vancomycin revisited ccc 2008

Vancomycin Revisited: A Reappraisalof Clinical Use

Burke A. Cunha, MD, MACPa,b,*aInfectious Disease Division, Winthrop-University Hospital,

Mineola, NY 11501, USAbState 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 isactive against a variety of other gram-positive organisms, other antibioticsare preferred to treat infections due to these organisms (Table 1). In criticalcare medicine, vancomycin has been mainly used to treat infections whereMRSA is the presumed cause of infection. These include central intravenousline infections, soft tissue infections, bone infections, shunt infections inhemodialysis patients, bacteremia, and acute bacterial endocarditis. Thewidespread use of empiric vancomycin has resulted in adverse effects [1–5].

The initial unpurified formulations of vancomycin were associated withreports 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–associatednephrotoxicity [8,9]. The few reports of potential vancomycin nephrotoxicitydescribed patients receiving vancomycin and known nephrotoxic medica-tions. Vancomycin plus an aminoglycoside does not appear to increase thenephrotoxic potential of the aminoglycoside [10–15]. Endotoxin or cytokinerelease from gram-negative bacilli treated with an aminoglycoside and van-comycin may be responsible for an increase in creatinine in some cases, whichmay have been mistakenly ascribed to vancomycin toxicity [16]. Because van-comycin monotherapy is not nephrotoxic, the use of vancomycin serumlevels to avoid nephrotoxicity has no basis [3,17,18]. Because vancomycinis 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

Crit Care Clin 24 (2008) 393–420

* Infectious Disease Division, Winthrop-University Hospital, 259 First Street, Mineola,

NY 11501.

0749-0704/08/$ - see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2007.12.012 criticalcare.theclinics.com

http://www.criticalcare.theclinics.com

Table 1

Vancomycin: clinically useful microbiologic spectrum

Clinically effective Clinically ineffective

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-negative aerobic cocci� Neisseria meningitidis

Gram-positive anaerobic cocci� Peptococcus

� Peptostreptococcus

Gram-negative aerobic bacilli� Escherichia coli

� Klebsiella pneumoniae

� Pseudomonas aeruginosa

Gram-positive aerobic bacilli� Corynebacterium sp

� Lactobacillus sp

Gram-positive aerobic bacilli� Listeria monocytogenes

Gram-positive anaerobic bacilli� Clostridium sp

Gram-negative anaerobic bacilli� Bacteroides fragilis

Group D enterococci� Enterococcus faecalis (VSE)a

Group D enterococci� 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].

394 CUNHA

decrease in renal function). In those responding to vancomycin therapy andin those with a normal volume of distribution (Vd), vancomycin levels areunhelpful, 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 nota consideration, high-dose vancomycin (eg, 2 g intravenously every 12 hours[60 mg/kg/d]) has been used in special situations, eg, osteomyelitis withoutnephrotoxicity [23,24]. After years of clinical experience, vancomycin sideeffects have become more fully appreciated. In addition to ‘‘red neck’’ or‘‘red man’’ syndrome, leukopenia, thrombocytopenia, and, rarely, suddendeath 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 increasedprevalence of vancomycin-resistant enterococci (VRE) worldwide. Vanco-mycin-sensitive enterococci (VSE) represent the main group D enterococcalcomponent of feces. Vancomycin has sufficient anti-VSE activity to decreaseVSE in the fecal flora, resulting in a commensurate increase VRE in stools[26–30]. Although the spectrum of infection caused by VSE and VRE arethe 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].

395VANCOMYCIN REVISITED

Another negative effect of vancomycin use over the years has been a rel-ative increase S aureus resistance [33–37]. Vancomycin therapy results incell-wall thickening of S aureus strains, of both methicillin-sensitive S aureus(MSSA) and methicillin-resistant S aureus (MRSA). Vancomycin-mediatedcell-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 antibioticsshould 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 primarilyadministered via the intravenous route in the critical care setting. Oral van-comycin is the preferred therapy for Clostridium difficile diarrhea because itis not absorbed, is active against C difficile, and achieves high intraluminalconcentrations in the colon [1,3,32]. Because intravenous vancomycin doesnot penetrate into the bowel lumen, intravenous vancomycin has no rolein 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 intravenouslyevery 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 is0% 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 renalclearances than do non-IVDAs, and may require higher doses (Box 1) [1].

Vancomycin is not removed by hemodialysis [1,3]. In anuric patientsa 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 serumconcentration is 3.5 mg/mL after 18 days) [1,32,55,56]. In patients usingnew ‘‘high flux’’ membranes for hemodialysis, about 40% of vancomycinis removed. Therefore, a post–‘‘high flux’’ hemodialysis dose (eg, 500 mgintravenously, which is w50% of the anuric dose) should be administeredpost-hemodialysis [57].

Box 1. Vancomycin: pharmacokinetic and pharmacodynamiccharacteristics

Pharmacokinetic parametersUsual 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/mLTrough: 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 < MICPrimary mode of elimination: renalDosage adjustments:

CrCl 50–80 mL/min: dose = 500 mg intravenously every12 hours

CrCl 10–50 mL/min: dose = 500 mg intravenously every24 hours

CrCl <10 mL/min: dose = 1 g intravenous every weekPost-hemodialysis dose: nonePost–‘‘high flux’’ hemodialysis dose: 500 mg intravenous

every 12 hoursPost–peritoneal dialysis dose: noneCVVH dose: 1 gm intravenous every 24 hours

Data from Cunha BA, editor. Antibiotic essentials, 7th edition. Royal Oak (MI):Physicians Press; 2008; with permission.

396 CUNHA

Peritoneal dialysis (PD) removes no vancomycin. Therefore, after an ini-tial 1-g intravenous dose, vancomycin should be dosed for a CrCl less than10 mL/min and no post-PD dose is necessary [1,32]. For patients with peri-tonitis on chronic ambulatory peritoneal dialysis (CAPD), vancomycin maybe added to peritoneal dialysis fluid. A 1-g intravenous loading dose ofvancomycin may be given to such patients after dialysis, followed by therenally adjusted maintenance anuric dose [1,32]. In addition, to maintainequilibrium between the dialysate fluid and the serum compartment,


vancomycin may also be given intraperitoneally (2–30 mg of vancomycinper liter of dialysis fluid) with each CAPD [1,32]. Vancomycin has beenused to treat CNS infections, but CNS penetration of vancomycin is vari-able. Vancomycin administered intravenously achieves only about 15% ofsimultaneous serum levels in the CSF in patients with meningitis. If highCSF 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 iseliminated unchanged in the urine during the first 24 hours. After a single1-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, pleuralfluid, 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 ofIV 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 ofrenal insufficiency have been devised and all are based on CrCl [1,6,21].Formerly, vancomycin was administered as 500 mg intravenously every6 hours. Today vancomycin is usually administered as 1 g intravenouslyevery 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 intravenouslyevery 12 hours (30 mg/kg/d) [1,3,32]. Even when used in prolonged highdoses 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 dosingwas based on vancomycin levels [65,66]. However, vancomycin has no neph-rotoxic potential. Thus, there is no rationale for using routine vancomycinlevels to dose patients to avoid nephrotoxicity. Accurate vancomycin dosingis readily achieved more quickly, simply, less expensively, and without riskof 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 unnecessaryvancomycin dosing changes [73–78].

Box 2. Vancomycin tissue concentrations*

Bone concentrationsCortical bone

Uninfected: w5%Infected: w10%

Cancellous boneUninfected: w5%Infected: <5%

Synovial fluid concentrationsUninflamed synovial fluid: w20%

Urine ConcentrationsUninfected urine: 100% (normal renal function)

Stool concentrationsFeces:

Intravenous: 0%Orally: 1000%

CSF concentrationsUninflamed 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

398 CUNHA

There is often considerable delay between the time vancomycin peaksand troughs are reported [70,74–76]. Two or more days have usuallyelapsed when dosing adjustments are made, which means adjustments invancomycin dosing are based on previous, but no longer relevant estimatesof, renal function (CrCl) [70,76]. The other practical difficulty with vanco-mycin serum peak and trough levels is in the timing of the samples whichinfluences 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


patients receiving vancomycin on ‘‘high flux’’ hemodialysis, a posthemodial-ysis dose should be given to replace the vancomycin removed. Since about40% 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 oftherapy in patients with unusual Vd, such as burn patients, or in thosepatients not responding to appropriately dosed vancomycin (ie, patientsshowing vancomycin ‘‘tolerance’’ or resistance). For these purposes, vanco-mycin serum levels should be obtained. Except to assess therapeutic efficacyor ‘‘apparent therapeutic failure’’ there is no rationale for obtaining vanco-mycin serum levels [69–78].

