CORRELATION BETWEEN IN-VITRO AND IN-VIVO ACTIVITY OF AMOXICILLIN AGAINST STREPTOCOCCUS-PNEUMONIAE IN A MURINE PNEUMONIA MODEL

We studied the relationship between in vitro bacteriological parameter s [minimal inhibitory concentration (MIC), minimal bactericidal concen tration (MBC) and killing rate, defined as the reduction in the inocul um within 1, 3 or 6 hr] and in vivo activity of amoxicillin against 12 strains of Streptococcus; pneumoniae, with penicillin MICs of <0.01 t o 16 mu g/ml, in a cyclophosphamide-induced neutropenic; murine pneumo nia model. Dose-response curves were determined for amoxicillin agains t each strain, and three quantitative parameters of in vivo amoxicilli n activity were defined, i.e., maximal attainable antimicrobial effect attributable to the drug [i.e., reduction in log colony-forming units (CFU) per lung, compared with untreated controls], dose required to r each 50% of maximal effect and dose required to achieve a reduction of 1 log CFU/lung. We demonstrated a highly significant correlation betw een the dose required to reach 50% of maximal effect and MIC (Spearman r = 0.98, P < .0001) or MBC (Spearman r = 0.95, P < .0001) for amoxic illin against strains of S. pneumoniae with a wide range of amoxicilli n MICs (0.01-8 mu g/ml). Significant correlations between the dose req uired to achieve a reduction of 1 log CFU/lung and MIC (Spearman r = 0 .98, P < .0001) or MBC (Spearman r = 0.95, P < .0001) were also observ ed. In contrast, there were no significant correlations between the ma ximal attainable antimicrobial effect attributable to the drug and MIC , MBC or killing rate or between killing rate and the dose required to reach 50% of maximal effect or the dose required to achieve a reducti on of 1 log CFU/lung. We conclude that in vitro susceptibility test re sults (MICs and MBCs) correlated well with in vivo amoxicillin activit y against pneumococcal strains, including highly penicillin-resistant strains, in this animal model. Furthermore, these data suggest that th e estimated MIC breakpoints for amoxicillin against S. pneumoniae woul d be 2 mu g/ml for intermediate-resistant and 4 mu g/ml for resistant, although this remains to be confirmed in clinical studies.