Crit Care Clin 24 (2008) 393–420 Vancomycin Revisited: A Reappraisal of Clinical Use Burke A. Cunha, MD, MACPa,b,* a Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501, USA b State University of New York, School of Medicine, Stony Brook, NY, USA Over the years, vancomycin has become the mainstay of methicillin-resistant Staphylococcus aureus (MRSA) therapy. Although vancomycin 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 . 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 * Infectious Disease Division, Winthrop-University Hospital, 259 First Street, Mineola,NY 11501.0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.ccc.2007.12.012 criticalcare.theclinics.com
394 CUNHATable 1Vancomycin: clinically useful microbiologic spectrumClinically eﬀective Clinically ineﬀectiveGram-positive aerobic cocci Gram-negative aerobic cocci Staphylococci (MSSA/MRSA), Neisseria meningitidis Nonenterococcal streptococci (Groups A, B, C, G) Staphylococcus epidermidis (coagulase negative staphylococci) (MSSE/MRSE) Penicillin-resistant Streptococcus pneumoniaeGram-positive anaerobic cocci Gram-negative aerobic bacilli Peptococcus Escherichia coli Peptostreptococcus Klebsiella pneumoniae Pseudomonas aeruginosaGram-positive aerobic bacilli Gram-positive aerobic bacilli Corynebacterium sp Listeria monocytogenes Lactobacillus spGram-positive anaerobic bacilli Gram-negative anaerobic bacilli Clostridium sp Bacteroides fragilisGroup D enterococci Group D enterococci Enterococcus faecalis (VSE)a Enterococcus faecium (VRE) Abbreviations: MRSE, methicillin-resistant Staphylococcus epidermidis; MSSA, methicillin-sensitive Staphylococcus aureus; MSSE, methicillin-sensitive Staphylococcus epidermidis; VRE,vancomycin-resistant enterococci; VSE, vancomycin-sensitive enterococci. a Only when combined with an aminoglycoside (eg, gentamicin). Data from Refs. [1,3,4].decrease in renal function). In those responding to vancomycin therapy 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].
VANCOMYCIN REVISITED 395 Another negative eﬀect of vancomycin use over the years has been a rel-ative increase S aureus resistance [33–37]. Vancomycin therapy results 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) . 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 .
396 CUNHA Box 1. Vancomycin: pharmacokinetic and pharmacodynamic characteristics Pharmacokinetic parameters Usual adult dose: 1 g intravenously every 12 hours (30 mg/kg/ d); 2 g intravenously every 12 hours (60 mg/kg/d) Peak serum levels: 63 mg/mL (1-g dose); 120 mg/mL (2-g dose) Excreted unchanged (urine): 90% Serum half-life: 6 hours (normal); 180 hours (end-stage renal disease) Plasma protein binding: 55% Vd: 0.7 L/kg Therapeutic serum levels: Peak 1 g 25 mg/mL; 2g 50 mg/mL Trough: 1 g ‚ 7.5 m/mL; 2 g ‚ 15 m/mL Pharmacodynamic characteristics ‘‘Concentration dependent’’ kinetics at concentrations MIC ‘‘Concentration independent’’ kinetics (time dependent) at concentrations MIC Primary mode of elimination: renal Dosage adjustments: CrCl 50–80 mL/min: dose = 500 mg intravenously every 12 hours CrCl 10–50 mL/min: dose = 500 mg intravenously every 24 hours CrCl 10 mL/min: dose = 1 g intravenous every week Post-hemodialysis dose: none Post–‘‘high ﬂux’’ hemodialysis dose: 500 mg intravenous every 12 hours Post–peritoneal dialysis dose: none CVVH dose: 1 gm intravenous every 24 hours Data from Cunha BA, editor. Antibiotic essentials, 7th edition. Royal Oak (MI): Physicians Press; 2008; with permission. Peritoneal dialysis (PD) removes no vancomycin. Therefore, after an ini-tial 1-g intravenous dose, vancomycin should be dosed for a CrCl less 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 REVISITED 397vancomycin 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].