Vancomycin microbiologic activity and efficacy

Antistaphylococcal activity

Staphylococcus epidermidisThe 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 usuallyrelated to prosthetic implant materials (ie, infections involving prostheticjoints, prosthetic heart valves, and CNS shunts). These infections are diffi-cult to eradicate with antimicrobial therapy alone because antibiotics areunable to eradicate these organisms in the glycocalyx on prostheticmaterials.

Methicillin-resistant Staphylococcus aureus
Vancomycin has been used to treat serious staphylococcal infections,
especially MRSA. The prevalence of MRSA has increased during the pastseveral decades with three clinical variants recognized. Two of these arehospital-acquired MRSA (HA-MRSA) and community-onset MRSA(CO-MRSA). CO-MRSA strains originate in the hospital, circulate in thecommunity, 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 thecommunity.

However, CA-MRSA infections have two distinctive clinical presentationsreadily differentiating them from CO-MRSA strains, which represent themajority of MRSA admitted from the community (community onset) to thehospital. CA-MRSA infections usually present either as severe pyoderma oras necrotizing/hemorragic CAP. Although still rare, these two clinical CA-MRSA syndromes are recognizable by their clinical presentations. Strains ofCA-MRSA, particularly those with the Panton-Valentine leukocidin gene(PVL positive), are unusually virulent with a high degree of cytotoxic

400 CUNHA

activity, which accounts for their extensive tissue destruction and twounique clinical presentations. While these strains are genetically distinctive(ie, Staphylococcal chromosome cassette [SCC] mec IV), most hospitallaboratories cannot perform studies to identify PVL positive strains. Clini-cians must rely on the clinical presentation to identify CA-MRSA strainsversus the great majority of MRSA strains from the community, which arenearly all CO-MRSA. In spite of the increased virulence of CA-MRSAPVL positive strains, these organisms are surprisingly sensitive to olderantibiotics, such as doxycycline, clindamycin, and trimethoprim-sulfame-thoxazole (TMP-SMX), but these antibiotics are not effective againstHA-MRSA strains. Vancomycin, linezolid, daptomycin, minocycline, andtigecycline are active against HA-MRSA, CO-MRSA, and CA-MRSAstrains. 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, itsexcessive use over time has resulted in two major clinical problems. Firstly,extensive intravenous (not oral) vancomycin use has resulted in an increasein the prevalence of E faecium (VRE), as well as increased vancomycin re-sistance [81]. The increase in VRE isolates is explained by the activity ofvancomycin against the VSE component in the fecal flora, which is the pre-dominant enterococcal species in the fecal flora. By decreasing VSE in thefecal flora, there is a commensurate increase in VRE in feces. There hasbeen an increase worldwide in VRE prevalence due to vancomycin overuse. Instead, other anti-MRSA antibiotics that do not have this effect shouldbe 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 bactericidalconcentration (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-positiveorganisms, including staphylococci but is bacteriostatic against enterococci.Resistance to vancomycin is mediated by alterations in the permeability ofouter membrane porins in S aureus. Vancomycin binds rapidly and irrevers-ibly 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 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 tovancomycin 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 beascribed to underdosing vancomycin. Even with optimal vancomycindosing, persistent MRSA bacteremias and therapeutic failures are not un-common in clinical practice. Vancomycin therapy increases staphylococcalcell-wall thickening, particularly in hVISA strains. Cell-wall thickening re-sults in ‘‘permeability-mediated’’ resistance to vancomycin as well as toother antistaphylococcal antibiotics. For these reasons, vancomycin mayno longer be the preferred antibiotic for treatment of serious systemicMRSA infections. Other effective MRSA antibiotics are available andmay be used in place of vancomycin (eg, minocycline, linezolid, tigecycline,and daptomycin). The empiric use of vancomycin to treat MRSA-colonizedpatients should be minimized to avoid further increases in VRE prevalenceand MRSA resistance [1,6,32,93].

Vancomycin: clinical uses

Methicillin-sensitive Staphylococcus aureus and methicillin-resistantStaphylococcus aureus bacteremias

The finding of S aureus, either of the MSSA or MRSA variety, is commonin 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 withbacteremia.

