Pharmacodynamic (kinetic) considerations in the treatment of moderately severe infections with cefotaxime

Information about the pharmacodynamics of beta-lactams has accumulated rapidly over the last 20 years, and their application to cefotaxime are discussed in this review. Application of pharmacodynamics requires an integration of the pharmacokinetic and in vitro properties of the agent. Cefotaxime is similar to other beta-lactams in that it has little concentration-dependent killing and produces no postantibiotic effect against Gram-negative bacteria. However, it has a microbiologically active metabolite, deascetylcefotaxime, which can show synergy, partial synergy, or an additive effect in combination with the parent drug. More than any other technique, animal models have been able to elucidate the pharmacokinetic parameters that predict efficacy in vivo. They have shown that for beta-lactams it is the time that levels exceed the minimum inhibitory concentration (MIC) that is the most important determinant of efficacy. For bacteria to have no postantibiotic effect, plasma levels need to exceed the MIC for the whole of the dosing interval to achieve maximum killing at the site of infection. When applying these concepts as the most stringent criteria for efficacy using pharmacokinetic values from young, healthy volunteers, it can be shown that organisms with MICs of < or = 0.03 microgram/ml for a 1-g dose and 0.06 microgram/ml for a 2-g dose to achieve optimum efficacy with 12-h dosing of cefotaxime. However, two clinical studies have demonstrated trough levels much greater than would be predicted from these pharmacokinetic values, as a result of the effects of decreased renal function accompanying sepsis and older age. These studies showed that organisms with MICs < or = 1 microgram/ml for a 1-g dose or 2 micrograms/ml for a 2-g 12-h dose were covered for the whole of the dosing interval. Thus, all strains of Enterobacteriaceae and pathogenic Neisseria spp. that lack resistance mechanisms to third-generation cephalosporins would be covered using 12-h dosing schedules.