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Impact of Low-Level Resistance to Fluoroquinolones Due to qnrA1 and qnrS1 Genes or a gyrA Mutation on Ciprofloxacin Bactericidal Activity in a Murine Model of Escherichia coli Urinary Tract Infection

Impact of Low-Level Resistance to Fluoroquinolones Due to qnrA1 and qnrS1 Genes or a gyrA Mutation on Ciprofloxacin Bactericidal Activity in a Murine

Impact of Low-Level Resistance to Fluoroquinolones Due to qnrA1 and qnrS1 Genes or a gyrA Mutation on Ciprofloxacin Bactericidal Activity in a Murine Model of Escherichia coli Urinary Tract Infection   (Citations: 4)
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We investigated the impact of low-level resistance to fluoroquinolones on the bactericidal activity of cipro- floxacin in a murine model of urinary tract infection. The susceptible Escherichia coli strain CFT073 (cipro- floxacin MIC (CIP MIC) of 0.008 g/ml) was compared to its transconjugants harboring qnrA1 or qnrS1 and to an S83L gyrA mutant. The three derivatives showed similar low-level resistance to fluoroquinolones (CIP MICs, 0.25 to 0.5 g/ml). Bactericidal activity measured in vitro after 1, 3, an d6ho fexposure to 0.5 g/ml of ciprofloxacin was significantly lower for the derivative strains (P < 0.01). In the murine model of urinary tract infection (at least 45 mice inoculated per strain), mice were treated with a ciprofloxacin regimen of 2.5 mg/kg, given subcutaneously twice daily for 2 days. In mice infected with the susceptible strain, ciprofloxacin significantly decreased viable bacterial counts (log10 CFU/g of tissue) in the bladder (4.2 0.5 versus 5.5 1.3; P 0.001) and in the kidney (3.6 0.8 versus 5.0 1.1; P 0.003) compared with those of untreated mice. In contrast, no significant decrease in viable bacterial counts was observed with any of the three derivative strains. The area under the concentration-time curve from 0 to 24 h/MIC and the maximum concentration of drug in serum/MIC ratios measured in plasma were indeed equal to 827 and 147, respectively, for the parental strain, and only 12.4 to 24.8 and 2.2 to 4.4, respectively, for the derivative strains. In conclusion, low-level resistance to fluoroquinolones conferred by a qnr gene is associated with decreased bactericidal activity of ciprofloxacin, similar to that obtained with a gyrA mutation. Urinary tract infection (UTI) due to Escherichia coli is the most common bacterial infection. Fluoroquinolones are com- monly used for the treatment of UTI because isolated micro- organisms are frequently resistant to aminopenicillins and tri- methoprim-sulfamethoxazole (22), and fluoroquinolones are given orally. However, resistance to fluoroquinolones in E. coli has increased due to their large use (13, 23). Classical mech- anisms of quinolone resistance are due to chromosomal mu- tations in the genes encoding their targets (quinolone resis-
Journal: Antimicrobial Agents and Chemotherapy - ANTIMICROB AGENTS CHEMOTHER , vol. 53, no. 10, pp. 4292-4297, 2009
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