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

402 CUNHA

culture positivity and bacteremia when dealing with blood culture reportspositive for MSSA, MRSA, or CoNS. One or two out of four positive bloodcultures usually represent blood culture contamination rather than infec-tion. High-grade blood culture positivitydthree of four or four of fourdis usually indicative of bacteremia. If it is established that the patient hasbacteremia, the clinician’s next task is to determine whether it is a transientor sustained bacteremia. Staphylococci bacteremia is said to be persistentwhen MSSA or MRSA is present repeatedly in consecutive blood culturesdemonstrating high blood culture positivity (ie, three of four or four offour). 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 ofimplanted prosthetic materials, usually indicates a prosthetic material- ordevice-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 mostcommon cause of high-gradeMSSA,MRSA, or CoNS bacteremia are centralvenous 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 thediagnosis confirmed by semiquantitative catheter tip cultures. Treatment forCVC 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 afterCVCremoval for semiquantitative catheter tip culture, another linemay be re-placed over a guide wire without risk of pneumothorax, pending catheter tipresults. If the semiquantitative catheter tip cultures are later reported as neg-ative, the newcatheter placed over a guidewiremay remain inplace. If cathetertip cultures are positive (ie, R15 colonies of the same organism as causing thebacteremia), then the line replaced over the guide wire should be removed anda new CVC placed in a different anatomic location (Boxes 3 and 4) [96,97].

Continuous Methicillin-sensitive Staphylococcus aureus andmethicillin-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 degreeof activity against MSSA or MRSA, depending upon the hospital’s predom-inant S aureus type (ie, MSSA versus MRSA) while a workup to determinethe cause of the persistent bacteremia is undertaken. The most common un-derlying causes of persistent MSSA or MRSA bacteremia are intravascularinfections (ie, CVC-related infections) or acute bacterial endocarditis or par-avalvular abscess, and less commonly are due to persistent bacteremias fromnon-cardiac staphylococcal abscesses and, even less commonly, bone infec-tions [47,97–101].

Box 3. Vancomycin: appropriate prophylacticand 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 previoussubacute bacterial endocarditis or prosthetic valveendocarditis (plus gentamicin)

Therapy� MRSA, CoNS CNS shunt (ventriculo-atrial,

ventriculo-peritoneal) infectionsa

� MRSA hemodialysis catheter infectionsb

� Endocarditisc

Streptococus viridans subacute bacterial endocarditis (inpenicillin-allergic patients)

CoNS prosthetic valve endocarditis due to MSSE or MRSEVSE 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-resistantStaphylococcus aureus central intravenous line infections

The majority of intravenous line infections related to CVCs are due toskin organisms (ie, MSSA, MRSA, MSSE, or MRSE). Because vancomycinis active against these skin pathogens, it is frequently used as empiric mono-therapy for presumed CVC line infections. There are two problems with thisapproach. In institutions where the predominant pathogen causing CVCline infections is MSSA, rather than MRSA, other agents should be usedin 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 thicknessamong staphylococci. Vancomycin-induced thickened bacterial cell walls

Box 4. Clinical situations in which vancomycinshould 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 antibioticsIntravenous MRSA antibiotics: linezolid, daptomycin,

tigecycline, minocyclineOral MRSA antibiotics: linezolid, minocycline

404 CUNHA

are manifested as an increase in MICs, delayed resolution of infection, ortherapeutic 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.’’ Theincrease in MICs, often observed during vancomycin therapy, is reflectiveof cell-wall thickening. A preferred approach to the empiric treatment toCVC line infections pending CVC removal is to use meropenem in institu-tions where CVC infections are more frequently due to MSSA/GNBs thanto MRSA. In institutions where the reverse is true, and MRSA is animportant CVC pathogen, empiric therapy with tigecycline is preferableto combination therapy with vancomycin plus an anti–GNB antibiotic(Box 5).

Methicillin-sensitive Staphylococcus aureus and methicillin-resistantStaphylococcus aureus hemodialysis catheter infections

The treatment of hemodialysis catheter infections in hemodialysis pa-tients has been a major area of vancomycin usage because vancomycin iseliminated by glomerular filtration. The increased half-life of vancomycinin anuria may be used to a therapeutic advantage in patients with MSSA/MRSA infections in end stage renal disease on hemodialysis. As with otherforeign body infections due to gram-positive organisms, shunt removal isusually necessary for elimination the infection. Vancomycin has been usedprophylactically and therapeutically in hemodialysis patients to treat dialy-sis catheter infections due to MSSA and MRSA [32,102–104].