398 CUNHA Box 2. Vancomycin tissue concentrations* Bone concentrations Cortical bone Uninfected: w5% Infected: w10% Cancellous bone Uninfected: w5% Infected: 5% Synovial ﬂuid concentrations Uninﬂamed synovial ﬂuid: w20% Urine Concentrations Uninfected urine: 100% (normal renal function) Stool concentrations Feces: Intravenous: 0% Orally: 1000% CSF concentrations Uninﬂamed meninges: 0% (prophylaxis of CSF seeding) Inﬂamed meninges: 15% (therapy of acute bacterial meningitis) Heart concentrations Cardiac valves: 20% Lung concentrations Lung parenchyma: 10% Bile concentrations Unobstructed bile: w50% Ascitic ﬂuid concentrations Ascites: 10% * Relative to simultaneous serum levels There is often considerable delay between the time vancomycin 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
VANCOMYCIN REVISITED 399patients 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 . 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 eﬃcacyAntistaphylococcal activityStaphylococcus epidermidis The main use of parenteral vancomycin over the years has been in thetreatment 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 CUNHAactivity, 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 . 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 resistanceEnterococci 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
VANCOMYCIN REVISITED 401cross-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 usesMethicillin-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 CUNHAculture 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-grade MSSA, 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 afterCVC removal for semiquantitative catheter tip culture, another line may 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 new catheter placed over a guide wire may remain in place. 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].
VANCOMYCIN REVISITED 403 Box 3. Vancomycin: appropriate prophylactic and therapeutic uses Prophylaxis Prosthetic (orthopaedic/cardiovascular) implant surgery MSSA/MRSA infections in hemodialysis patients Subacute bacterial endocarditis for: Oral and upper respiratory tract procedures (Streptococcus viridans) (in penicillin allergic patients) Gastrointestinal and genitourinary procedures (E faecalis, VSE) procedures in patients with previous subacute bacterial endocarditis or prosthetic valve endocarditis (plus gentamicin) Therapy MRSA, CoNS CNS shunt (ventriculo-atrial, ventriculo-peritoneal) infectionsa MRSA hemodialysis catheter infectionsb Endocarditisc Streptococus viridans subacute bacterial endocarditis (in penicillin-allergic patients) CoNS prosthetic valve endocarditis due to MSSE or MRSE VSE subacute bacterial endocarditisd a Preferred therapy (eg, linezolid). b Preferred therapy (eg, daptomycin or linezolid). c Alternative therapy preferred. d Combined with gentamicin.Methicillin-sensitive Staphylococcus aureus and methicillin-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
404 CUNHA Box 4. Clinical situations in which vancomycin should be avoided Prophylaxis General surgical procedures MSSA/MRSA neurosurgical shunts MSSA/MRSA chest tubes MSSA/MRSA intravenous lines MSSA/MRSA in febrile leukopenia Therapy MRSA colonization of respiratory secretions, wounds, or urine (avoid treating colonization; treat only infection) Most serious systemic MRSA infections Preferentially use other anti-MRSA antibiotics Intravenous MRSA antibiotics: linezolid, daptomycin, tigecycline, minocycline Oral MRSA antibiotics: linezolid, minocyclineare 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].
