Comprehensive evaluation of ciprofloxacin in combination with beta-lactam antibiotics against Enterobacteriaceae and Pseudomonas aeruginosa

Abstract

1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazine-1-ylquinoline-3-carboxylic acid (ciprofloxacin, Bay o-9867, Bay q-3939) was evaluated by checkerboard assay in combination with ampicillin, ticarcillin, mezlocillin, azlocillin, piperacillin, cefamandole, cefoxitin, cefotaxime, and ceftazidime. A total of 220 clinical isolates of enterobacteriaceae and Pseudomonas aeruginosa (11 species, 20 strains each) were examined. Predominantly additive combination effects were seen with all antibiotic combinations tested. Synergy was obtained with only a few test strains while antagonistic drug interactions were not observed at all. Time-kill experiments which were performed to assess the bactericidal activities, confirmed these findings. The antibiotic combinations were also evaluated in vivo using a model of experimental thigh muscle infection in neutropenic mice. In-difference or additive therapeutic effects resulted when the beta-lactam compounds and ciprofloxacin were given in combination at doses which were also effective alone. Subinhibitory doses of azlocillin and mezlocillin, on the other hand, appeared to increase the efficacy of ciprofloxacin. The influence of various application schedules was examined by time-kill experiments and in mice. Sequential administration of the drugs at intervals of 2 h did not alter the combination effects regardless of the sequence of administration.