Related Experiment Videos
Resistance occurring after fluoroquinolone therapy of experimental Pseudomonas aeruginosa peritonitis
M Michéa-Hamzehpour1, R Auckenthaler, P Regamey
1Département de Microbiologie Médicale, Centre Médical Universitaire, Geneva, Switzerland.
Abstract:
Resistance emerging after fluoroquinolone therapy was investigated in a murine model of Pseudomonas aeruginosa infection. Mice were infected intraperitoneally by one of six strains and treated with pefloxacin or ciprofloxacin. In mice challenged with a low inoculum (1.6 X 10(5) CFU), no resistance occurred. With a higher inoculum (1.5 X 10(8) CFU) and after a single dose of antibiotic, posttherapy (PT1) strains with decreased susceptibility to quinolones (4- to 32-fold less) were isolated at a variable rate. The presence of talcum (125 mg) in the peritoneal cavity increased the risk of resistance after therapy. Pefloxacin (25 or 200 mg/kg) and ciprofloxacin (25 mg/kg) yielded similar resistance rates (61 to 77%), but ciprofloxacin (10 mg/kg) produced more resistance (83%) than did ciprofloxacin (50 mg/kg) (44%) (P less than 0.02). Combined with a quinolone, ceftazidime (P less than 0.001) or amikacin (P less than 0.01), but not piperacillin, reduced the emergence of resistance. After several doses of ciprofloxacin, it was found that 25-mg/kg doses every 12 h produced more resistance than did 25-mg/kg doses every 8 h or 50-mg/kg doses every 12 h. Compared with the preceding experiments using parent strains, ciprofloxacin and pefloxacin were less efficient in killing bacteria in mice infected with PT1 strains. Moreover, in one of these mice, a highly resistant PT2 strain (64-fold MIC increase for the quinolones) emerged. Besides increased MICs of the quinolones, there was a two- to eightfold increase in imipenem MIC for all PT1 and PT2 strains without alteration of other beta-lactam and aminoglycoside susceptibility. Some PT1 strains also showed a decreased susceptibility to trimethoprim and chloramphenicol. During therapy with a quinolone, resistance can emerge rapidly, especially when there is a large number of bacteria or a foreign body present. This risk may depend on the dosing schedule and may be reduced by combined therapy.
Insights
Fluoroquinolone resistance in Pseudomonas aeruginosa emerges rapidly in mice with high bacterial loads or foreign bodies, influenced by dosing. Combination therapy can reduce this risk.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Fluoroquinolone antibiotics are crucial for treating Pseudomonas aeruginosa infections.
- Emergence of antimicrobial resistance is a significant clinical challenge.
- Understanding resistance mechanisms is vital for effective treatment strategies.
Purpose of the Study:
- To investigate the emergence of resistance to fluoroquinolones during Pseudomonas aeruginosa infection in a murine model.
- To identify factors influencing fluoroquinolone resistance, including bacterial inoculum, presence of foreign bodies, antibiotic dosing, and combination therapy.
Main Methods:
- A murine model of intraperitoneal Pseudomonas aeruginosa infection was established using six different strains.
- Mice were treated with pefloxacin or ciprofloxacin at various doses and schedules.
- The presence of talcum as a foreign body was evaluated.
- Post-therapy strains were isolated and tested for susceptibility to quinolones and other antibiotics.
- Minimum Inhibitory Concentrations (MICs) were determined.
Main Results:
- High bacterial inoculum and the presence of talcum significantly increased the rate of fluoroquinolone resistance.
- Specific dosing regimens of ciprofloxacin led to higher resistance rates compared to others.
- Combination therapy with ceftazidime or amikacin reduced fluoroquinolone resistance emergence.
- Post-therapy strains exhibited decreased susceptibility to quinolones and, in some cases, imipenem, trimethoprim, and chloramphenicol.
- A highly resistant strain (PT2) emerged in one mouse.
Conclusions:
- Fluoroquinolone resistance can emerge rapidly in Pseudomonas aeruginosa infections, particularly with high bacterial loads or foreign bodies.
- Antibiotic dosing schedules and combination therapies play a critical role in modulating resistance.
- The study highlights the need for careful consideration of treatment parameters to mitigate resistance development.