Correlation of in vitro activity and pharmacokinetic parameters with effect in vivo for antibiotics. Observations from experimental pneumococcus infection.

The correlation between in vitro activity, pharmacokinetic properties and effect in vivo of antibiotics has so far received relatively little attention, and the optimal dosing strategy for most antibiotics is still a matter of dispute. A review on this subject is presented based on observations from an experimental pneumococcus infection model in mice. The pneumococcus is particularly suitable as pathogen in experimental infection models for antibiotic research, since it is clinically relevant, susceptible to a range of antibiotics, and naturally virulent to most laboratory animals without the need for potentiating factors. The course of pneumococcus infection in animals is discussed in detail, including the parameters for measuring antibiotic effect in vivo. In screening models the most simple and relevant parameter is survival/death of the animal, which is usually incorporated in the determination of a 50% endpoint, e.g. the ED50 (50% effective dose). Among the variety of factors of potential influence upon the ED50, the importance of the bacterial growth kinetics in vivo is emphasized. Considering the correlation of pharmacokinetic properties with effect in vivo three parameters are considered important: The peak antibiotic concentration, the area under the drug concentration curve (AUC), and the time the antibiotic concentration remains above the minimal inhibitory concentration (time greater than MIC). For the beta-lactam antibiotics evidence is accumulating that the time greater than MIC is the most important. Comparing 14 cephalosporins in the mouse-protection test with intraperitoneal inoculation of a pneumococcus type 3, the time greater than MIC calculated from the pharmacokinetic profiles of a 5 mg/mouse dose for all the 14 cephalosporins showed a high correlation with the ED50. When studying the serum antibiotic concentrations at doses similar to the ED50's for various cephalosporins and penicillins, the time greater than MIC was the parameter that varied the least. Neither the peak drug concentrations nor the AUC's showed any correlation with effect in vivo. The role of the time greater than MIC in context with other factors such as extravascular penetration of antibiotics, serum protein binding and the post-antibiotic effect is discussed. Most other experimental studies concerning dosing strategy for the beta-lactam antibiotics, including the few clinical studies available, confirm the importance of the time factor. The clinical implication for this group of antibiotics therefore is to strive for a constant, not necessarily high, concentration above the MIC.(ABSTRACT TRUNCATED AT 400 WORDS)