An experimental Klebsiella pneumoniae pneumonia in rats was used to study the influence of continuous or of intermittent (8-hr intervals) administration of ceftazidime on therapeutic efficacy. Antimicrobial response was evaluated with respect to the calculated total daily dose that protected 50% of the animals from death (PD50) until 16 days after termination of a four-day treatment. When antibiotic treatment was started 5 hr after bacterial inoculation, the PD50 values after continuous and after intermittent administration of ceftazidime were 0.36 and 1.42 mg/kg per day, respectively (P less than .001). With a delay in the administration of the antibiotic to 34 hr after inoculation, the respective PD50 values were 1.08 and 13.06 mg of ceftazidime/kg per day (P less than .001). These studies show an improved therapeutic efficacy that increased with a delay in treatment when ceftazidime was administered by continuous infusion as compared with administration at 8-hr intervals. Continuous administration of PD50 doses of ceftazidime resulted in serum levels that were constantly below the MIC of the infecting Klebsiella strain.
An experimental Streptococcus pneumoniae pneumonia was used to study the influence of continuous versus intermittent administration of penicillin G on therapeutic efficacy in normal rats and in rats whose phagocytic capacities were impaired by decomplementation with cobra venom factor. Response to antibiotic treatment was evaluated with respect to numbers of bacteria in left lung, blood and pleural fluid. Penicillin treatment was started 36 h after bacterial inoculation, and continued for four days. With intermittent intramuscular administration of penicillin normal rats were cured after daily doses of 4 mg/kg at 12 h intervals, whereas decomplemented rats recovered only after daily doses of 100 or 102 mg/kg at 12 h or 8 h intervals, respectively. When penicillin was administered by way of continuous infusion, daily doses of 3.5 mg/kg were required for a cure of infections in both normal rats and in decomplemented rats. This treatment resulted in a constant level of 0.05 micrograms of penicillin per ml, which was slightly above the minimum bactericidal concentration for the infecting strain. These findings show that maintenance of bactericidal levels of penicillin were particularly important in curing severe infection in rats with impaired defense.
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The efficacies of several dosage schedules of cefazolin, cefotaxime, and ceftazidime, started 12 or 36 h after infection, were examined in experimental pneumonia caused by Klebsiella pneumoniae in rats. The therapeutic activities of the cephalosporins were compared with the antibacterial activities in vitro and the serum concentration curves. The course of experimental pneumonia was rapid and characterized by tissue necrosis. Response to antimicrobial treatment was evaluated with respect to mortality and numbers of bacteria in lung (left lobe), blood, and pleural fluid. When antibiotic treatment was started early, i.e., 12 h after bacterial inoculation, cefotaxime and ceftazidime were equally effective and superior to cefazolin. Eleven doses of 10 mg of cefotaxime or ceftazidime per kg or 11 doses of 60 mg of cefazolin per kg were required to improve the survival rate. With a delay in administration to 36 h after inoculation, the efficacy of the cephalosporins decreased markedly. In the three dosages tested, cefazolin was ineffective. Survival improved with the administration of nine doses of 60 mg of cefotaxime per kg or nine doses of 10 mg of ceftazidime per kg. These results are not in accordance with the ratio of in vitro activities of cefotaxime and ceftazidime or the serum concentration curves.
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