Development of a new experimental model of penicillin-resistant Streptococcus pneumoniae pneumonia and amoxicillin treatment by reproducing human pharmacokinetics

The increase of penicillin-resistant Streptococcus pneumoniae (PRSP) pneumo nia results in a greater risk of antibiotic treatment failure. In vitro dat a are not sufficient predictors of clinical efficacy, and animal models may be insufficiently contributive, since they often use immunocompromised ani mals and do not always respect the human pharmacokinetics of antibiotics. W e developed an experimental PRSP pneumonia model in immunocompetent rabbits , by using intrabronchial instillation of PRSP (MIC = 4 mg/liter), without any adjuvant, This reproducible model was used to assess amoxicillin effica cy by reproducing human serum pharmacokinetics following 1-g oral or intrav enous administrations of amoxicillin every 8 h, Evaluation was performed by using clinical, CT scan, macroscopic, histopathologic, and microbiological criteria. Experimental pneumonia in untreated rabbits was similar to untre ated severe human bacteremic untreated pneumonia; in both rabbits and human s, (i) cumulative survival was close to 50%, (ii) red or gray lung congesti on and pleuritis were observed, and (iii) lung and spleen concentrations re ached 5 and 4 log(10) CFU/g. A 48-h treatment resulted in a significant bac terial clearance in the lungs (1.53 versus 5.07 log(10) CFU/ml, P < 0.001) and spleen (1.00 versus 4.40 log(10) CFU/ml, P < 10(-6)) and a significant decrease in mortality (0% versus 50%, P = 0.02) in treated versus untreated rabbits. No difference was observed on macroscopic and histopathologic les ions between treated and untreated rabbits (P = 0.36 and 0.78, respectively ), Similar results were obtained by using a fully penicillin-susceptible S. pneumoniae strain (MIC = 0.01 mg/liter), Our findings suggest that (i) thi s new model can be contributive in the evaluation of antibacterial agents a nd (ii) 1 g of amoxicillin three times a day may be sufficient to treat PRS P pneumonia in immunocompetent humans.