Vol. 291, Issue 3, 1086-1092, December 1999

Streptococcus pneumoniae Pneumonia in Mice: Optimal Amoxicillin Dosing Predicted from a Pharmacokinetic-Pharmacodynamic Model

Pierre Moine and Jean Xavier Mazoit

Service et Laboratoire d'Anesthésie, Centre Hospitalier Universitaire de Bicêtre, Université Paris-Sud, Faculté de Médecine du Kremlin-Bicêtre. Le Kremlin-Bicêtre, France (P.M., J.X.M.); and Contrat de Recherche Institut National de la Santé et de la Recherche Médicale CRI 4U 002 D Pharmacologie de la résistance aux anti-infectieux, Centre Hospitalier Universitaire Bichat-Claude Bernard, Paris, France (P.M.)

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 µg/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 h¹. 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.