Box 5. Diagnostic clinical pathway: persistent S aureus(MSSA, MRSA) bacteremias

Differentiate S aureus blood culture positivity (1/4 or 1/2) frombacteremia.

With S aureus bacteremia, differentiate low-intensity intermittentbacteremia (1/2 or 2/4 positive blood cultures) from continuoushigh-intensity bacteremia (3/4–4/4 positive blood cultures).

Determine the source of S aureus bacteremia.AbscessesCentral intravenous linesImplanted prosthetic devices/materialsAcute bacterial endocarditisSoft 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 todiagnose or rule out acute bacterial endocarditis.

Data from Cunha BA. Persistent S aureus bacteremia: clinical pathwayfor diagnosis & treatment. Antibiotics for Clinicians 2006;10(S1):39–46; withpermission.


Methicillin-sensitive Staphylococcus aureus and methicillin-resistantStaphylococcus aureus acute bacterial endocarditis

The diagnostic approach to persistent S aureus bacteremia is relativelystraightforward. First, in patients with CVCs, this source of infection shouldbe ruled out first because since CVC infections are readily diagnosable andeasily treated by CVC removal. If there is no CVC in place, or if theremoved CVC semiquantitative catheter tip cultures are negative, thenendocarditis should be the next diagnostic consideration. MSSA orMRSA endocarditis presents as acute bacterial endocarditis (ABE). Exceptfor IVDAs, patients presenting with MSSA or MRSA acute bacterial endo-carditis, usually present with fever of 102�F or higher. In addition, MSSA orMRSA 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.

406 CUNHA

In patients with subacute bacterial endocarditis and positive blood culturesdue to subacute bacterial endocarditis pathogens, cardiac echocardiographyis indicated in patients who have a heart murmur. Cardiac echocardiographymay be the transthoracic (TTE) or the transesophageal (TEE) variety. Forscreening purposes, TTE is preferred to TEE. For detection of prostheticvalve endocarditis and myocardial abscess TEE is preferred. In patientswith subacute bacterial endocarditis, the indication for a TTE or a TEE isthe presence of continuous bacteremia due to a known subacute bacterialendocarditis 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 orMRSA 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 effectivelyeliminated from further consideration. If the high-grade continuous MSSAor MRSA bacteremia continues, the echocardiography should be reviewedfor a potential paravalvularmyocardial abscess. If amyocardial abscess is sus-pected, TEE, is the preferred echocardiographic modality to demonstratea 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 ofhaving prosthetic valve endocarditis if there is fever and a continuous high-grade bacteremia with a known endocarditis pathogen. Fever is usually pres-ent, butmurmurs are difficult to appreciate because of the sounds generated bythe prosthetics valve. Subacute bacterial endocarditis, acute bacterial endo-carditis, and prosthetic valve endocarditis may be accompanied by peripheralfindings 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 areusually due to CoNS of the MSSE or MRSE variety. CNS shunt infectionsusually require shunt removal. If suppression is desired, vancomycin maybe given parenterally and, if necessary, CSF concentrations may be furtherincreased by intraventricular administration. Usually the best way to admin-ister intrathecal vancomycin is via an Ommaya reservoir. Vancomycin CSFlevels may be obtained in patients to assure adequate CSF levels, but resolu-tion of shunt infections almost always requires shunt removal. It is preferableto use an antibiotic with good CSF penetration (eg, linezolid) [1,31,32].

Febrile neutropenia

Recently, some clinicians have added vancomycin to regimens to treatfebrile neutropenia in compromised hosts receiving chemotherapy. Theincreased incidence of gram-positive infections in febrile neutropenia arenot due to neutropenia per se, but are due to central line catheters or

Box 6. Diagnostic clinical pathway: MSSA/MRSAacute bacterial endocarditis

Differentiate S aureus blood culture positivity (1/2 or 1/4 positiveblood cultures) from bacteremia (3/4–4/4 positive bloodcultures).

With S aureus bacteremia, differentiate low-intensity intermittentbacteremia (1/2 or 2/4 positive blood cultures) from continuoushigh-intensity bacteremia (3/4–4/4 positive blood cultures).

