Basis of anti-infective therapy: pharmacokinetic-pharmacodynamic criteria and methodology for dual dosage individualisation

Abstract

Antimicrobial therapy should be designed on the basis of microbiological, as well as pharmacokinetic, criteria; microbiological parameters provide information about the susceptibility of the pathogen responsible for the infectious process while pharmacokinetic parameters give information about the potential ability of the drug in question to reach and remain at the sites of infection in the body. Microbiological parameters such as the minimum inhibitory concentration, minimum bactericidal concentration, bacterial titre, bactericidal rate and 'post-antibiotic effect' (PAE) must be considered. Among the pharmacokinetic parameters, the maximum serum concentration at steady state (CmaxSS), area under the concentration-time curve (AUC) and length of time that the serum concentrations exceed a particular value are the most useful in this context. Different relationships between these parameters, known as efficacy indices, have been established to predict the potential efficacy of antibacterial therapy. Antimicrobial dosage individualisation should be based on the optimisation of the efficacy index that best correlates with patient response. It seems appropriate to establish the degree of correlation among the different efficacy indices and clinical response observed in patients by means of a correlation analysis. This type of analysis can be either retrospective or prospective and may be based on linear or maximum response models. Simulation of the plasma concentration curves obtained with the particular regimen administered offers a methodology which is easy to apply and provides the pharmacokinetic information necessary to calculate the different efficacy indices. Information about the susceptibility of the pathogen to the antibacterial in question and about the response to the treatment used is also necessary for the correlation analysis. This type of analysis determines which of the indices is best correlated with efficacy and, hence, is the index to be optimised when attempting to individualise antibacterial therapy for different situations.