., Hindler J.F., Ward K.W., et al: Increased vancomycin MICs for Staphylococcus
aureus. Clinical isolates from a university hospital during a 5-year period. J Clin
Microbiol 44. 3883-3886.2006;
[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 41. 5-14.2003;
[39] Cui L., Tominaga E., Hiramatsu K.: Correlation between reduced daptomycin susceptibility
and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob
Agents Chemother 50. 1079-1082.2006;
[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), September 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 50. 1581-1585.2006;
[42] Patel J.B., Jevitt L.A., Hageman J., et al: An association between a reduced susceptibility
to daptomycin and reduced susceptibility to vancomycin in Staphylococcus aureus. Clin Infect
Dis 42. (11): 1652-1653.2006;
[43] Howden B.P., Ward P.B., Charles P.G.P., et al: Treatment outcomes for serious infections
caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility.
Clin Infect Dis 38. 521-528.2004;
[44] Charles P.G., Ward P.B., Johnson P.D., et al: Clinical features associated with bacteremia
due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect
Dis 38. 448-451.2004;
[45] Moore M.R., Perdreau-Remington F., Chambers H.F.: 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 47. 1262-1266.2003;
[46] Howden B.P., Johnson P.D., Ward P.B., et al: Isolates with low-level vancomycin
resistance associated with persistent methicillin-resistant Staphylococcus aureus bacteremia.
Antimicrob Agents Chemother 50. 3049-3057.2006;
[47] Wong S.S., Ng T.K., Yam W.C., et al: Bacteremia due to Staphylococcus aureus with
reduced susceptibility to vancomycin. Diagn Microbiol Infect Dis 36. 261-268.2000;
[48] Fridkin S.K.: Vancomycin-intermediate and -resistant Staphylococcus aureus: what the
infectious disease specialist needs to know. Clin Infect Dis 32. 108-115.2001;
[49] Bouza E., Burillo A., Munoz P.: Antimicrobial therapy of Clostridium difficile–associated
diarrhea. Med Clin North Am 90. 1141-1163.2006;
[50] Cunha B.A., Klein N.C.: Vancomycin. In: Yoshikawa T., ed. Antibiotics in the elderly,
Marcel DekkerNew York1994: p. 311–22
[51] Gump D.W.: Vancomycin for treatment of bacterial meningitis. Rev Infect Dis 3. 289292.1981;
[52] Nagl M., Neher C., Hager J., et al: Bactericidal activity of vancomycin in cerebrospinal
fluid. Antimicrob Agents Chemother 43. 1932-1934.1999;
[53] Skhirtladze K., Hutschala H., Fleck T., et al: Impaired target site penetration of
vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents
Chemother 50. 1372-1375.2006;
[54] Massias L., Dubois C., de Lentdecker P., et al: Penetration of vancomycin in uninfected
sternal bone. Antimicrob Agents Chemother 36. 2539-2541.1992;
[55] Ackerman B.H., Vannier A.M.: Necessity of a loading dose when using vancomycin in
critically ill patients. J Antimicrob Chemother 29. 460-461.1992;
[56] Cunha B.A., Deglin J., Chow M., et al: Pharmacokinetics of vancomycin in patients
undergoing chronic hemodialysis. Rev Infect Dis 3. 269-272.1981;
[57] DelDot M.E., Lipman J., Tett S.E.: Vancomycin pharmacokinetics in critically ill patients
receiving continuous venovenous haemodiafiltration. Br J Clin Pharmacol 58. 259-268.2004;
[58] Lutsar I., McCracken , Jr. , Jr.G.H., Friedland I.R.: Antibiotic pharmacodynamics in
cerebrospinal fluid. Clin Infect Dis 27. 1117-1127.1998;
[59] Byl B., Jacobs F., Wallemacq P., et al: Vancomycin penetration of uninfected pleural fluid
exudate after continuous or intermittent infusion. Antimicrob Agents Chemother 47. 20152017.2003;
[60] Cruciani M., Gatti G., Lazzarini L., et al: Penetration of vancomycin into human lung
tissue. J Antimicrob Chemother 38. 865-869.1996;
[61] Cruciani M., Gatti G., Lazzarini L., et al: Penetration of vancomycin in severe
staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents
Chemother 38. 865-869.1996;
[62] Rybak M.J.: The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin
Infect Dis 18. 544-546.1994;
[63] Zimmermann A.E., Katona B.G., Plaisance K.I.: Association of vancomycin serum
concentrations with outcomes in patients with gram-positive bacteremia.
Pharmacotherapy 15. 85-91.1995;
[64] James J.K., Palmer S.M., Levine D.R., et al: Comparison of conventional dosing versus
continuous-infusion vancomycin therapy for patients with suspected or documented grampositive infections. Antimicrob Agents Chemother 40. 696-700.1996;
[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 9. 420-426.1997;
[66] Masur H., Francioli P., Ruddy M., et al: Vancomycin serum levels and toxicity in chronic
haemodialysis patients with Staphylococcus aureus bacteremia. Clin Nephrol 20. 85-88.1983;
[67] Andres I., Lopez R., Pou L., et al: Vancomycin monitoring: one or two serum levels?.
