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Failure of Current Cefepime Breakpoints To Predict Clinical Outcomes of Bacteremia Caused by Gram-Negative Organisms

Division of Infectious Diseases, University of Pittsburgh Medical Center, Suite 3A Falk Medical Building, 3601 Fifth Avenue, Pittsburgh, Pennsylvania 15213,¹ Beth Israel Deaconess Medical Center, Boston, Massachusetts,² Albany Medical Center, Albany, New York,³ University of Queensland, Royal Brisbane & Women's Hospital, Brisbane, Australia⁴

Received 26 November 2006/ Returned for modification 27 December 2006/ Accepted 2 July 2007

For commonly encountered gram-negative bacilli, a MIC of cefepime of 8 µg/ml or less was defined by the Clinical and Laboratory Standards Institute as "susceptible" prior to the commercial release of the antibiotic. We assessed 204 episodes of bacteremia caused by gram-negative organisms for which patients received cefepime (typically 1 to 2 g every 12 h) as the primary mode of therapy. The cefepime MIC breakpoint derived by classification and regression tree (CART) software analysis to delineate the risk of 28-day mortality was 8 µg/ml. Patients infected with gram-negative organisms treated with cefepime at a MIC of 8 µg/ml had a mortality rate of 54.8% (17/31 died), compared to 24.1% (35/145 died) for those treated with a cefepime MIC of <8 µg/ml. The rate of mortality for those treated with a cefepime MIC of 8 µg/ml was 56.3% (9/16 died), compared to 53.3% (8/15 died) for those treated with cefepime at a MIC of >8 µg/ml. A multivariable analysis including severity of illness indices showed that treating patients with bacteremia due to gram-negative organisms with a cefepime MIC of 8 µg/ml was an independent predictor of mortality (P 0.001). There was no significant difference in outcome according to the dosage regimen utilized. Pharmacodynamic assessments that were presented previously would suggest that cefepime treatment (particularly a dosage of 1 g every 12 h) has a low probability of target attainment associated with successful in vivo outcome when the cefepime MIC is 8 µg/ml. It would appear reasonable, based on pharmacodynamic and clinical grounds, to lower the breakpoints for cefepime in countries where the cefepime dosage of 1 to 2 g every 12 h is the licensed therapy for serious infections, so that organisms with a cefepime MIC of 8 µg/ml are no longer regarded as susceptible to the antibiotic.

Published ahead of print on 15 October 2007.