Impact of netilmicin regimens on the activities of ceftazidime-netilmicin combinations against Pseudomonas aeruginosa in an in vitro pharmacokinetic model

Abstract

The antibacterial activities of ceftazidime and netilmicin were studied in a two-compartment in vitro model. Pseudomonas aeruginosa cultures were exposed to changing drug concentrations that mimic human pharmacokinetics. Netilmicin alone reduced the numbers of organisms in cultures of the susceptible strains by more than 99% within 4 h; however, regrowth occurred after 8 h. Although ceftazidime alone killed more slowly than netilmicin, only one of the five strains regrew within 28 h. When both drugs were combined, rapid initial killing occurred without subsequent regrowth. Studied after 24 h in combination with ceftazidime, netilmicin was as effective when given as a single daily dose as when administered in three daily doses that provided 50% more aminoglycoside per day. Decreased bacterial susceptibility was seen after ceftazidime exposure for one strain and after netilmicin exposure for all originally netilmicin-susceptible strains. No such reduction in susceptibility was observed during exposure to the combination. The results of standard in vitro checkerboard tests for synergism were predictive of the initial (4 to 8 h) but not the final (24 to 28 h) assessment of drug interaction in the pharmacokinetic model.