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Antimicrobial Agents and Chemotherapy, October 1999, p. 2484-2492, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Development of a New Experimental Model of Penicillin-Resistant Streptococcus pneumoniae Pneumonia and Amoxicillin Treatment by Reproducing Human Pharmacokinetics

Lionel Piroth,1 Laurent Martin,2 Alexis Coulon,1 Catherine Lequeu,1 Michel Duong,1 Marielle Buisson,1 Henri Portier,1 and Pascal Chavanet1,*

Service des Maladies Infectieuses et Tropicales, Microbiologie Médicale et Moléculaire (EA562), Hôpital du Bocage,1 and Service d'Anatomie Pathologique, Centre Hospitalier Universitaire de Dijon,2 Dijon Cedex, France

Received 25 September 1998/Returned for modification 20 February 1999/Accepted 16 June 1999

The increase of penicillin-resistant Streptococcus pneumoniae (PRSP) pneumonia results in a greater risk of antibiotic treatment failure. In vitro data are not sufficient predictors of clinical efficacy, and animal models may be insufficiently contributive, since they often use immunocompromised animals and do not always respect the human pharmacokinetics of antibiotics. We 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 efficacy by reproducing human serum pharmacokinetics following 1-g oral or intravenous 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 untreated severe human bacteremic untreated pneumonia; in both rabbits and humans, (i) cumulative survival was close to 50%, (ii) red or gray lung congestion and pleuritis were observed, and (iii) lung and spleen concentrations reached 5 and 4 log10 CFU/g. A 48-h treatment resulted in a significant bacterial clearance in the lungs (1.53 versus 5.07 log10 CFU/ml, P < 0.001) and spleen (1.00 versus 4.40 log10 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 lesions 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) this new model can be contributive in the evaluation of antibacterial agents and (ii) 1 g of amoxicillin three times a day may be sufficient to treat PRSP pneumonia in immunocompetent humans.

* Corresponding author. Mailing address: Service des Maladies Infectieuses et Tropicales, Hôpital du Bocage, BP 1542, 21034 Dijon Cedex, France. Phone: (33) 3 80 29 36 37. Fax: (33) 3 80 29 36 38. E-mail: p.chavanet{at}planetb.fr.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2484-2492, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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