Streptococcus pneumoniae pneumonia in mice: Optimal amoxicillin dosing predicted from a pharmacokinetic pharmacodynamic model

In an attempt to better understand the interaction of amoxicillin with Stre ptococcus pneumoniae in the lung, and to determine the parameters of therap eutic efficacy of the antimicrobial agent amoxicillin, we used a pharmacoki netic-pharmacodynamic model to describe the overall dose-effect relationshi p of amoxicillin against 12 strains of S. pneumoniae with penicillin minimu m inhibitory concentrations ranging from <0.01 to 16 mu g/ml in a neutropen ic murine pneumonia model. We were able to correlate amoxicillin dosing, ph armacokinetics, and the temporal changes in bacterial count in lung. Moreov er, survival rates measured in one strain at different dosing were signific antly related to the number of bacteria in lung calculated from the pharmac okinetic-pharmacodynamic model. Disappearance of amoxicillin from the effec t compartment appeared to be very slow and the rate constant (k(e0)) govern ing this process was significantly different between strains, ranging from 0.00131 to 0.03945 h(-1). These findings have two major implications: 1) af ter a single dose of amoxicillin, bacterial counts in lung rapidly decrease d and the bacterial growth remained suppressed during a long period of time after cessation of exposure of microorganisms to amoxicillin; and 2) the d uration of bacterial growth suppression was related to the intrinsic proper ties of S. pneumoniae strains rather than to host environment because k(e0) was significantly different between strains. These two premises clearly de monstrate that bacterial growth suppression is related to an in vivo postan tibiotic effect. Furthermore, we have shown that the major determinant of a moxicillin in vivo bactericidal activity and therapeutic efficacy appeared to be the dose of amoxicillin because amoxicillin exhibits a rapid dose-dep endent killing regardless of the S. pneumoniae strain. Our findings may hav e implications for the clinical use of amoxicillin. In view of our results, the guidance to increase the amoxicillin-loading dose in pneumococcal pneu monia appears to be immediately clinically relevant.