ABSTRACT
The impact of the dosage schedule on the therapeutic efficacy of antibiotics was investigated in experimental Klebsiella pneumoniae pneumonia and septicemia in leukopenic rats. The daily doses (mg/kg) that protected 50% of the animals from death, when calculated for administration at 6 h intervals or by continuous infusion, were as follows: ceftazidime 24.4 and 1.5 (p less than 0.001), gentamicin 2.8 and 3.8 (p greater than 0.05), and ciprofloxacin 3.3 and 6.5 (p less than 0.05), respectively. This correlates with the observation that ceftazidime killed Klebsiella pneumoniae slowly but constantly, and relatively independently of concentration, whereas killing by gentamicin or ciprofloxacin was rapid, and markedly dependent on antibiotic concentration. Exposure of bacteria for 1 h to concentrations of fivefold the MBC did not give rise to a postantibiotic effect for any of the drugs. In our model ceftazidime was far more effective when given continuously than when administered at 6 h intervals. On the other hand, the activity of gentamicin was not influenced by the mode of administration, whereas ciprofloxacin was slightly more effective when given intermittently. However, to avoid misleading conclusions regarding the use of antibiotics in humans, the pharmacokinetic differences between rats and man must be considered when interpreting these results.
