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Selection and characterization of cefepime-resistant gram-negative bacteria
1Department of Medical Microbiology, Medical School, University of Birmingham, UK.
The Journal of Antimicrobial Chemotherapy
|November 1, 1991
Summary
Mutant bacteria developed reduced susceptibility to cefepime and other beta-lactams due to changes in outer membrane proteins and beta-lactamase activity. These alterations in bacterial resistance mechanisms are crucial for understanding antibiotic efficacy.
Area of Science:
- Microbiology
- Antimicrobial Resistance
- Bacterial Genetics
Background:
- Antibiotic resistance is a growing global health threat.
- Extended-spectrum cephalosporins like cefepime are vital for treating serious Gram-negative infections.
- Understanding the mechanisms of resistance development is crucial for effective antimicrobial stewardship.
Purpose of the Study:
- To investigate the mechanisms of resistance development in Gram-negative bacteria exposed to cefepime.
- To characterize the genetic and protein alterations in bacterial mutants exhibiting decreased susceptibility to cefepime and cefpirome.
Main Methods:
- Exposure of NCTC type strains and clinical isolates of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii, Providencia stuartii, and Pseudomonas aeruginosa to cefepime at various concentrations.
- Selection and characterization of resistant mutants, including analysis of beta-lactamase expression and outer membrane protein (Omp) profiles.
- Determination of minimum inhibitory concentrations (MICs) and assessment of beta-lactamase hydrolytic activity.
Main Results:
- Mutants with decreased susceptibility to cefepime and cefpirome were selected at a frequency of approximately 10(-8).
- Specific outer membrane protein losses (e.g., OmpF-like) and derepressed beta-lactamase production were observed in various species.
- Mutant strains showed cross-resistance to other beta-lactams and nalidixic acid, with purified beta-lactamases hydrolyzing cefepime.
Conclusions:
- Outer membrane protein alterations and beta-lactamase deregulation are key mechanisms for reduced susceptibility to cefepime in Gram-negative bacteria.
- The combination of OmpF loss and derepressed beta-lactamase production appears necessary for decreased susceptibility in Enterobacter cloacae.
- These findings highlight the complex interplay of genetic and phenotypic changes driving antimicrobial resistance.