CEFEPIME-AZTREONAM - A UNIQUE DOUBLE BETA-LACTAM COMBINATION FOR PSEUDOMONAS-AERUGINOSA

An in vitro pharmacokinetic model was used to determine if aztreonam c ould enhance the pharmacodynamics of cefepime or ceftazidime against a n isogenic panel of Pseudomonas aeruginosa 164, including wild-type (W T), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achiev ed in serum with 1- or 2-g intravenous doses, elimination pharmacokine tics were simulated, and viable bacterial counts were measured over th ree 8-h dosing intervals. In studies with cefepime and cefepime-aztreo nam against the PD strain, samples were also filter sterilized, assaye d for active cefepime, and assayed for nitrocefin hydrolysis activity before and after overnight dialysis, Against WT strains, the cefepime- aztreonam combination was the most active regimen, but viable counts a t 24 h were only 1 log below those in cefepime-treated cultures. Again st PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 log s of killing by 24 h, Hydrolysis and bioassay studies demonstrated tha t aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular env ironment. In contrast to cefepime-aztreonam, the pharmacodynamics of c eftazidime-aztreonam were not enhanced over those of aztreonam alone. Further pharmacodynamic studies with five other P. aeruginosa strains producing increased levels of cephalosporinase demonstrated that the e nhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreona m can enhance the antibacterial activity of cefepime against derepress ed mutants of P. aeruginosa producing increased levels of cephalospori nase. This positive interaction appears to be due in part to the abili ty of aztreonam to protect cefepime from extracellular cephalosporinas e inactivation. Clinical evaluation of this combination is warranted.