VANCOMYCIN REVISITED 405 Box 5. Diagnostic clinical pathway: persistent S aureus (MSSA, MRSA) bacteremias Differentiate S aureus blood culture positivity (1/4 or 1/2) from bacteremia. With S aureus bacteremia, differentiate low-intensity intermittent bacteremia (1/2 or 2/4 positive blood cultures) from continuous high-intensity bacteremia (3/4–4/4 positive blood cultures). Determine the source of S aureus bacteremia. Abscesses Central intravenous lines Implanted prosthetic devices/materials Acute bacterial endocarditis Soft tissue and bone infections Review antibiotic-related factors. Determine drug dose/dosing interval. Determine MIC/MBCs. Evaluate in vivo versus in vitro effectiveness. Evaluate potential of permeability-related resistance due to vancomycin cell-wall thickening. With high-intensity continuous S aureus bacteremia, obtain a transthoracic or transesophageal echocardiogram to diagnose or rule out acute bacterial endocarditis. Data from Cunha BA. Persistent S aureus bacteremia: clinical pathway for diagnosis treatment. Antibiotics for Clinicians 2006;10(S1):39–46; with permission.Methicillin-sensitive Staphylococcus aureus and methicillin-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 paravalvular myocardial abscess. If a myocardial 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, but murmurs 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
VANCOMYCIN REVISITED 407 Box 6. Diagnostic clinical pathway: MSSA/MRSA acute bacterial endocarditis Differentiate S aureus blood culture positivity (1/2 or 1/4 positive blood cultures) from bacteremia (3/4–4/4 positive blood cultures). With S aureus bacteremia, differentiate low-intensity intermittent bacteremia (1/2 or 2/4 positive blood cultures) from continuous high-intensity bacteremia (3/4–4/4 positive blood cultures). Acute bacterial endocarditis is not a complication of low- intensity/intermittent S aureus bacteremia. TTE/TEE unnecessary, but will verify no vegetations. If continuous high-grade MSSA/MRSA bacteremia, obtain a TTE or TEE to document cardiac vegetations and/or paravalvular abscess and conﬁrm diagnosis of acute bacterial endocarditis. Diagnostic criteria for MSSA/MRSA acute bacterial endocarditis Essential features Continuous high-grade MSSA/MRSA bacteremia Cardiac vegetations on TTE/TEE No other source Nonessential features Fever ‚102 F (non-IVDAs) Cardiac murmura a With early MSSA/MRSA, a murmur is not present. Later, a new murmur in acute bacterial endocarditis indicates a vegetation or valvular destruction. Data from Cunha BA: MSSA/MRSA acute bacterial endocarditis (ABE): clinical pathway for diagnosis treatment. Antibiotics for Clinicians 2006;10(S1):29–34.chemotherapy infusion devices in these patients. Depending upon the ge-ography/epidemiology of the balance between MSSA versus MRSA 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) with MRSA, then anti-MRSA therapy should
408 CUNHATable 2Delayed resolution or failure of vancomycin therapy of MSSA or MRSA bacteremia and acutebacterial endocarditis Failure rates Duration of bacteremia ReferencesMSSA bacteremia Nafcillin: 4% Nafcillin: 2 days Sande  Vancomycin: 20% Vancomycin: 7 days (20% O3 days) (12% O7 days)MSSA acute bacterial Nafcillin: 1.4%–26% Nafcillin: 2 days Gentry  endocarditis Vancomycin: 37%–50% Vancomycin: 5 days Geraci  Esposito  Chang MRSA acute bacterial Nafcillin: Not applicable Small  endocarditis Vancomycin: O7 daysbe 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 forTable 3Combination therapy for MSSA and MRSA acute bacterial endocarditisAntibiotic combinations Comments ReferencesMSSA acute bacterial endocarditis Nafcillin þ gentamicin Outcomes same without gentamicin Cha  Vancomycin þ gentamicin Lee MRSA acute bacterial endocarditis Vancomycin Duration of bacteremia: 7 days Levine  Vancomycin þ rifampin Duration of bacteremia: 9 days Shelburne  (antagonistic; not synergistic)
VANCOMYCIN REVISITED 409ABE 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 . 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 CUNHAbacteremias 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) 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
