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Antimicrob. Agents Chemother. doi:10.1128/AAC.00294-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Salmonella enterica Serovar Typhi: Antimicrobial drug resistance in Asia and the molecular mechanism of reduced susceptibility to the fluoroquinolones

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK; Patan Hospital, Kathmandu, Nepal; International Vaccine Institute, Seoul, South Korea; Department of Paediatrics, Aga Khan University, Karachi, Pakistan; National Institute of Cholera and Enteric Diseases, Kolkata, India; National Institute of Health Research and Development, Jakarta, Indonesia; Guangxi Centers for Disease Control and Prevention, Nanning, Guangxi, China; National Institute of Hygiene and Epidemiology, Hanoi, Vietnam; International Centre for Diarrheal Disease Research (ICDDR), Dhaka, Bangladesh; The Wellcome Trust Sanger Institute, Cambridge, UK; Department of Medical Microbiology and Genitourinary Medicine, Duncan Building, University of Liverpool, UK; London School of Hygiene and Tropical Medicine, London, UK; Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait; Wellcome Trust-Mahosot Hospital, Oxford Tropical Medicine Research Collaboration, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People's Democratic Republic; An Giang Provincial Hospital, Long Xuyen, An Giang, Vietnam; 18. Dong Thap Provincial Hospital, Cao Lanh, Dong Thap, Vietnam

^* To whom correspondence should be addressed. Email: cdolecek{at}oucru.org.

	Abstract

This study describes the pattern and extent of drug resistance in 1821 strains of Salmonella enterica serovar Typhi (S. Typhi) isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibility to the fluoroquinolones in these strains. In 1440 S. Typhi collected in southern Vietnam, the proportion of MDR has remained at high levels since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 S. Typhi from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan and central Vietnam collected in 2002 to 2004, variable rates of multidrug resistance (16-37%) and nalidixic acid resistance (5-51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia.

The Ser83Phe substitution in GyrA was the predominant alteration in S. Typhi from Vietnam (117/127 isolates, 92.1%). No mutations in gyrB, parC and parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harbouring a single amino acid substitution at codon 83 or 87 of GyrA, this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of S. Typhi harbouring both the single and double amino acid substitutions.