Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy

The recent emergence of meticillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin has prompted clinicians to prescribe vancomycin therapy targeting high trough concentrations (15-20 mg/L). Relevant studies (n=12) analysing the occurrence of nephrotoxicity with high-dose therapy were reviewed. Most studies were retrospective and the temporal relationship between elevated trough levels and development of nephrotoxicity was unclear, precluding a definitive cause-effect analysis. Available data suggest an association between vancomycin trough level and risk of nephrotoxicity as a function of intensity and duration of therapy (>7 days), compounded by concomitant receipt of nephrotoxins, vasopressor therapy and underlying physiological impairment. In separate studies in which a high trough concentration was measured prior to the onset of nephrotoxicity, the frequency of occurrence was 21-28% in patients with concomitant risks compared with 7% in patients without risks. A similar comparison between risk and no-risk groups who attained a standard trough concentration (10-15 mg/L) indicates the rates of occurrence as 9-21% vs. 2%. Onset of nephrotoxicity ranged from 4 days to 8 days from the start of therapy. The degree of renal dysfunction was modest, with a reported decrease of 35-45% in creatinine clearance from baseline. Resolution occurred in >70% of patients by the time of discharge. Future studies should detail clearly the temporal relationship between drug exposure and onset of nephrotoxicity, confounding risk factors, extent of injury and time course of recovery, and should also determine the relative risk versus benefit of high-dose vancomycin versus alternative agents.