title: Plasmid-Mediated OqxAB Is an Important Mechanism for Nitrofurantoin Resistance in Escherichia coli.
abstract: Increasing consumption of nitrofurantoin (NIT) for treatment of acute uncomplicated urinary tract infections (UTI) highlights the need to monitor emerging NIT resistance mechanisms. This study investigated the molecular epidemiology of the multidrug-resistant efflux gene oqxAB and its contribution to nitrofurantoin resistance by using Escherichia coli isolates originating from patients with UTI (n = 205; collected in 2004 to 2013) and food-producing animals (n = 136; collected in 2012 to 2013) in Hong Kong. The oqxAB gene was highly prevalent among NIT-intermediate (11.5% to 45.5%) and -resistant (39.2% to 65.5%) isolates but rare (0% to 1.7%) among NIT-susceptible (NIT-S) isolates. In our isolates, the oqxAB gene was associated with IS26 and was carried by plasmids of diverse replicon types. Multilocus sequence typing revealed that the clones of oqxAB-positive E. coli were diverse. The combination of oqxAB and nfsA mutations was found to be sufficient for high-level NIT resistance. Curing of oqxAB-carrying plasmids from 20 NIT-intermediate/resistant UTI isolates markedly reduced the geometric mean MIC of NIT from 168.9 μg/ml to 34.3 μg/ml. In the plasmid-cured variants, 20% (1/5) of isolates with nfsA mutations were NIT-S, while 80% (12/15) of isolates without nfsA mutations were NIT-S (P = 0.015). The presence of plasmid-based oqxAB increased the mutation prevention concentration of NIT from 128 μg/ml to 256 μg/ml and facilitated the development of clinically important levels of nitrofurantoin resistance. In conclusion, plasmid-mediated oqxAB is an important nitrofurantoin resistance mechanism. There is a great need to monitor the dissemination of this transferable multidrug-resistant efflux pump.
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China plho@hkucc.hku.hk.
authors.forename: Pak-Leung
authors.identifier: http://orcid.org/0000-0002-8811-1308
authors.initials: PL
authors.lastname: Ho
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Ka-Ying
authors.initials: KY
authors.lastname: Ng
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Wai-U
authors.initials: WU
authors.lastname: Lo
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Pierra Y
authors.initials: PY
authors.lastname: Law
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Eileen Ling-Yi
authors.initials: EL
authors.lastname: Lai
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Queen Mary Hospital and Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
authors.forename: Kin-Hung
authors.initials: KH
authors.lastname: Chow
mesh_terms: D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000378:metabolism / Q000494:pharmacology*; D002999:Clone Cells; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D019450:Genes, MDR; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D017720:Molecular Epidemiology; D058885:Multilocus Sequence Typing; D009154:Mutation; D009582:Nitrofurantoin / Q000378:metabolism / Q000494:pharmacology*; D009601:Nitroreductases / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism*; D012093:Replicon; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology
chemical_list: D000892:Anti-Infective Agents, Urinary; D029968:Escherichia coli Proteins; D009582:Nitrofurantoin; C116053:NfsA protein, E coli; D009601:Nitroreductases