JAC Advance Access originally published online on September 19, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1054-1057; doi:10.1093/jac/dkl361
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In vivo selection during ofloxacin therapy of Escherichia coli with combined topoisomerase mutations that confer high resistance to ofloxacin but susceptibility to nalidixic acid
1 Service de Bactériologie-Virologie-Hygiène, AP-HP CHU Henri Mondor Université Paris XII, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex, France 2 Unité de Contrôle Épidémiologique et Prévention de l'Infection, AP-HP CHU Henri Mondor Créteil, France 3 Inserm U722 and University Paris 7 Denis Diderot Site Xavier Bichat, France
Received 26 May 2006; returned 2 July 2006; revised 25 July 2006; accepted 10 August 2006
*Corresponding author. Tel: +33-1-49-81-28-31; Fax: +33-1-49-81-28-39; E-mail: emmanuelle.cambau{at}hmn.aphp.fr
Objectives: To investigate quinolone resistance mechanisms in an Escherichia coli clinical isolate (Ar2) resistant to ofloxacin but susceptible to nalidixic acid selected after 10 days of ofloxacin therapy in a patient with prostatitis.
Methods: Molecular typing (ERIC-PCR and RAPD), antibiotic susceptibility and gyrA, gyrB, parC and parE QRDR sequences were compared for E. coli Ar2 and a wild-type E. coli (Ar1) isolated 2 months earlier in the same patient. Ofloxacin-resistant mutants were selected in vitro in order to reproduce the mutations observed and the original phenotype.
Results: The two strains were similar with regard to antibiotic susceptibility except quinolones and for ERIC-PCR and RAPD patterns, suggesting a clonal relationship and acquisition of quinolone resistance by chromosomal mutation. Quinolone MICs were 3, 0.12, 0.05 and 0.02 mg/L of nalidixic acid, ofloxacin, levofloxacin and ciprofloxacin, respectively, for E. coli Ar1 and 6, 32, 8 and 1 mg/L, respectively, for E. coli Ar2. The strain Ar2 harboured two substitutions, Gly-81
Asp in GyrA and Ser-80Arg in ParC. Introduction into E. coli Ar2 of the wild-type gyrA fully complemented fluoroquinolone resistance. Although the strain was not a hypermutator, ofloxacin first-step resistant mutants with gyrA mutations were easily obtained from E. coli Ar1 and 25% of them were at codon 81. In vitro stepwise combination of Gly-81Asp in GyrA and Ser-80Arg in ParC reproduced the original phenotype in E. coli KL16.
Conclusions: A double topoisomerase mutant was selected in vivo by 10 days ofloxacin. The mutations were originally combined for a result of ofloxacin resistance but nalidixic acid susceptibility.
Keywords: fluoroquinolones , parC , DNA gyrase A , QRDRs , gyrA , prostatitis
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