Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter

Abstract

In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

Fig 1

Forest plot (using Mantel-Haenszel [M-H] analysis) of events denoting nephrotoxicity associated with vancomycin, comparing rates for trough levels of ≥15 mg/dl and <15 mg/dl. Squares indicate point estimates, and the size of the square indicates the weight of each study.

Fig 2

Forest plot (using Mantel-Haenszel [M-H] analysis) of events denoting nephrotoxicity associated with vancomycin, comparing rates for initial trough levels of ≥15 mg/dl and <15 mg/dl. Squares indicate point estimates, and the size of the square indicates the weight of each study. All initial trough levels were obtained at the time or shortly after steady state was achieved (i.e., after the 3rd dose) and not greater than 4 days into therapy (see Table 2 for more details).

Fig 3

Incidence of vancomycin nephrotoxicity with rising trough levels (8, 22, 36, 50).

Fig 4

Forest plot (using Mantel-Haenszel [M-H] analysis) of events denoting nephrotoxicity associated with vancomycin, comparing rates for patients residing in ICU or the ward at the time of diagnosis. Squares indicate point estimates, and the size of the square indicates the weight of each study.

Fig 5

Forest plot (using Mantel-Haenszel [M-H] analysis) of events denoting nephrotoxicity associated with vancomycin, comparing rates for patients receiving and not receiving concomitant nephrotoxins at the time of diagnosis. Squares indicate point estimates, and the size of the square indicates the weight of each study. NT, nephrotoxins.