Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by gram-negative organisms

For commonly encountered gram-negative bacilli, a MIC of cefepime of 8 mu g/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 mu g/ml. Patients infected with gram-negative organisms treated with cefepime at a MIC of >= 8 mu g/ml had a mortality rate of 54.8% (17/31 died), compared to 24.1% (351145 died) for those treated with a cefepime MIC of <8 mu g/ml. The rate of mortality for those treated with a cefepime MIC of 8 mu g/ml was 56.3% (9/16 died), compared to 53.3% (8/15 died) for those treated with cefepime at a MIC of >8 mu g/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 mu g/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 mu g/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 mu g/ml are no longer regarded as susceptible to the antibiotic.