Acute bacterial endocarditis is not a complication of low-intensity/intermittent S aureus bacteremia. TTE/TEEunnecessary, but will verify no vegetations.

If continuous high-grade MSSA/MRSA bacteremia, obtain a TTEor TEE to document cardiac vegetations and/or paravalvularabscess and confirm diagnosis of acute bacterial endocarditis.

Diagnostic criteria for MSSA/MRSA acute bacterial endocarditisEssential features

Continuous high-grade MSSA/MRSA bacteremiaCardiac vegetations on TTE/TEENo other source

Nonessential featuresFever ‚102�F (non-IVDAs)Cardiac murmura

a With early MSSA/MRSA, a murmur is not present. Later, a new murmur inacute bacterial endocarditis indicates a vegetation or valvular destruction.

Data from Cunha BA: MSSA/MRSA acute bacterial endocarditis (ABE): clinicalpathway 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 strainsin patients in the community, empiric treatment with an anti-MSSA or ananti-MRSA agent may be desired until the temporary or semipermanentcatheter is removed or replaced. For patients presenting with febrile neutro-penia treated with an antibiotic effective against Pseudomonas aeruginosawith good anti-MSSA activity, additional antistaphylococcal therapy isusually unnecessary. Antibiotics commonly used empirically in febrile neu-tropenia (eg, levofloxacin, meropenem) have anti-MSSA activity. In febrileneutropencia, 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 aeruginosatherapy. If fungal infection can be ruled out, a temporary or semipermanentcentral line infection should be suspected. If blood cultures are persistentlypositive (high-grade positivity) withMRSA, then anti-MRSA therapy should

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%

Vancomycin: 20%

Nafcillin: 2 days

Vancomycin: 7 days

(20% O3 days)

(12% O7 days)

Sande [110]

MSSA acute bacterial

endocarditis

Nafcillin: 1.4%–26%

Vancomycin: 37%–50%

Nafcillin: 2 days

Vancomycin: 5 days

Gentry [111]

Geraci [112]

Esposito [4]

Chang [98]

MRSA acute bacterial

endocarditis

Nafcillin: Not applicable

Vancomycin: O7 days

Small [115]

408 CUNHA

be given until the device is removed. The routine use of vancomycin in com-bination therapy with an anti-P aeruginosa antibiotic for febrile neutropeniashould be discouraged to minimize further increases in VRE prevalence andpermeability-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 monotherapyhas 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 usedto 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–relatedinfections 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)


ABE should consist of antistaphylococcal antibiotic that has a high degreeof activity against the presumed pathogen, does not cause resistance, doesnot cause the emergence of other organism (eg, VRE), and has a good safetyprofile. In the treatment of MSSA bacteremias, vancomycin has been shownto be inferior to vancomycin in terms of delayed resolution of bacteremia. IfMSSA is the pathogen in bacteremia or endocarditis, vancomycin shouldnot be used as therapy in these patients and preferably another agent shouldbe used. In penicillin-allergic patients, vancomycin is often used empiricallyto treat MSSA or MRSA bacteremias. However, there are many alternativeantibiotics 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 singleagent. Clinicians often assume there is benefit in adding a second drug forenhanced antistaphylococcal activity. It has been shown that vancomycinplus gentamicin offers no benefit in the treatment of MSSA bacteremias.Another common misconception is that the addition of rifampin or otherdrugs to vancomycin will enhance the antistaphylococcal activity of the pri-mary anti-MSSA/MRSA agent. It has been shown the rifampin is likely tobe antagonistic, not synergistic, against S aureus [110]. While rifampin hasa high degree of in vitro activity against S aureus, rifampin monotherapyshould not be used because of resistance. The practice of adding an amino-glycoside or rifampin to antistaphylococcal antibiotics has no benefit andmay 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 infectionsdue to MSSA (ie, CVC line infections, acute bacterial endocarditis, pros-thetic valve endocarditis, and so on), may be treated with antibiotics otherthan vancomycin (ie, meropenem, TMP-SMX, daptomycin). As withMSSA, there are numerous therapeutic alternatives to vancomycin for thetreatment of serious MRSA infections. Useful antibiotics to treat allMRSA types (HA-MRSA, CO-MRSA, CA-MRSA) include daptomycinlinezolid, 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. Prolongedvancomycin exposure selects out heteroresistant strains (hVISA). Thesestrains are the ones that have thickened cell walls as the result ofvancomycin exposure. Thickened cell walls are manifested as an increasein MICs and decreased cell-wall permeability to vancomycin as well as toother 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 parenteraltreatment of serious systemic infections due to MSSA, MRSA, or CoNS.Available therapeutic alternatives do not increase the prevalence of VREand do not result in cell-wall thickening and permeability-mediatedresistance. Alternative agents more quickly resolve MSSA/MRSA

