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

Cefepime, a fourth-generation cephalosporin, is currently one of the primar y agents used in combination with an aminoglycoside when treating Pseudomon as aeruginosa infections. The bactericidal activity of cefepime administere d as intermittent doses (IT) or continuous infusion (CI) both alone and in combination with once-daily tobramycin (ODT) against two clinical strains o f P. aeruginosa was compared using an in vitro infection model. Cefepime co ncentrations simulated human pharmacokinetics after a 1-gram Q12 regimen, o r a 1-gram loading dose followed by a 2-gram Q24 CI regimen; the ODT regime n mimicked peak concentrations of greater than or equal to 10 x MIC. All re gimen 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 tobram ycin 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. aeruginos a isolates was compared to initial inocula for all treatment regimens. Init ial bolus doses of both IT and CI regimens resulted in a similar decrease i n the log(10) CFU/ml of both organisms over the first 12 h of the study. Af ter subsequent doses, however, both IT regimens showed greatly diminished b actericidal activity, while both CI regimens were persistently bactericidal without the observation of significant regrowth. As a result, a statistica l difference in log(10) CFU/ml between both IT and CI regimens with and wit hout 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 activ ity by maximizing the percent of the dosing interval that concentrations re mained above the MIC resulting in undiminished bacterial inhibition when co mpared to IT regimens. These data further suggest that CI is the most effic ient method of administration of beta-lactam antibiotics.