Ther Drug Monit 19. 614-619.1997;
[68] Sayers J.F., Shimasaki R.: Routine monitoring of serum vancomycin concentrations: The
answer lies in the middle. Clin Pharm 7. 18.1988;
[69] Moellering , Jr. , Jr.R.C.: Monitoring serum vancomycin levels: climbing the mountain
because it is there?. Clin Infect Dis 18. 544-546.1994;
[70] Rodvold K.A., Zokufa H., Rotschafer J.C.: Routine monitoring of serum vancomycin
concentrations: Can waiting be justified?. Clin Pharm 6. 655-658.1987;
[71] Freeman C.D., Quintiliani R., Nightingale C.H.: Vancomycin therapeutic drug monitoring:
Is it necessary. Ann Pharmacother 27. 594-598.1993;
[72] Saunders N.J.: Vancomycin administration and monitoring reappraisal. J Antimicrob
Chemother 36. 279-282.1995;
[73] Karam C.M., McKinnon P.S., Neuhauser M.M., et al: Outcome assessment of minimizing
vancomycin monitoring and dosing adjustments. Pharmacotherapy 19. 257-266.1999;
[74] Darko W., Medicis J.J., Smith A., et al: Mississippi mud no more: cost-effectiveness of
pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity.
Pharmacotherapy 23. 643-650.2003;
[75] Cantu T.G., Yamanaka-Yuen N.A., Lietman P.S.: Serum vancomycin concentrations:
reappraisal of their clinical value. Clin Infect Dis 18. 533-543.1994;
[76] Cunha B.A.: Vancomycin serum levels: unnecessary, unhelpful, and costly. Antibiotics
for Clinicians 8. 273-277.2004;
[77] Cunha B.A., Mohan S.S., Hamid N., et al: Cost ineffectiveness of serum vancomycin
levels. Eur J Clin Microbiol Infect Dis 13. 509-511.2007;
[78] Allegaert K., van den Anker J.N.: Predictability of vancomycin pharmacokinetics in
neonates. Eur J Clin Microbiol Infect Dis 26. 847-848.2007;
[79] Cunha B.A.: Clinical manifestations and antimicrobial therapy of methicillin resistant
Staphylococcus aureus (MRSA). Clin Microbiol Infect 11. 33-42.2005;
[80] Alder J.D.: Staphylococcus aureus: antibiotic resistance and antibiotic selection.
Antibiotics for Clinicians 10. (S1): 19-24.2006;
[81] Krol V., Cunha B.A., Schoch P.E., et al: Empiric gentamicin and vancomycin therapy for
bacteremias in chronic dialysis outpatient units in the era of antibiotic resistance. J
Chemother 18. 490-493.2006;
[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 23. 10201025.1996;
[83] Saribas S., Bagdatli Y.: Vancomycin tolerance in enterococci. Chemotherapy 50. 250254.2004;
[84] Watanakunakorn C.: Antibiotic-tolerant Staphylococcus aureus. J Antimicrob
Chemother 4. 561-568.1978;
[85] Cunha B.A., Mickail N., Eisenstein L.: E faecalis vancomycin sensitive enterococci (VSE)
bacteremia unresponsive to vancomycin successfully treated with high dose daptomycin. Heart
Lung 36. 456-461.2007;
[86] Hussain F.M., Boyle-Vavra S., Shete P.B., et al: Evidence for a continuum of decreased
vancomycin susceptibility in unselected Staphylococcus aureus clinical isolates. J Infect
Dis 186. 661-667.2002;
[87] Sakoulas G., Moise-Broder P.A., Schentag J.J., et al: Relationship of MIC and bactericidal
activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus
bacteremia. J Clin Microbiol 42. 2398-2402.2004;
[88] Schwaber M.J., Wright S.B., Carmeli Y., et al: Clinical implications of varying degrees of
vancomycin susceptibility in methicillin-resistant Staphylococcus aureus bacteremia. Emerg
Infect Dis 9. 657-664.2003;
[89] Srinivasan A., Dick J.D., Perl T.M.: Vancomcyin resistance in staphylococci. Clin
Microbiol Rev 15. 430-438.2002;
[90] Walsh T.R., Howe R.A.: The prevalence and mechanisms of vancomycin resistance in
Staphylococcus aureus. Annu Rev Microbiol 56. 657-675.2002;
[91] Wooton M., Walsh T.R., Macgowan A.P.: Evidence for reduction in breakpoints used to
determine vancomycin susceptibility in Staphylococcus aureus. Antimicrob Agents
Cheomther 49. 3982-3983.2005;
[92] Ward P.B., Johnson P.D., Grabsch E.A., et al: Treatment failure due to methicillinresistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin. Med J
Aust 175. 480-483.2001;
[93] Wooten M., MacGowan A.P., Walsh T.R.: Comparative bactericidal activities of
daptomycin and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA)
and Heterogenous GISA isolates. Antimicrob Agents Chemother 50. 4195-4197.2006;
[94] Burillo A., Bouza E.: Epidemiology of MSSA and MRSA: colonization and infection.
