A new approach to optimal antibiotic dosage regimen by coupling pharmacokinetics and killing curve parameters

Antibiotic therapy is directed against bacteria responsible for infectious pathology which are able to resist treatment mainly when the dosage is misadapted. The choice of the initial dosage regimen actually takes into account toxicological, bacteriological and pharmacokinetic parameters. The determination of the classical bacteriological data is performed in vitro using fixed drug concentrations that are far from human therapy conditions, and moreover the efficiency is not well defined. The estimation of the pharmacokinetic parameters is realized in animals, healthy subjects or ill patients but takes into account only the drug disposition without correspondence with the kinetics of the antibiotic effect on the bacteria. Thus, each type of evaluation is made independently from the others without any correlation between the observed phenomena. It appears, therefore, interesting to propose a new approach including pharmacokinetic and bacteriological data to enable approximation of drug efficacy. The coupled evaluation of individual pharmacokinetic estimation and the killing curve determinations of an antibiotic will allow this type of development. On the basis of these data, a preliminary profile of the optimal dosage would be possible. This methodology has been applied to three antibiotics: teicoplanin, amikacin and ofloxacin and demonstrates a time- or dose-dependent activity, with interesting possibilities for optimization of dosage.