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Emergence of resistance after therapy with antibiotics used alone or combined in a murine model
Abstract:
A murine model of peritonitis allowing detection and quantification of in-vivo acquired resistance during short term therapy has been used in order to evaluate the capacity of antimicrobial combinations to limit emergence of resistance, as compared to individual components of the regimens. Mice were challenged intraperitoneally with 10(8) cfu of bacteria. Two hours later, a single antibiotic dose was injected subcutaneously: amikacin (15 mg/kg), ceftriaxone (50 mg/kg), pefloxacin (25 mg/kg), amikacin + ceftriaxone, amikacin + pefloxacin or ceftriaxone + pefloxacin. Escherichia coli and Staphylococcus aureus never became resistant. Single drug therapy yielded resistant mutants in Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae and Pseudomonas aeruginosa as follows: 74% of ceftriaxone-treated animals, 57% of pefloxacin treated animals and 27% of amikacin treated animals. All the tested combinations reduced the frequency of in-vivo acquired resistance produced by single drugs, and no combination selected resistance when the separate agents of the combination did not. Combining antimicrobial agents limits the risk of emergence of resistance during antibiotic therapy.
Insights
Combining antibiotics effectively limits the emergence of antimicrobial resistance in bacterial infections. This study shows that combination therapy reduces resistance development compared to single-drug treatments.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antimicrobial resistance is a growing global health threat.
- Understanding resistance emergence during therapy is crucial for effective treatment strategies.
Purpose of the Study:
- To evaluate the capacity of antimicrobial combinations to limit the emergence of in-vivo acquired resistance.
- To compare combination therapy with individual antimicrobial agents in a murine peritonitis model.
Main Methods:
- A murine model of peritonitis was established using bacterial challenge.
- Animals received single or combination antibiotic doses (amikacin, ceftriaxone, pefloxacin).
- In-vivo acquired resistance was detected and quantified in specific bacterial pathogens.
Main Results:
- Single-drug therapy resulted in significant resistance emergence in Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
- Combination antimicrobial therapy consistently reduced the frequency of in-vivo acquired resistance compared to monotherapy.
- No tested combination selected for resistance when individual agents did not.
Conclusions:
- Combining antimicrobial agents is an effective strategy to limit the risk of developing resistance during antibiotic therapy.
- Antimicrobial combinations demonstrate superior efficacy in preventing resistance compared to individual drugs.