In an attempt to better understand the interaction of
amoxicillin with Streptococcus pneumoniae in the lung, and to determine the parameters of therapeutic efficacy of the
antimicrobial agent amoxicillin, we used a pharmacokinetic-pharmacodynamic model to describe the overall dose-effect relationship of
amoxicillin against 12 strains of S. pneumoniae with
penicillin minimum inhibitory concentrations ranging from <0.01 to 16 microg/ml in a neutropenic murine
pneumonia model. We were able to correlate
amoxicillin dosing, pharmacokinetics, and the temporal changes in bacterial count in lung. Moreover, survival rates measured in one strain at different dosing were significantly related to the number of bacteria in lung calculated from the pharmacokinetic-pharmacodynamic model. Disappearance of
amoxicillin from the effect compartment appeared to be very slow and the rate constant (k(e0)) governing this process was significantly different between strains, ranging from 0.00131 to 0.03945 h(-1). These findings have two major implications: 1) after a single dose of
amoxicillin, bacterial counts in lung rapidly decreased and the bacterial growth remained suppressed during a long period of time after cessation of exposure of microorganisms to
amoxicillin; and 2) the duration of bacterial growth suppression was related to the intrinsic properties of S. pneumoniae strains rather than to host environment because k(e0) was significantly different between strains. These two premises clearly demonstrate that bacterial growth suppression is related to an in vivo postantibiotic effect. Furthermore, we have shown that the major determinant of
amoxicillin in vivo bactericidal activity and therapeutic efficacy appeared to be the dose of
amoxicillin because
amoxicillin exhibits a rapid dose-dependent killing regardless of the S. pneumoniae strain. Our findings may have implications for the clinical use of
amoxicillin. In view of our results, the guidance to increase the
amoxicillin-loading dose in
pneumococcal pneumonia appears to be immediately clinically relevant.