Impact of low-level fluoroquinolone resistance genes qnrA1, qnrB19 and qnrS1 on ciprofloxacin treatment of isogenic Escherichia coli strains in a murine urinary tract infection model

J Antimicrob Chemother. 2012 Oct;67(10):2438-44. doi: 10.1093/jac/dks224. Epub 2012 Jun 8.


Objectives: To study the impact of qnrA1, qnrB19 and qnrS1 on the ciprofloxacin treatment of urinary tract infection (UTI).

Methods: From a wild-type (wt) Escherichia coli UTI isolate, three isogenic strains were constructed carrying low-level ciprofloxacin resistance genes qnrA1, qnrB19 or qnrS1 (ciprofloxacin MIC range: 0.19-0.38 mg/L). Time-kill studies were performed for all four isogenic strains at the following concentrations: 1×, 2×, 4×, 8× and 16× MIC. Ciprofloxacin serum and urine pharmacokinetics was determined to calculate a murine dose equivalent (AUC(24)) to the standard human dose of 500 mg twice daily, which corresponded to 0.2 mg/mouse four times daily. In the murine UTI model, mice infected with each of the isogenic qnr strains or the wt strain were treated with ciprofloxacin (0.2 mg/mouse) or saline (only the E. coli wt) subcutaneously four times daily for 3 days starting 24 h after bacterial inoculation.

Results: In vitro, the strains responded to ciprofloxacin concentrations of 4-16× MIC by several log(10) reductions. In vivo, despite ciprofloxacin reaching urine concentrations far exceeding the MICs for the strains (500 mg/L), ciprofloxacin was significantly less efficient at reducing the urine and bladder bacterial counts of qnrA1-, qnrB19- and qnrS1-positive strains compared with the ciprofloxacin-treated wt strain (P < 0.05). None of the four strains infected the kidneys well, with median cfu counts of <1 log(10).

Conclusions: Although qnr genes only confer low levels of resistance to ciprofloxacin, a reduced bactericidal activity of ciprofloxacin was observed in both urine and bladder in the murine model of UTI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Load
  • Ciprofloxacin / administration & dosage*
  • Ciprofloxacin / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Bacterial*
  • Escherichia coli / drug effects*
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • Female
  • Genes, Bacterial / genetics
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Microbial Viability / drug effects
  • Mutation
  • Selection, Genetic
  • Treatment Failure
  • Urinary Bladder / microbiology
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / microbiology
  • Urine / microbiology


  • Anti-Bacterial Agents
  • Ciprofloxacin