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Antimicrobial Agents and Chemotherapy, January 2007, p. 208-214, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00004-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Amoxicillin Is Effective against Penicillin-Resistant Streptococcus pneumoniae Strains in a Mouse Pneumonia Model Simulating Human Pharmacokinetics

INSERM EMI-U 9933, Faculté de Médecine Xavier Bichat, Paris, France

Received 3 January 2006/ Returned for modification 13 February 2006/ Accepted 14 October 2006

High-dose oral amoxicillin (3 g/day) is the recommended empirical outpatient treatment of community-acquired pneumonia (CAP) in many European guidelines. To investigate the clinical efficacy of this treatment in CAP caused by Streptococcus pneumoniae strains with MICs of amoxicillin 2 µg/ml, we used a lethal bacteremic pneumonia model in leukopenic female Swiss mice with induced renal failure to replicate amoxicillin kinetics in humans given 1 g/8 h orally. Amoxicillin (15 mg/kg of body weight/8 h subcutaneously) was given for 3 days. We used four S. pneumoniae strains with differing amoxicillin susceptibility and tolerance profiles. Rapid bacterial killing occurred with an amoxicillin-susceptible nontolerant strain: after 4 h, blood cultures were negative and lung homogenate counts under the 2 log₁₀ CFU/ml detection threshold (6.5 log₁₀ CFU/ml in controls, P < 0.01). With an amoxicillin-intermediate nontolerant strain, significant pulmonary bacterial clearance was observed after 24 h (4.3 versus 7.9 log₁₀ CFU/ml, P < 0.01), and counts were undetectable 12 h after treatment completion. With an amoxicillin-intermediate tolerant strain, 24-h bacterial clearance was similar (5.4 versus 8.3 log₁₀ CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log₁₀ CFU/ml. Similar results were obtained with an amoxicillin-resistant and -tolerant strain. Day 10 survival rates were usually similar across strains. Amoxicillin with pharmacokinetics simulating 1 g/8 h orally in humans is bactericidal in mice with pneumonia due to S. pneumoniae for which MICs were 2 to 4 µg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.

Published ahead of print on 23 October 2006.