Ciprofloxacin treatment failure in a murine model of pyelonephritis due to an AAC(6')-Ib-cr-producing Escherichia coli strain susceptible to ciprofloxacin in vitro.

Abstract

AAC(6')-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide for Escherichia coli. Since it confers in vitro only a low level of resistance to ciprofloxacin, we evaluated its impact on the in vivo activity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboring aac(6')-Ib-cr, into the quinolone-susceptible strain E. coli CFT073-RR and its D87G gyrA mutant. MICs were 0.015, 0.06, 0.25, and 0.5 μg/ml against E. coli strains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrA(r), and CFT073-RR GyrA(r)/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 except E. coli CFT073-RR GyrA(r)/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 with E. coli CFT073 (1.6 versus 4.3 log10 CFU/g of kidney compared to untreated controls; P = 0.0001), while no significant decrease was observed for E. coli CFT073-RR/p449 (2.7 versus 3.1 log10 CFU/g; P = 0.84), E. coli CFT073-RR GyrA(r) (4.2 versus 4.1 log10 CFU/g; P = 0.35), or E. coli CFT073-RR GyrA(r)/p449 (2.9 versus 3.6 log10 CFU/g; P = 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure against gyrA-containing mutants, this was not the case for the aac(6')-Ib-cr-containing strains, suggesting an in situ hydrolysis of ciprofloxacin in the latter case.

• Authors: T Guillard, E Cambau, F Chau, L Massias, C de Champs, B Fantin
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 12 Pg. 5830-5 (Dec 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 24018262 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Ciprofloxacin
• DNA Gyrase

Topics

• Animals
• Anti-Bacterial Agents (metabolism, pharmacokinetics, pharmacology)
• Ciprofloxacin (metabolism, pharmacokinetics, pharmacology)
• DNA Gyrase (genetics)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Resistance, Bacterial (genetics)
• Escherichia coli (drug effects, genetics, metabolism)
• Escherichia coli Infections (drug therapy, microbiology)
• Female
• Hydrolysis
• Mice
• Mice, Inbred CBA
• Microbial Sensitivity Tests
• Mutation
• Plasmids
• Pyelonephritis (drug therapy, microbiology)
• Transformation, Bacterial
• Treatment Failure