title: Amoxicillin is effective against penicillin-resistant Streptococcus pneumoniae strains in a mouse pneumonia model simulating human pharmacokinetics.
abstract: 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 > or =2 microg/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 log(10) CFU/ml detection threshold (6.5 log(10) 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 log(10) 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 log(10) CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log(10) 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 microg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.
authors.affiliation: Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire d'Angers, 4 rue Larrey, 49933 Angers Cedex 9, France. piabgueguen@chu-angers.fr
authors.forename: Pierre
authors.initials: P
authors.lastname: Abgueguen
authors.forename: Esther
authors.initials: E
authors.lastname: Azoulay-Dupuis
authors.forename: Violaine
authors.initials: V
authors.lastname: Noel
authors.forename: Pierre
authors.initials: P
authors.lastname: Moine
authors.forename: Veronique
authors.initials: V
authors.lastname: Rieux
authors.forename: Bruno
authors.initials: B
authors.lastname: Fantin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bedos
mesh_terms: D000658:Amoxicillin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D010406:Penicillins / Q000494:pharmacology*; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D010406:Penicillins; D000658:Amoxicillin