ArticleAntimicrobial agents and chemotherapy2007
Effect of dosing and dosing frequency on the efficacy of ceftizoxime and the emergence of ceftizoxime resistance during the early development of murine abscesses caused by Bacteroides fragilis and Enterobacter cloacae mixed infection.
Article in Antimicrobial agents and chemotherapy, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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10 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram-Negative Bacteria? A Systematic Review.Clinical pharmacokinetics · 2019Pooled it
- A microfluidic hollow-fiber infection model (µHFIM): monitoring bacterial response to dynamic drug treatment with single-cell resolution.Microsystems & nanoengineering · 2026Article
- Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.Clinical microbiology reviews · 2024Review
- Emergence of Resistance inAntimicrobial agents and chemotherapy · 2021Article
- Aggressive or moderate drug therapy for infectious diseases? Trade-offs between different treatment goals at the individual and population levels.PLoS computational biology · 2019Article
- Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction.BioMed research international · 2016Review
- Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?PLoS computational biology · 2016Article
- The path of least resistance: aggressive or moderate treatment?Proceedings. Biological sciences · 2014Article
- Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Attenuation of colistin bactericidal activity by high inoculum of Pseudomonas aeruginosa characterized by a new mechanism-based population pharmacodynamic model.Antimicrobial agents and chemotherapy · 2010Article
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4 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The efficacy of beta-lactams is thought to be dependent on the time that the unbound concentrations exceed the MIC (fT>MIC). However, the pharmacokinetic/pharmacodynamic index (PDI) that correlates best to the selection of resistance is not yet clear. The selection of ceftizoxime (CZX)-resistant Enterobacter cloacae mutant strains during the development of murine mixed-infection abscesses was studied to determine the PDI that is important for the emergence of resistance and the PDI value needed for the prevention of resistance. Studies were carried out 24 h after inoculation with Bacteroides fragilis ATCC 23745 and E. cloacae 22491. Six to 1,536 mg of CZX/kg of body weight/day given every 2 h (q2h), q4h, q6h, or q8h was started 30 min before inoculation and continued for 24 h. Resistant mutants were isolated to determine mutant frequencies (MF). The fT>MIC varied from 9 to 98% for E. cloacae, the peak concentration (unbound fraction) was 0.6 to 578 mg/liter, and the area under the concentration-time curve (unbound fraction) (fAUC) was 1.9 to 553 mg.h/liter. The fAUC-to-MIC ratio best explained the in vivo efficacy. CZX-resistant B. fragilis and E. cloacae mutants were isolated from untreated controls at an MF of 10(-5) to 10(-7). The MF of resistant B. fragilis did not increase during therapy. The selection of resistant E. cloacae strains at an MF of 10(-1) to 10(-2) was related to the fT>MIC and the ratio of fAUC to MIC following an inverse U shape. However, the ratio of fAUC to MIC was the stronger driver of resistance. The highest MFs were 0.7 to 0.9 at an fAUC-to-MIC ratio of approximately 250. We conclude that the ratio of fAUC to MIC is the PDI that correlated best to the in vivo efficacy of CZX and probably also to the emergence of resistant E. cloacae mutants. An fAUC-to-MIC ratio of 1,000 was needed to prevent the emergence of this resistance.
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