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.
OBJECTIVE
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.
Department of Microbiological Surveillance and Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark. lja@ssi.dk
Lotte
L
Jakobsen
Vincent
V
Cattoir
Klaus S
KS
Jensen
Anette M
AM
Hammerum
Patrice
P
Nordmann
Niels
N
Frimodt-Møller
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D058491:Bacterial Load; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D005798:Genes, Bacterial / Q000235:genetics; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D012641:Selection, Genetic; D017211:Treatment Failure; D001743:Urinary Bladder / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D014556:Urine / Q000382:microbiology
D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin