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Optimal times above MICs of ceftibuten and cefaclor in experimental intra-abdominal infections
C O Onyeji1, D P Nicolau, C H Nightingale
1Department of Pharmacy and Research, Hartford Hospital, Connecticut 06115.
Abstract:
The duration of time that serum drug levels remain above the MIC (time above the MIC) for the pathogen has been shown to be the most significant parameter determining the efficacies of beta-lactam antibiotics. In the described study, we investigated the optimal time above the MIC of ceftibuten and cefaclor using a nonneutropenic mouse model of intra-abdominal infections caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. The abilities of the drugs to protect mice against the organisms were determined in mouse protection tests, and the doses were fractionated to produce various dosing regimens with different times above the MIC. All drug-organism combinations showed a significant correlation (r > 0.9) between drug efficacy and the time above the MIC. Also, with ceftibuten treatment, the different dosing regimens that produced equal times above the MIC resulted in the same efficacy, whereas with cefaclor, an apparent dose-dependent effect was observed. These results showed that for a 100% recovery from K. pneumoniae and E. coli infections, the optimal times above the MIC with ceftibuten treatment were 2.2 and 1.6 h, respectively. Relatively high doses of both antibiotics were required to ensure recovery from S. pneumoniae infections. In vitro time-kill studies demonstrated that cefaclor exhibits a marked inoculum effect against the pathogens, and there was a concentration-dependent killing at a large inoculum size. On the other hand, ceftibuten showed no inoculum effect. It is suggested that optimization of both dose and time above the MIC appears to be necessary for the treatment of S. aureus infections with cefaclor, and this may apply to other beta-lactams tht exhibit marked inoculum effects.
Insights
Time above the Minimum Inhibitory Concentration (MIC) is key for beta-lactam antibiotic efficacy. This study found optimal times for ceftibuten and cefaclor against common bacteria, revealing drug-specific dosing needs.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- The efficacy of beta-lactam antibiotics is significantly influenced by the duration serum drug levels remain above the Minimum Inhibitory Concentration (MIC).
- Understanding the optimal time above MIC is crucial for effective antibiotic therapy.
- This study focuses on ceftibuten and cefaclor, common beta-lactam antibiotics.
Purpose of the Study:
- To determine the optimal time above MIC for ceftibuten and cefaclor in treating intra-abdominal infections.
- To investigate the relationship between drug efficacy and time above MIC for various bacterial pathogens.
- To compare the pharmacokinetic/pharmacodynamic (PK/PD) properties of ceftibuten and cefaclor.
Main Methods:
- Utilized a nonneutropenic mouse model of intra-abdominal infections.
- Infected mice with Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae.
- Employed mouse protection tests and fractionated dosing regimens to achieve varied times above MIC.
- Conducted in vitro time-kill studies to assess inoculum effects.
Main Results:
- A strong correlation (r > 0.9) was observed between drug efficacy and time above MIC for all drug-organism combinations.
- Ceftibuten demonstrated consistent efficacy across different dosing regimens with equal times above MIC.
- Cefaclor showed an apparent dose-dependent effect, with a marked inoculum effect observed in vitro.
- Optimal times above MIC for 100% recovery were 2.2 h for K. pneumoniae and 1.6 h for E. coli with ceftibuten.
Conclusions:
- Time above MIC is a critical determinant of efficacy for ceftibuten and cefaclor.
- Ceftibuten's efficacy is primarily driven by time above MIC, while cefaclor exhibits dose-dependent effects and inoculum effects.
- Optimizing both dose and time above MIC is essential for cefaclor, particularly against S. aureus and potentially other beta-lactams with inoculum effects.
- Specific time above MIC targets are identified for ceftibuten against K. pneumoniae and E. coli.