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The diminishing value of vancomycin
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In the past 20 years, the widespread utilization of vancomycin — a great deal of which was empiric and unwarranted — has led to changes in the antimicrobial susceptibility and, in some cases, the development of resistant Staphylococcus aureus, both of which have been associated with clinical treatment failures.
We have witnessed elevations in the minimum inhibitory concentration of vancomycin for MRSA, as well as the emergence of heterogeneous (or heteroresistant) vancomycin-intermediate S. aureus (hVISA) containing subpopulations of vancomycin-intermediate S. aureus (VISA). Under the selective pressure of vancomycin administration, the VISA phenotypes are favored, eventually becoming the uniform population in that specific clinical setting. Because detection of hVISA is problematic for most clinical microbiology laboratories, this phenomenon often goes unnoticed. Furthermore, strains of fully vancomycin-resistant S. aureus (VRSA) have been identified, albeit rarely.
Lack of comparison trials
Other antimicrobial agents possessing anti-MRSA activity have been approved over the years: dalfopristin/quinupristin (Synercid, Pfizer Laboratories), linezolid (Zyvox, Pharmacia & Upjohn) — and soon tedizolid (Sivextro, Cubist Pharmaceuticals), daptomycin (Cubicin, Cubist Pharmaceuticals), tigecycline (Tygacil, Wyeth Pharmaceuticals), telavancin (Vibativ, Theravance), dalbavancin (Dalvance, Durata Therapeutics), ceftaroline (Teflaro, Forest Laboratories) and oritavancin (Orbactiv, The Medicines Company). Unfortunately, only daptomycin vs. vancomycin for S. aureus bacteremia and endocarditis, and linezolid vs. vancomycin for MRSA pneumonia, have been compared with vancomycin in clinical trials for the treatment of any condition other than acute bacterial skin and skin-structure infections.
Larry Bush
Donald Kaye
Assigning the status “S” (sensitive), based upon the breakpoint of less than 2 mcg/mL chosen by the Clinical and Laboratory Standards Institute (CLSI) for vancomycin vs. MRSA isolates and suggesting that in such instances vancomycin is an appropriate antimicrobial choice for serious infections, clearly fails to appreciate the pharmacokinetics and pharmacodynamics of vancomycin.
Vancomycin has never demonstrated equivalency to beta-lactam agents and was proved inferior to beta-lactams in treating methicillin-sensitive S. aureus bacteremia. Although no randomized clinical trial designed to treat MRSA infections has found another antibiotic superior to vancomycin, the ability to demonstrate superiority in either arm may have been hampered by protocol design and the inherent flaws and pitfalls associated with noninferiority trials. Nonetheless, many published investigations have looked at the consequence of elevated vancomycin MICs (>1.5 mcg/mL), most of which were able to demonstrate a link between high vancomycin-MIC MRSA infections and poorer outcomes, whether defined as persistence of bacteremia, recurrence of infection or increased overall mortality.
A place for vancomycin
What noticeably stands out is that in not one meta-analysis does vancomycin appear to perform better than the compared MRSA agent but has almost always been found to be an inferior treatment choice (to the point of achieving statistical significance in some studies). Acknowledging that genotypic features of both MSSA and MRSA associated with high vancomycin MICs may account for the suboptimal outcomes observed in patients harboring such strains of S. aureus, the negative effect of higher vancomycin MIC values on the in vivo pharmacodynamic performance of this antibiotic certainly should not be underestimated. Achievement of the agreed-upon pharmacodynamic parameter (ie, ratio of the area under the concentration/time curve to MIC [AUC/MIC] >400) deemed adequate for necessary bactericidal activity occurs less than 50% of the time when the MRSA vancomycin MIC value is 1.5 mcg/mL, and is barely attainable when the MIC is 2 mcg/mL.
Furthermore, current automated susceptibility testing methods relied upon by most clinical microbiology laboratories do not accurately reflect the higher MICs produced when methods considered the reference standards, such as broth microdilution and E test, are applied to the same specimen. Additionally, targeting higher serum trough vancomycin levels (15-20 mcg/mL) may still not allow for reaching the optimal pharmacodynamic goal and has proved to carry with it a higher probability of drug-induced nephrotoxicity. Based on this understanding of pharmacokinetics/pharmacodynamics and the principles of in vitro studies, it would seem justified that the CLSI should lower the vancomycin breakpoint for MRSA to 1 mcg/mL or less, in similar fashion to their revision of breakpoints (susceptible now equal to 1 mcg/mL or less) for Enterobacteriaceae and cephalosporins in the absence of any new clinical trial data.
In the only published clinical trial comparing any new anti-MRSA agent to vancomycin or a semisynthetic penicillin for the treatment of S. aureus bacteremia and endocarditis (a more vigorous test of antimicrobial efficacy), daptomycin was equally effective in the treatment of patients with endocarditis caused by MSSA or MRSA, but had numerically higher success rates than vancomycin when MRSA was the pathogen. In an evaluation subsequent to that published study, the lack of daptomycin superiority over vancomycin may have been influenced by the fact that all strains in the vancomycin arm had MICs of 1 mcg/mL or less. Interestingly, clinical practice guidelines from the Infectious Diseases Society of America for the treatment of MRSA infections has assigned a strength of recommendation and quality of evidence score of A-I to daptomycin and A-II to vancomycin for such infections.
In our opinion, because of all of the above issues, when faced with a MRSA infection having a vancomycin MIC of greater than 1 mcg/mL, the clinician should consider using an alternative antibiotic to consistently arrive at the desired AUC/MIC 400 or greater, as this goal may be difficult to achieve when the concentration of vancomycin necessary to inhibit these strains of MRSA is greater than 1 mcg/mL.
Cost of new agents
Understandably, the higher cost of the newer anti-MRSA antimicrobial agents dissuades their use, especially when none have proved to be superior to vancomycin. Even so, with all available data and a firm understanding of pharmacodynamic principles in relation to antimicrobial therapy, it is doubtful that a clinician without knowing the price of the antibiotic would favor vancomycin over newer alternative agents when treating a serious infection involving MRSA with a reported MIC greater than 1 mcg/mL.
The diminished reliability of vancomycin MRSA activity, ongoing concern with toxicity, inconvenient dosing and administration, and decline in clinical efficacy, together with options of other equally, if not more effective, anti-MRSA antimicrobial agents has served to tarnish vancomycin, perhaps to the point of near retirement.
Regardless of differences in opinion of the value of vancomycin, it is clear that the empiric use of vancomycin should be restricted to appropriate clinical settings and should be discontinued after there is no longer an empiric indication (ie, antibiotic stewardship).
Kim SH. Antimicrob Agents Chemother. 2008;52:192-197.
Rehm SJ. J Antimicrob Chemother. 2008;62:1413-1421.
Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and is an Infectious Disease News Editorial Board member.
Disclosure: Bush and Kaye report no relevant financial disclosures.