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Postantibiotic and post-beta-lactamase inhibitor effects of amoxicillin plus clavulanate
C E Thorburn1, S J Molesworth, R Sutherland
1Department of Microbial Cell Sciences and Physiology, SmithKline Beecham Pharmaceuticals, Surrey, United Kingdom.
Abstract:
The postantibiotic effect (PAE) of amoxicillin-clavulanate was studied for strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Escherichia coli. A PAE of approximately 2 h was seen for beta-lactamase-positive and -negative strains of S. aureus following 2 h of exposure to twice the MIC and did not increase at 16 times the MIC. The PAE observed with H. influenzae was clearly related to the growth rate of the organism. A PAE of 0.8 h was found for amoxicillin (four times the MIC) against a beta-lactamase-negative strain of H. influenzae (generation time, 26.3 min) and a PAE of 1.74 h was found for amoxicillin-clavulanate (twice the MIC) against a beta-lactamase-positive strain (generation time, 32.2 min). When the beta-lactamase-positive strain was growing more slowly (generation time, 120 min), the PAE of amoxicillin-clavulanate increased to > 3.32 h. The PAE of amoxicillin-clavulanate at 2/1 micrograms/ml on a beta-lactamase-producing strain of M. catarrhalis was > 2.9 h, and, as expected, the PAEs of twice the MIC on K. pneumoniae and E. coli were generally short (< 1 h). The post-beta-lactamase inhibitor effect (PLIE), determined after removal of only clavulanate, was also examined for beta-lactamase-positive strains. This was more prolonged (approximately 3 to 4 h) than the corresponding PAE for S. aureus, H. influenzae, and M. catarrhalis. The PLIE was related to the amount of beta-lactamase produced and required the presence of amoxicillin in the initial exposure period. These data may have implications for reducing the dosage of amoxicillin-clavulanate.
Insights
The postantibiotic effect (PAE) of amoxicillin-clavulanate varies by bacteria. Longer PAE was observed in slower-growing bacteria, suggesting potential for reduced amoxicillin-clavulanate dosing.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- The postantibiotic effect (PAE) describes the lag in bacterial growth after antibiotic exposure.
- Amoxicillin-clavulanate is a widely used antibiotic combination.
- Understanding PAE is crucial for optimizing antibiotic dosing regimens.
Purpose of the Study:
- To investigate the postantibiotic effect (PAE) of amoxicillin-clavulanate against various bacterial strains.
- To explore the influence of bacterial growth rate and beta-lactamase production on amoxicillin-clavulanate PAE.
- To examine the post-beta-lactamase inhibitor effect (PLIE) of amoxicillin-clavulanate.
Main Methods:
- Determined the PAE of amoxicillin-clavulanate against Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Escherichia coli.
- Varied antibiotic concentrations (twice and 16 times the MIC) and exposure times.
- Assessed the PLIE by removing only clavulanate after exposure.
Main Results:
- Amoxicillin-clavulanate exhibited a PAE of approximately 2 hours for S. aureus, regardless of beta-lactamase status or concentration.
- PAE for H. influenzae was growth rate-dependent, with longer effects observed in slower-growing strains.
- M. catarrhalis showed a PAE > 2.9 hours, while K. pneumoniae and E. coli had shorter PAEs (< 1 hour).
- The PLIE was more prolonged (3-4 hours) than PAE for certain bacteria and depended on beta-lactamase production.
Conclusions:
- The PAE of amoxicillin-clavulanate is variable across different bacterial species and influenced by growth rate and beta-lactamase activity.
- The prolonged PLIE suggests a significant contribution of clavulanate in extending the antibiotic effect.
- These findings may support the potential for reduced amoxicillin-clavulanate dosing strategies.