Cefepime-aztreonam: a unique double beta-lactam combination for Pseudomonas aeruginosa

Abstract

An in vitro pharmacokinetic model was used to determine if aztreonam could enhance the pharmacodynamics of cefepime or ceftazidime against an isogenic panel of Pseudomonas aeruginosa 164, including wild-type (WT), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achieved in serum with 1- or 2-g intravenous doses, elimination pharmacokinetics were simulated, and viable bacterial counts were measured over three 8-h dosing intervals. In studies with cefepime and cefepime-aztreonam against the PD strain, samples were also filter sterilized, assayed 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 at 24 h were only 1 log below those in cefepime-treated cultures. Against PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 logs of killing by 24 h. Hydrolysis and bioassay studies demonstrated that aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular environment. In contrast to cefepime-aztreonam, the pharmacodynamics of ceftazidime-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 enhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreonam can enhance the antibacterial activity of cefepime against derepressed mutants of P. aeruginosa producing increased levels of cephalosporinase. This positive interaction appears to be due in part to the ability of aztreonam to protect cefepime from extracellular cephalosporinase inactivation. Clinical evaluation of this combination is warranted.

FIG. 1

Schematic representation of the two-compartment pharmacokinetic model. Each arrow represents a peristaltic pump within the system. Peak concentrations of antibiotic were dosed into the central reservoir and were pumped through the lumens of hollow fibers in the hollow-fiber cartridge (HFC). Pores (molecular weight limit, 30,000) in the fiber walls allowed antibiotic to diffuse freely from the lumen of the hollow fibers into the peripheral compartment of the hollow-fiber cartridge where the bacteria were inoculated. Antibiotic was eliminated from the central reservoir by the addition of drug-free broth from a diluent reservoir and elimination of drug-containing broth into the elimination reservoir. As the antibiotic concentrations in the central reservoir decreased, the antibiotic concentrations within the peripheral compartment also decreased as drug diffused into the lumens of the hollow fibers to maintain equilibrium between the two compartments.

FIG. 2

Single-dose pharmacokinetic profiles of 2.0-g (A) and 1.0-g (Panel B) intravenous doses of cefepime, ceftazidime, and aztreonam in the peripheral compartment of the IVPM after dosing peak concentrations into the central reservoir. Drug levels were measured by bioassay. Each datum point represents the mean drug level in the peripheral compartment (in micrograms per milliliter) for duplicate experimental runs. Error bars show SDs.

FIG. 3

Time-kill pharmacodynamics of 1.0-g (A and B) and 2.0-g (C) doses of cefepime (FEP), ceftazidime (CAZ), and aztreonam (ATM) alone and combinations of cefepime-aztreonam (FEP+ATM) and ceftazidime-aztreonam (CAZ+ATM) against wild-type P. aeruginosa 164 (A), PD isogenic mutant P. aeruginosa 164PD (B), and FD isogenic mutant P. aeruginosa 164FD (C). Each datum point represents the mean numbers of CFU per milliliter of MHB from the peripheral compartment for duplicate experiments. Error bars show SDs.

FIG. 3

Time-kill pharmacodynamics of 1.0-g (A and B) and 2.0-g (C) doses of cefepime (FEP), ceftazidime (CAZ), and aztreonam (ATM) alone and combinations of cefepime-aztreonam (FEP+ATM) and ceftazidime-aztreonam (CAZ+ATM) against wild-type P. aeruginosa 164 (A), PD isogenic mutant P. aeruginosa 164PD (B), and FD isogenic mutant P. aeruginosa 164FD (C). Each datum point represents the mean numbers of CFU per milliliter of MHB from the peripheral compartment for duplicate experiments. Error bars show SDs.

FIG. 4

Kinetics of extracellular cephalosporinase accumulation during the treatment of P. aeruginosa 164PD with cefepime and cefepime-aztreonam. Cephalosporinase activity was measured spectrophotometrically at 489 nm with nitrocefin as the substrate. Each datum point represents the nanomoles of nitrocefin hydrolyzed per minute per milliliter of filter-sterilized culture from the peripheral compartment. Samples removed at each time point were divided into two aliquots to measure cephalosporinase activity before and after overnight dialysis against phosphate buffer.

FIG. 5

Time-kill pharmacodynamics of 1.0- and 2.0-g doses of cefepime (FEP), ceftazidime (CAZ), and aztreonam (ATM) alone and combinations of cefepime-aztreonam (FEP+ATM) and ceftazidime-aztreonam (CAZ+ATM) against derepressed mutants P. aeruginosa 113M (A), P. aeruginosa 111M (B), P. aeruginosa GB57 (C), P. aeruginosa GB66 (D), and P. aeruginosa GB3. Each datum point represents the mean numbers of CFU per milliliter of MHB from the peripheral compartment for duplicate experiments. Error bars show SDs.

FIG. 5

Time-kill pharmacodynamics of 1.0- and 2.0-g doses of cefepime (FEP), ceftazidime (CAZ), and aztreonam (ATM) alone and combinations of cefepime-aztreonam (FEP+ATM) and ceftazidime-aztreonam (CAZ+ATM) against derepressed mutants P. aeruginosa 113M (A), P. aeruginosa 111M (B), P. aeruginosa GB57 (C), P. aeruginosa GB66 (D), and P. aeruginosa GB3. Each datum point represents the mean numbers of CFU per milliliter of MHB from the peripheral compartment for duplicate experiments. Error bars show SDs.