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

Abstract

ABSTRACTAAC(6′)-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide forEscherichia coli. Since it confersin vitroonly a low level of resistance to ciprofloxacin, we evaluated its impact on thein vivoactivity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboringaac(6′)-Ib-cr, into the quinolone-susceptible strainE. coliCFT073-RR and its D87GgyrAmutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml againstE. colistrains 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. coliCFT073-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. coliCFT073 (1.6 versus 4.3 log10CFU/g of kidney compared to untreated controls;P= 0.0001), while no significant decrease was observed forE. coliCFT073-RR/p449 (2.7 versus 3.1 log10CFU/g;P= 0.84),E. coliCFT073-RR GyrAr(4.2 versus 4.1 log10CFU/g;P= 0.35), orE. coliCFT073-RR GyrAr/p449 (2.9 versus 3.6 log10CFU/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 situhydrolysis of ciprofloxacin in the latter case.