VANCOMYCIN REVISITED 411 Box 8. Suboptimal uses of vancomycin Empiric treatment of central intravenous line infections In locations where MSSA/GNBs MRSA CVC pathogens Remove intravenous line as soon as possible Therapy of MRSA bacteremia/acute bacterial endocarditis Delayed clinical responses Therapeutic failures Intraperitoneal therapy of S aureus/CoNS CAPD peritonitis Intravenous therapy achieves therapeutic concentration in ascitic ﬂuid. Requires another antibiotic for anti–gram-negative bacillary coverage. Monotherapy of VSE Bacteriostatic if monotherapy used. Adequate anti-VSE activity only if given with an aminoglycoside (eg, gentamicin) S aureus chronic osteomyelitis Prevention of S pneumoniae CSF ‘‘seeding’’ (2 to CAP pneumococcal bacteremia) Unnecessary when using antibiotics that achieve therapeutic CSF concentrations (eg, ceftriaxone) Data from Cunha BA, editor. Infections in critical care medicine. 2nd edition. New York: Informa Health Care USA, Inc.; 2007. For the therapy of gram-positive CNS infections, other agents are phar-macokinetically preferable to vancomycin. Linezolid, available orally 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
412Table 4Vancomycin: clinical use and therapeutic alternativesClinical uses Disadvantages, problems Therapeutic alternatives Advantages of alternative antibioticsMonotherapy Central IV catheter (CVC) infections Increased VRE prevalence Removal of CVC High-degree MRSA activity ‘‘that may be due to MRSA’’ Increased permeability-mediated Daptomycin (6 mg/kg IV Also covers MSSA, VSE resistance every 24 hours) No increased resistance/VRE MIC ‘‘drift’’ Linezolid (600 mg IV every 12 hours) MRSA bacteremias, acute bacterial Increased permeability-mediated Daptomycin (6–12 mg/kg Most rapidly bactericidal MRSA endocarditis resistance IV every 24 hours) antibiotic Delayed therapeutic response Eﬀective in vancomycin CUNHA (persistent bacteremia) ‘‘treatment failures’’ MIC ‘‘drift’’ Linezolid (600 mg Also available orally IV every 12 hours) for prolonged therapy No increased resistance/VRE MRSA osteomyelitis Vancomycin: often delayed Linezolid (600 mg Also available orally response with 30 mg/kg/d; better IV/orally every 12 hours) for prolonged therapy results with 60 mg/kg/d Minocycline (100 mgIV/ No increased resistance/VRE Increased permeability-mediated orally every 12 hours) Inexpensive and also available resistance orally for prolonged therapy. Increased MICs during therapy MIC ‘‘drift’’ MRSA nosocomial and Essential to avoid ‘‘covering’’ Linezolid (600 mg IV Eﬀective in rare cases of bona ventilator associated pneumonia MSSA/MRSA respiratory every 12 hours) ﬁde MRSA nosocomial (rare) secretion colonization pneumonia and ventilator- Increases permeability-mediated associated pneumonia resistance Therapeutic parenchymal lung MIC ‘‘drift’’ concentrations
Combination Therapy Vancomycin and ceftriaxone ‘‘Double drug’’ therapy Ceftriaxone (1–2 g IV every Good CSF penetration prevents to prevent ‘‘seeding’’ of CSF unnecessary. Vancomycin: 12 hours) PRSP ‘‘seeding’’ of CSF from bacteremic S pneumoniae relatively low CSF concentrations Ceftriaxone monotherapy provides (PRSP) CAP adequate CSF concentrations if PRSP seeding of CSF Vancomycin plus gentamicin therapy Vancomycin alone ‘‘bacteriostatic’’ Daptomycin (6 mg/kg IV MICs for VSE/VRE greater than of E faecalis (VSE) subacute bacterial against VSE every 24 hours) those for MSSA/MRSA endocarditis Vancomycin bactericidal only Use 12 mg/kg IV every 24 hours when combined with an for VSE endocarditis aminoglycoside (eg, gentamicin) Linezolid (600 mg IV Available orally for prolonged every 12 hours) therapy of VSE subacute bacterial endocarditis VANCOMYCIN REVISITED Bacteriostatic but eﬀective in subacute bacterial endocarditis Abbreviations: IV, intravenous; PSRP, penicillin-resistant S pneumoniae. 413
414 CUNHAantibiotic. 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  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.  Louria DB, Kaminski T, Buchman J. Vancomycin in severe staphylococcal infections. Arch Intern Med 1961;107:225–40.  Cunha BA. Vancomycin. Med Clin North Am 1995;79:817–31.  Esposito AL, Gleckman RA. Vancomcyin: a second look. JAMA 1977;238:1756–7.  Menzies D, Goel K, Cunha BA. Vancomycin. Antibiotics for Clinicians 1998;2:97–9.
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