[New development in clinical pharmacology of anti-infective agents]

MORE RAPID DRUG DEVELOPMENT: Great advances have been made in the clinical pharmacology of anti-infectives. Good "candidates" are selected after a series of pharmacokinetic and pharmacodynamic explorations. One of the objectives of pharmacodynamic studies is to accelerate drug development, mandatory due to the considerable cost of pharmaceutical research, preclinical microbiology and toxicology studies, and inevitable failures in the preliminary stages. The search for new compounds has taken advantage of new rapid techniques such as micro-organism screening, accelerated chemical synthesis, and combinatory chemistry in our era of genomic biology. FROM ANIMAL MODELS TO MAN: After the initial microbiology studies, animal testing is an indispensable prerequisite for preselecting a compound for development. Pharmacokinetic/pharmacodynamic properties (PK/PD) establish correlations between in vitro tests and efficacy in experimental models of infection. They define the bactericidal power, the correlation between in vivo concentration and the MIC, and indicate whether the agent is time- or concentration-dependent. The relationships between PK/PD parameters and bacterial resistance are also analyzed. INTRACELLULAR PK/PD: As many new anti-infectives are targeted against the large number of facultative or obligatory intracellular bacterial species, intracellular parameters are also studied at this stage to determine the compound's intracellular affinity. The degree of intracellular accumulation, subcellular localization, intracellular kinetics and efflux must be studied. Intracellular pharmacodynamics depend on a number of well-explored mechanisms expressed by the antibiotic's bioactivity in the intracellular medium.