Amoxicillin is effective against penicillin-resistant Streptococcus pneumoniae strains in a mouse pneumonia model
Pierre Abgueguen1, Esther Azoulay-Dupuis, Violaine Noel
1Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire d'Angers, 4 rue Larrey, 49933 Angers Cedex 9, France. piabgueguen@chu-angers.fr
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.
Insights
High-dose amoxicillin effectively treats community-acquired pneumonia (CAP) in mice, even with resistant Streptococcus pneumoniae strains. Bacterial killing rates depend on both resistance and tolerance, impacting treatment outcomes.
Area of Science:
- Pharmacology
- Microbiology
- Infectious Diseases
Background:
- High-dose oral amoxicillin (3 g/day) is a common European guideline for community-acquired pneumonia (CAP).
- Investigating amoxicillin efficacy against Streptococcus pneumoniae with elevated minimum inhibitory concentrations (MICs) is crucial.
Purpose of the Study:
- To evaluate the clinical efficacy of amoxicillin in treating bacteremic pneumonia caused by Streptococcus pneumoniae strains with amoxicillin MICs ≥ 2 µg/ml.
- To assess the impact of bacterial resistance and tolerance on amoxicillin's killing rate in a murine model.
Main Methods:
- A lethal bacteremic pneumonia model was established in leukopenic mice with induced renal failure to mimic human amoxicillin pharmacokinetics (1 g/8 h orally).
- Mice received amoxicillin (15 mg/kg subcutaneously every 8 hours) for 3 days.
- Four S. pneumoniae strains with varying amoxicillin susceptibility and tolerance profiles were used.
Main Results:
- Rapid bacterial killing was observed with a susceptible, nontolerant strain, with blood cultures negative within 4 hours.
- Significant pulmonary bacterial clearance occurred within 24 hours for intermediate-susceptible strains, with undetectable counts post-treatment.
- Intermediate-tolerant and resistant-tolerant strains showed slower bacterial clearance, with detectable lung homogenate counts 12 hours after treatment completion.
- Day 10 survival rates were generally similar across all tested strains.
Conclusions:
- Amoxicillin, at human-simulated oral doses, demonstrates bactericidal activity against S. pneumoniae strains with MICs of 2-4 µg/ml in a murine pneumonia model.
- The rate of bacterial killing is influenced by both the resistance level and the tolerance of S. pneumoniae strains.
- These findings highlight the importance of considering bacterial tolerance in addition to resistance when assessing amoxicillin efficacy for CAP treatment.
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