The impact of the pre-treatment interval on antimicrobial efficacy in a biological model.

The impact of pre-treatment intervals on the antipseudomonal efficacy of gentamicin, ticarcillin and ceftazidime was studied in an experimental thigh infection model in normal and granulocytopenic mice. Human-equivalent doses were used for simulating human pharmacokinetic profiles of the two study beta-lactam drugs. A lethal inoculum of a virulent strain of Pseudomonas aeruginosa was injected into the thigh muscle. Treatment was started at various post-infection intervals. Antimicrobial efficacy was assessed by determinations of surviving organisms at the site of infection, and plasma drug concentrations were determined in the same mice. The age of infection had a substantial impact on antipseudomonal efficacy of the three study drugs even though high, brief supra-MIC concentrations of gentamicin and persistent supra-MIC concentrations of the beta-lactam drugs were obtained. A pre-treatment interval of six or more hours abolished the bactericidal effect of all three study drugs despite accumulation of the drugs to multiple-MBC plasma concentrations. We believe that the impact of pre-treatment intervals on antimicrobial efficacy is of paramount importance for the interpretation of antimicrobial activity studies in experimental models of infection, although the mechanisms remain to be elucidated.