Pharmacodynamics of intermittent- and continuous-infusion cefepime alone and in combination with once-daily tobramycin against Pseudomonas aeruginosa in an in vitro infection model

Cefepime, a fourth-generation cephalosporin, is currently one of the primary agents used in combination with an aminoglycoside when treating Pseudomonas aeruginosa infections. The bactericidal activity of cefepime administered as intermittent doses (IT) or continuous infusion (CI) both alone and in combination with once-daily tobramycin (ODT) against two clinical strains of P. aeruginosa was compared using an in vitro infection model. Cefepime concentrations simulated human pharmacokinetics after a 1-gram Q12 regimen, or a 1-gram loading dose followed by a 2-gram Q24 CI regimen; the ODT regimen mimicked peak concentrations of greater than or equal to 10 x MIC. All regimen simulations were run in duplicate over 48 h and a growth control (no antimicrobials added) was run concurrently. Strains tested, PSA5 and PSA10, had MICs of 2 and 8 mu g/ml to cefepime, respectively; both MICs to tobramycin were 1.0 mu g/ml. CI regimens resulted in concentrations approximately 6 x and 2 x the MIC for PSA5 and PSA10, respectively. The change in log(10) colony-forming units (CFU) per milliliter over time for both P. aeruginosa isolates was compared to initial inocula for all treatment regimens. Initial bolus doses of both IT and CI regimens resulted in a similar decrease in the log(10) CFU/ml of both organisms over the first 12 h of the study. After subsequent doses, however, both IT regimens showed greatly diminished bactericidal activity, while both CI regimens were persistently bactericidal without the observation of significant regrowth. As a result, a statistical difference in log(10) CFU/ml between both IT and CI regimens with and without ODT was realized at 24, 36 and 48 h for each isolate. Unlike IT dosing, CI cefepime alone or in combination with ODT optimizes bactericidal activity by maximizing the percent of the dosing interval that concentrations remained above the MIC resulting in undiminished bacterial inhibition when compared to IT regimens. These data further suggest that CI is the most efficient method of administration of beta-lactam antibiotics.