Pharmacokinetics and antibacterial efficacy in vivo of beta-lactam combinations against Proteus vulgaris.

The pharmacokinetics and antibacterial efficacy of mezlocillin, cefotaxime, cefoperazone and the mezlocillin/cefalosporin combinations, respectively, were studied by adopting the granuloma pouch model in rats. Exudate concentrations of mezlocillin were higher after combined i.v. injection with a cefalosporin as determined microbiologically and by high performance liquid chromatography (HPLC). Cefoperazone levels, however, were not affected. Not metabolized cefotaxime concentrations as determined by HPLC were also not increased following simultaneous injection with mezlocillin. Cefotaxime metabolite concentrations, however, were generally higher than unchanged cefotaxime and increased upon repeated administration of cefotaxime alone and to a greater extent when combined with mezlocillin. Antibacterial efficacy of mono- or combined chemotherapy was correlated to beta-lactamase inducibility of the test strains insofar as drugs acting as good or moderate enzyme inducers were ineffective in vivo. The combined therapy of mezlocillin with cefotaxime was effective in this case. This result was also correlated to the bioavailability of the beta-lactams in infected pouches. Due to the degree of beta-lactamase inducibility and production, drug levels were either decreased or not detectable.

Kinetic in vitro studies of antibacterial effects of the combination of new penicillins and cefalosporins against Proteus vulgaris.

In vitro studies simulating human as well as animal pharmacokinetics were performed in order to assess the combination effect of mezlocillin plus cefotaxime or cefoperazone. Different Proteus vulgaris strains exhibiting varying degrees of in vivo response to the antibiotics were selected for this study. Retardation of bactericidal efficacy was caused by the combination of mezlocillin plus cefoperazone in those strains exhibiting high degrees of beta-lactamase inducibility and being exposed to high levels of cefoperazone; lower drug levels caused indifferent effects. In any case, cultures were completely sterilized during the study period. Among the three beta-lactams studied, cefoperazone was the best beta-lactase inducer, while cefotaxime and mezlocillin exhibited only minor inducer activity. The combination of mezlocillin with cefotaxime, being only minimally active as beta-lactamase inducers, caused either indifferent or synergistic effects when simulating drug disposition in humans or animals. beta-Lactamase-negative strains exhibited only indifferent effects. The augmented bioavailability of mezlocillin due to its simultaneous administration with a cefalosporin resulted in an increased antibacterial efficacy.