The Nephrotoxicity of Vancomycin

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Vancomycin is the drug of choice for methicillin‐resistant Staphylococcus aureus (MRSA)1 but has been associated with significant nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible. Herein, we critically examine relevant available data in adult patients. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism and discuss efficacy and safety data. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for acute kidney injury (AKI) development are enumerated, and suggestions for practice and further research are given.
Vancomycin has been plagued with concerns about nephrotoxicity since its approval in 1958. Initial preparations were termed “Mississippi mud” and had significant impurities considered the major reason for the nephrotoxicity. Through improved purification procedures, current preparations contain ∼90–95% vancomycin B (the active moiety). The rate of nephrotoxicity with use of modern preparations varies in the literature, with the incidence ranging from as low as 0% in the absence of concurrent nephrotoxins to over 40%.2 Unfortunately, the majority of studies assessing nephrotoxicity are retrospective, often lacking a control group, and are typically subject to confounding by indication and other biases, as many of the patients are critically ill and have other potential reasons for kidney injury.
Numerous potential risk factors for development of AKI while receiving parenteral vancomycin therapy have been ascertained. Some factors are directly related to vancomycin exposure, such as total daily dose, duration of therapy, method of administration, trough level, and area under the concentration vs. time (AUC) curve. Others are patient‐related, including obesity, preexisting kidney disease, severity of illness, and receipt of concurrent nephrotoxins.
Overall, there is only moderate quality evidence linking vancomycin to renal injury. Sinha Ray et al. performed a systematic review and meta‐analysis restricted only to randomized controlled trials (RCTs) and cohort studies that compared vancomycin to another nonglycopeptide antibiotic. Seven RCTs (six compared to linezolid, one to ceftaroline) and six cohort studies (all compared to linezolid) were included, suggesting a small risk for AKI.3 The relative risk for AKI in the RCTs was 2.45 (P < 0.001), but none were considered at low risk for bias. Only two of six cohort studies showed significantly worse renal outcomes with vancomycin, and all studies were of moderate or high risk for bias. The strength of causal association was weakened, as kidney injury was neither a primary endpoint nor a prespecified secondary outcome in any of the trials.
By contrast, a safety analysis of an RCT comparing daptomycin with either vancomycin plus gentamicin or an antistaphylococcal penicillin plus gentamicin showed a similar rate of a clinically significant decrease in creatinine clearance with vancomycin (10 of 46, 22%) compared to penicillin (16 of 63, 25%).4 Both of these groups together, however, had a significantly higher rate than the daptomycin arm, an outcome ascribed to concurrent gentamicin. Carreno et al. reported an RCT of 100 at‐risk patients initially prescribed vancomycin in which 51 patients were randomized to continue vancomycin and 49 to receive alternative therapy.5 No difference in nephrotoxicity was found. Furthermore, it has been repeatedly reported that patients with nephrotoxicity associated with vancomycin use may have improvement of kidney function despite continuation of vancomycin.6 Hence, equipoise remains.
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