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Efficacy and Toxicity

Levita K. Hidayat, PharmD; Donald I. Hsu, PharmD; Ryan Quist, PhD; Kimberly A. Shriner, MD; Annie Wong-Beringer, PharmD

Arch Intern Med. 2006;166:2138-2144.

Background  Vancomycin hydrochloride treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with high minimum inhibitory concentration (MIC) has prompted recent guidelines to recommend a higher vancomycin target trough of 15 to 20 µg/mL.

Methods  A prospective cohort study of adult patients infected with MRSA was performed to determine the distribution of vancomycin MIC and treatment outcomes with vancomycin doses targeting an unbound trough of at least 4 times the MIC. The microbiology laboratory computer records were used to identify all patients from whom MRSA was isolated from August 1, 2004, through June 30, 2005. Primary outcome measures were clinical response, mortality, and nephrotoxicity. Patients were placed into subgroups based on target trough attainment and high vs low vancomycin MIC (2 vs <2 µg/mL) for efficacy and high vs low trough (15 vs <15 µg/mL) for nephrotoxicity analyses.

Results  Of the 95 patients in the study, 51 (54%) were infected with high-MIC strains and had pneumonia (77%) and/or bacteremia. An initial response rate of 74% was achieved if the target trough was attained irrespective of MIC. However, despite achieving the target trough, the high-MIC group had lower end-of-treatment responses (24/39 [62%] vs 34/40 [85%]; P = .02) and higher infection-related mortality (11/51 [24%] vs 4/44 [10%]; P=.16) compared with the low-MIC group. High MIC (P = .03) and Acute Physiology and Chronic Health Evaluation II score (P = .009) were independent predictors of poor response in multivariate analysis. Nephrotoxicity occurred only in the high-trough group (11/63 [12%]), significantly predicted by concomitant therapy with other nephrotoxic agents.

Conclusions  High prevalence of clinical MRSA strains with elevated vancomycin MIC (2 µg/mL) requires aggressive empirical vancomycin dosing to achieve a trough greater than 15 µg/mL. Combination or alternative therapy should be considered for invasive infections caused by these strains.

Author Affiliations: University of Southern California, Los Angeles (Drs Hidayat and Wong-Beringer), Huntington Memorial Hospital, Pasadena (Drs Hidayat, Shriner, and Wong-Beringer), and Western University, Pomona (Drs Hsu and Quist), Calif.

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