Ciprofloxacin Treatment Failure in a Murine Model of Pyelonephritis Due to an AAC(6′)-Ib-cr-Producing Escherichia coli Strain Susceptible to Ciprofloxacin In Vitro

AAC(6′)-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide forEscherichia coli . Since it confersin vitro only a low level of resistance to ciprofloxacin, we evaluated its impact on thein vivo activity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboringaac(6 ′)-Ib-cr , into the quinolone-susceptible strainE. coli CFT073-RR and its D87GgyrA mutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml againstE. coli strains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrAr , and CFT073-RR GyrAr /p449, respectively. Bactericidal activity was reduced at 1× the MIC for the three resistant derivatives, while at a fixed concentration of 0.5 μg/ml, 99.9% killing was observed for all strains exceptE. coli CFT073-RR GyrAr /p449. In the murine model of pyelonephritis, an optimal regimen of ciprofloxacin (10 mg/kg of body weight twice a day [b.i.d.]) significantly decreased the bacterial count in the kidneys of mice infected withE. coli CFT073 (1.6 versus 4.3 log10 CFU/g of kidney compared to untreated controls;P = 0.0001), while no significant decrease was observed forE. coli CFT073-RR/p449 (2.7 versus 3.1 log10 CFU/g;P = 0.84),E. coli CFT073-RR GyrAr (4.2 versus 4.1 log10 CFU/g;P = 0.35), orE. coli CFT073-RR GyrAr /p449 (2.9 versus 3.6 log10 CFU/g;P = 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure againstgyrA -containing mutants, this was not the case for theaac(6 ′)-Ib-cr -containing strains, suggesting anin situ hydrolysis of ciprofloxacin in the latter case.