Antibiotics for Clinicians 10. (S1): 3-10.2006;
[95] Kim S.H., Park W.B., Lee K.D., et al: Outcome of Staphylococcus aureus bacteremia in
patients with eradicable foci versus noneradicable foci. Clin Infect Dis 37. 794-799.2003;
[96] Evans M., Finch R.: Approach to staphylococcal central IV line infections and
bacteremias. Antibiotics for Clinicians 10. (S1): 25-28.2006;
[97] Cunha B.A.: Persistent S aureus bacteremia: clinical pathway for diagnosis & treatment.
Antibiotics for Clinicians 10. (S1): 39-46.2006;
[98] Chang F.Y., Peacock , Jr. , Jr.J.E., Musher D.M., et al: Staphylococcus aureus
bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter
study. Medicine (Baltimore) 82. 333-339.2003;
[99] Lodise T.P., McKinnon P.S., Swiderski L., et al: Outcomes analysis of delayed antibiotic
treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 36. 14181423.2003;
[100] Rotun S.S., Mcmath V., Schoonmaker D.J., et al: Staphylococcus aureus with reduced
susceptibility to vancomycin isolated from a patient with fatal bacteremia. Emerg Infect
Dis 5. 147-149.1999;
[101] Cunha B.A.: IV line infections. In: Cunha B.A., ed. Infectious diseases in critical care
medicine, 2nd edition Informa HealthcareNew York2007:
[102] Morris A.J., Bilinsky R.T.: Prevention of staphylococcal shunt infections by continuous
vancomycin prophylaxis. Am J Med Sci 262. 87-92.1971;
[103] Eykyn S., Phillips I., Evans J.: Vancomycin for staphylococcal shunt site infections in
patients on regular haemodialysis. Br Med J 3. 8-82.1970;
[104] Tofte R.W., Solliday J., Rotschafer J., et al: Staphylococcus aureus infection of dialysis
shunt: absence of synergy with vancomycin and rifampin. South Med J 74. 612-616.1981;
[105] Cunha B.A., Gill M.V., Lazar J.: Acute infective endocarditis. Infect Dis Clin North
Am 10. 811-834.1996;
[106] Cunha B.A.: MSSA/MRSA acute bacterial endocarditis (ABE): clinical pathway for
diagnosis & treatment. Antibiotics for Clinicians 10. (S1): 29-34.2006;
[107] Brusch J.L.: Infective endocarditis. Informa HealthcareNew York2007. p. 143–272
[108] Picazo J.J.: Association for Health Research and Development (ACINDES).
Management of the febrile neutropenic patient. Int J Antimicrob Agents 2. (S1): S120S122.2005;
[109] Cunha B.A.: Clinical approach to antibiotic therapy in the penicillin allergic patient. Med
Clin North Am 90. 1257-1264.2006;
[110] Bliziotis I.A., Ntziora F., Lawrence K.R., et al: Rifampin as adjuvant treatment of grampositive bacterial infections: a systemic review of comparative clinical trials. Eur J Clin Microbiol
Infect Dis 26. 849-856.2007;
[111] Gentry C.A., Rodvold K.A., Novack R.M., et al: Retrospective evaluation of therapies for
Staphylococcus aureus endocarditis. Pharmacotherapy 17. 990-997.1977;
[112] Geraci J.E., Wilson W.R.: Vancomycin therapy for infective endocarditis. Rev Infect
Dis 3. (Suppl): 1981;S520–58
[113] Small P.M., Chambers H.F.: Vancomycin for Staphylococcal aureus endocarditis in
intravenous drug users. Antimicrob Agents Chemother 34. 1227-1231.1990;
[114] Lee D.G., Chun H.S., Yim D.S., 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 47. 3768-3773.2003;
[115] Levine D.P., Fromm B.S., Reddy B.R.: Slow response to vancomycin or vancomycin plus
rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med 115. 674680.1991;
[116] Shelburne S.A., Musher D.M., Hulten K., et al: In vitro killing of community-associated
methicillin-resistant Staphylococcus aureus with drug combinations. Antimicrob Agents
Chemother 48. 4016-4019.2004;
[117] Cha R., Brown W.J., Ryback M.J.: Bactericidal activities of daptomycin, quinupristindalfopristin, and linezolid against vancomycin-resistant Staphylococcus aureus in an in vitro
pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents
Chemother 47. 3960-3963.2003;
[118] Kirst H.A., Thompson D.G., Nicas T.I.: Historical yearly usage of vancomycin.
Antimicrob Agents Chemother 42. 1303-1304.1998;
[119] Stevens D.L.: The role of vancomycin in the treatment paradigm. Clin Infect Dis 42. S51S57.2006;
[120] Pope S.D., Roecker A.: Vancomycin for treatment of invasive, multi-drug resistant
Staphylococcus aureus infections. Expert Opin Pharmacother 8. 1245-1261.2007;