410 CUNHA

bacteremias than vancomycin. The addition of gentamicin or rifampin tovancomycin does not enhance antistaphylococcal activity and may havea 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 systemicMRSA infections [1,118]. The widespread use of vancomycin over the yearshas resulted in increased prevalence of VRE in institutions worldwide. Re-cently, it has been shown that vancomycin induces cell-wall thickening amongstaphylococci, resulting in ‘‘permeability-mediated’’ resistance. To avoidthese problems associated with vancomycin, it is preferable to use otheranti-MRSA antibiotics in place of vancomycin. Fortunately, several otheranti-MRSA agents are available. Antibiotics with excellent anti-MRSA activ-ity include minocycline, linezolid, daptomycin, and tigecycline. Althoughvancomycin is available as an oral formulation for C difficile infections, it isineffective to treat systemic infections. For the parenteral treatment of serioussystemic 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) syndromeThrombocytopeniaLeukopeniaSudden deathIncreased VRE prevalenceRelated to volume of intravenous (not oral) useS. aureus infections: delayed resolution, therapeutic failures

MSSA/MRSA bacteremiasMSSA/MRSA acute bacterial endocarditis

S. aureus infections: permeability-mediated resistance(increased MICs)

Cell-wall thickening; decreased S. aureus penetration ofantibiotics (vancomycin and other anti-S aureusantibiotics)

� Not inexpensive

Box 8. Suboptimal uses of vancomycin

� Empiric treatment of central intravenous line infectionsIn locations where MSSA/GNBs > MRSA CVC pathogensRemove intravenous line as soon as possible

� Therapy of MRSA bacteremia/acute bacterial endocarditisDelayed clinical responsesTherapeutic failures

� Intraperitoneal therapy of S aureus/CoNS CAPD peritonitisIntravenous therapy achieves therapeutic concentration in

ascitic fluid. Requires another antibiotic foranti–gram-negative bacillary coverage.

� Monotherapy of VSEBacteriostatic 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 andintravenously, achieves high CSF levels when given in the usual dose (ie,600 mg intravenously or orally every 12 hours). Minocycline using the usualdose (100 mg intravenously or orally every 12 hours) also achieves therapeu-tic CSF levels. No data are available regarding treatment of CNS infectionswith 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 totreat S viridans subacute bacterial endocarditis in penicillin-allergic patients,but other agents are preferable to vancomycin for this use. Vancomycinmonotherapy is ‘‘bacteristatic’’ against VSE. Therefore, for VSE subacutebacterial endocarditis, an aminoglycoside should be added to vancomycinto achieve bactericidal anti-VSE activity alternate therapy for VSE subacutebacterial endocarditis (eg, meropenem, linezolid, or daptomycin) is available[3,32,119,120].

Aside from increased prevalence of VRE and increasing resistance amongstaphylococci, there are other reasons to avoid or minimize vancomycin use.Because vancomycin is an older drug, it is often thought of as an inexpensive

Table

Vanc ycin: clinical use and therapeutic alternatives

Clini uses Disadvantages, problems Therapeutic alternatives Advantages of alternative antibiotics

Mon erapy

� Ce l IV catheter (CVC) infections

‘‘th 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

� MR bacteremias, acute bacterial

end arditis


resistance

� Delayed therapeutic response

(persistent bacteremia)


� 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


� MR osteomyelitis � Vancomycin: often delayed

response with 30 mg/kg/d; better

results with 60 mg/kg/d


resistance

� Increased MICs during therapy


� Linezolid (600 mg

IV/orally every 12 hours)

� Minocycline (100 mgIV/

orally every 12 hours)

� Also available orally

for prolonged therapy


� MR nosocomial and

ven tor associated pneumonia

(ra

� Essential to avoid ‘‘covering’’

