Concentration-dependent bacterial killing, adaptive resistance and post-antibiotic effect of ciprofloxacin alone and in combination with gentamicin.

The clinical relevance of in vitro tests of antimicrobial activity, other than simple MIC and MBC observations, is increasingly recognised. Such tests include bacterial time-kill studies and post-antibiotic effect (PAE). The authors have studied these parameters in 11 Gram-negative and Gram-positive strains, all clinical isolates. Viable counts were done at 0, 2, 4, 6 and 24 h by a new microtitre method, and PAE was studied by both conventional methodology and by use of the Malthus Microbial Growth Analyser. Bacterial kill was inoculum-dependent and kill at high inocula concentration-dependent. No paradoxical reduction in kill was seen at high concentrations of ciprofloxacin (200 x MBC). PAE was concentration-dependent and addition of gentamicin can prolong PAE. Reduced sensitivity to further antibiotic exposure in the PAE period (adaptive resistance) was noticed and was dependent on antibiotic concentration in the first exposure. The significance of these findings to new dosage schemes is discussed. To optimise therapy in seriously ill patients, it may be relevant to increase the dose of ciprofloxacin currently used for treating serious infection.