Relevance of the inoculum effect of antibiotics in the outcome of experimental infections caused by Escherichia coli

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Abstract
The minimum dosage of antibiotics that reduced mortality in bacteraemic rats inoculated with two different Escherichia coli isolates was determined in an attempt to study the therapeutic importance of the inoculum effect. Low mortality rates (0–5%) at 48 h were obtained when antibiotics with minimal or no inoculum effect (ampicillin, cefuroxime, cefoxitin and gentamicin) were administered to yield serum levels 5 to 14 times the MIC, while antibiotics with a pronounced inoculum effect (piperacillin, cefotaxime and aztreonam) had to be administered to yield serum levels 57 to more than 1000 times the MIC determined with a standard (low) inoculum. All of the antibiotics with inoculum effect studied here are administered empirically in clinical practice at a higher dose than the microbiological and pharmacokinetic data would indicate (in order to reach peak serum concentrations exceeding the MICs of the pathogens by 4–10 times). Our experiment suggests that such high and empirical doses of antibiotics with inoculum effect may be justified.