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Antimicrobial Agents and Chemotherapy, October 2009, p. 4292-4297, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01664-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Nicolas Allou,1 Emmanuelle Cambau,1,2 Laurent Massias,3 Françoise Chau,1 and Bruno Fantin1,4*

Université Paris Diderot, EA3964, Paris, France,1 AP-HP, Hôpital Saint Louis, Microbiologie, Paris, France,2 AP-HP, Hôpital Bichat, Laboratoire de Toxicologie-Pharmacocinétique, Service de Pharmacie, Paris, France,3 AP-HP, Hôpital Beaujon, Paris, France4

Received 18 December 2008/ Returned for modification 15 April 2009/ Accepted 15 July 2009

We investigated the impact of low-level resistance to fluoroquinolones on the bactericidal activity of ciprofloxacin in a murine model of urinary tract infection. The susceptible Escherichia coli strain CFT073 (ciprofloxacin MIC [CIP MIC] of 0.008 µg/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 µg/ml). Bactericidal activity measured in vitro after 1, 3, and 6 h of exposure to 0.5 µg/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.

* Corresponding author. Mailing address: Hôpital Beaujon, Service de Médecine Interne, 100 boulevard du général Leclerc, 92110 Clichy, France. Phone: 33 1 40 87 58 90. Fax: 33 1 40 87 10 81. E-mail: bruno.fantin{at}bjn.aphp.fr

{triangledown} Published ahead of print on 27 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4292-4297, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01664-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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