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Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model
1Departement de Génétique et Microbiologie, Centre Médical Universitaire, Geneva, Switzerland.
Abstract:
Resistance emerging after ceftazidime or cefepime therapy was investigated in a peritonitis model. Mice were given a peritoneal challenge (10(8) cfu plus talcum) and treated by either antibiotic (50 mg/kg/dose, which produced similar antibiotic concentrations in peritoneal fluid in both cases). After one or three doses, resistance never developed in Serratia marcescens or Citrobacter freundii infections. After Enterobacter cloacae and Pseudomonas aeruginosa challenge, ceftazidime selected more resistance (21/36 cases) than did cefepime (1/36 cases). In mice challenged with resistant strains selected by ceftazidime therapy, cefepime (six doses) successfully treated 7/18 E. cloacae infections but 0/18 P. aeruginosa infections; ceftazidime was never effective. Neither cefepime nor ceftazidime cured mice infected with the resistant strain selected by cefepime. MICs were poor predictors of further emergence of resistance in mice inoculated with strains classified as susceptible, but antibiotic-containing agar gradients plated with a high inoculum (10(8) cfu) allowed better prediction. In selected clinical situations, cefepime may be preferable because it may be associated with less frequent emergence of resistance.
Insights
Cefepime therapy resulted in less emerging resistance than ceftazidime in a mouse peritonitis model, particularly against Enterobacter cloacae and Pseudomonas aeruginosa. Cefepime showed some efficacy against ceftazidime-selected resistance, but neither antibiotic cured cefepime-selected resistance.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Antibiotic resistance is a growing threat in treating bacterial infections.
- Third-generation cephalosporins like ceftazidime and fourth-generation cephalosporins like cefepime are crucial in treating serious Gram-negative infections.
- Understanding the emergence of resistance to these agents is vital for effective treatment strategies.
Purpose of the Study:
- To compare the emergence of bacterial resistance following ceftazidime versus cefepime therapy in a peritonitis model.
- To evaluate the in vivo efficacy of ceftazidime and cefepime against resistant strains selected by prior therapy.
Main Methods:
- A mouse peritonitis model was established using Gram-negative bacteria (Serratia marcescens, Citrobacter freundii, Enterobacter cloacae, Pseudomonas aeruginosa).
- Mice were treated with ceftazidime or cefepime (50 mg/kg/dose) after bacterial challenge.
- Resistance emergence was assessed after one or three doses, and subsequent treatment of resistant infections was evaluated.
Main Results:
- Ceftazidime selected for resistance more frequently than cefepime in E. cloacae and P. aeruginosa infections (21/36 vs. 1/36 cases).
- Cefepime successfully treated some ceftazidime-selected resistant E. cloacae infections, but not P. aeruginosa.
- Neither antibiotic was effective against cefepime-selected resistant strains. Agar gradient diffusion with high inoculum improved resistance prediction.
Conclusions:
- Cefepime may be associated with a lower emergence of resistance compared to ceftazidime in certain clinical scenarios.
- The emergence of resistance can impact the efficacy of subsequent antibiotic treatments.
- High-inoculum agar gradient diffusion may offer better prediction of resistance than standard MIC testing.