Resistance occurring after fluoroquinolone therapy of experimental Pseudomonas aeruginosa peritonitis

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 105 CFU), no resistance occurred. With a higher inoculum (1.5 x 108 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 < 0.02). Combined with a quinolone, ceftazidime (P < 0.001) or amikacin (P < 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 PT, 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 ,-lactam and aminoglycoside susceptibility. Some PT, 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.During the past decade, the emergence of resistance after therapy with newer ,-lactam compounds has been an increasing concern (12). In our laboratories, we have reproduced this phenomenon by using an experimental model of Enterobacter cloacae infection (6a). We showed that the emergence of resistance varied with the P-lactam compound given to the animal. When the newer fluoroquinolones appeared, it was hoped that the development of resistance during therapy would be avoided (6). As a result of the improved antibacterial activity of drugs such as pefloxacin and ciprofloxacin, the resistant variants found in the bacterial populations, although less susceptible than the parent strains, might still be regarded as susceptible to these drugs (6). Unfortunately, this did not hold true, and several preliminary therapeutic trials have shown that resistant strains emerging after therapy could generate therapeutic difficulties, especially in Pseudomonas infections (11,16). In this paper, we compared the abilities of pefloxacin and ciprofloxacin to produce resistance in our murine model, with six strains of Pseudomonas aeruginosa ...

Resistance to pefloxacin in Pseudomonas aeruginosa

“…In a pseudomonal peritonitis model, we showed previously that resistance emerges rapidly when mice are treated with pefloxacin or ciprofloxacin (26). In mice infected with a quinolone-susceptible P. aeruginosa isolate, posttherapy variants (strain PT1) emerged after a single dose of pefloxacin, showing an 8-to 16-fold decrease in susceptibility to quinolones.…”

Antibiotic Resistance Is Selected Primarily in Our Patients

“…22 In accordance with in vitro21 and experimental 4 findings, ciprofloxacin selected OprD deficient mutants, with reduced susceptibility to imipenem. In addition, enoxacin therapy has been shown to select cross-resistance affecting quinolones, some B- Resistance emerged in 3.6% to 35.7% of patients receiving third-generation cephalosporins, with an especially high risk attached to cefsulodin in P aeruginosa infectionsZ7 These resistances may occur despite combination with aminoglycosidesz7 and produced clinical failures in about half the cases,t2 some with serious consequences in patients with impaired host defenses.lg Imipenem selected resistance in about 5% of patients,12 almost solely in P aeruginosa infections, where the carbapenem can select OprD-deficient mutants.…”

Development of resistance during ceftazidime and cefepime therapy in a murine peritonitis model

“…S. marcescens 239 and 240, C.freunaHi 151 and 158 were strains isolated in blood cultures from patients not treated with /Mactam agents before the blood sampling. P. aeruginosa 302S and 305S were isolated from infected wounds (Michea-Hamzehpour et al, 1987).…”