MSSA/MRSA respiratory

secretion colonization

� Increases permeability-mediated

resistance



every 12 hours)

� 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

412

CUNHA

4

om

cal

oth

ntra

at

SA

oc

SA

SA

tila

re)

Combination Therapy

� Vancomycin and ceftriaxone

to prevent ‘‘seeding’’ of CSF

from bacteremic S pneumoniae

(PRSP) CAP

� ‘‘Double drug’’ therapy

unnecessary. Vancomycin:

relatively low CSF concentrations

� Ceftriaxone (1–2 g IV every

12 hours)

� 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)

� Daptomycin (6 mg/kg IV

every 24 hours)


every 12 hours)

� 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 effective

in subacute bacterial endocarditis

Abbreviations: IV, intravenous; PSRP, penicillin-resistant S pneumoniae.

413

VANCOMYCIN

REVISIT

ED

414 CUNHA

antibiotic. However, because vancomycin must be administered intrave-nously, the cost of intravenous administration and monitoring must beadded to the actual cost of vancomycin use. If serum vancomycin levelsare used to guide therapy, the cost of such levels plus the cost of serial serumcreatinine levels must also be included in the actual cost of administeringparenteral vancomycin. For patients requiring long-term parenteral therapywith vancomycin, peripherally inserted central catheters (PICCs) are oftenused. The use of a PICC line to administer vancomycin increases antibioticcost because other charges related to surgical insertion, radiological verifica-tion of PICC line placement, and the cost of home intravenous agenciesmust be added to vancomycin cost. While the cost of administering paren-teral antibiotics via PICC lines for vancomycin is similar to that for otherantibiotics, most infections for which vancomycin is administered parenter-ally may be treated equally effectively with oral linezolid which is much lessexpensive (see Boxes 4 and 5, Table 4).

Summary

The reassessment of vancomycin use today is based on an evaluation ofthe 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. Cliniciansshould appreciate the limited role of vancomycin today in MRSA therapy.Clinicians should also realize vancomycin has limited activity against MSSAand VSE. Other antibiotics are preferable against MSSA and VSE. Pres-ently, clinicians should consider alternatives to vancomycin because of thenegative effects of vancomycin therapy (ie, increased VRE prevalence andincreasing 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] LouriaDB,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.


[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] NahataMC. 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] GoetzMB, 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] RybakMJ, 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] MoelleringRCJr. Pharmacokinetics of vancomycin. JAntimicrobChemother 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,HsuDI,Quist R, et al. High dose vancomycin therapy formethicillin-resistant

Staphylococcus aureus infections. Arch Intern Med 2006;166:2138–44.

[25] VonDrygalski 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.

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, LancasterM. Increasing resistance to vancomycin and other glycopep-

tides in Staphylococcus aureus. Emerg Infect Dis 2001;7:327–32.

[34] Liu C, Chambers HF. Staphylococcus aureuswith 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 bymethicillin-resistant Staphylococcus aureuswith 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, YamWC, 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.


[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, ChowM, 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, McCrackenGH 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] CrucianiM, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue.

J Antimicrob Chemother 1996;38:865–9.

[61] CrucianiM,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] ZimmermannAE,Katona BG, PlaisanceKI. 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. ClinNephrol 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] RodvoldKA,ZokufaH,Rotschafer JC.Routinemonitoring of serumvancomycin 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.

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, LandmanD, SaurinaG, 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 inmethicillin-resistantStaphylococcus 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] WootenM,MacGowanAP,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, ParkWB, LeeKD, et al. Outcome of Staphylococcus aureus bacteremia in patients

with eradicable foci versus noneradicable foci. Clin Infect Dis 2003;37:794–9.


[96] EvansM, Finch R. Approach to staphylococcal central IV line infections and bacteremias.


[97] Cunha BA. Persistent S aureus bacteremia: clinical pathway for diagnosis & treatment.


[98] ChangFY, Peacock JE Jr,MusherDM, 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 pharmacodynamicmodel with simulated endocardial vegetations. AntimicrobAgents

Chemother 2003;47:3960–3.

[118] Kirst HA, Thompson DG, Nicas TI. Historical yearly usage of vancomycin. Antimicrob

Agents Chemother 1998;42:1303–4.

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.

vancomycin revisited ccc 2008

Documents