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

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 byStreptococcus 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 fourS. 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 toS. pneumoniae for which MICs were 2 to 4 μg/ml. The killing rate depends not only on resistance but also on tolerance of theS. pneumoniae strains.