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Antimicrobial Drug Resistance of Salmonella enterica Serovar Typhi in Asia and Molecular Mechanism of Reduced Susceptibility to the Fluoroquinolones

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam,¹ The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam,² Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, United Kingdom,³ Patan Hospital, Kathmandu, Nepal,⁴ International Vaccine Institute, Seoul, South Korea,⁵ Department of Paediatrics, Aga Khan University, Karachi, Pakistan,⁶ National Institute of Cholera and Enteric Diseases, Kolkata, India,⁷ National Institute of Health Research and Development, Jakarta, Indonesia,⁸ Guangxi Centers for Disease Control and Prevention, Nanning, Guangxi, China,⁹ National Institute of Hygiene and Epidemiology, Hanoi, Vietnam,¹⁰ International Centre for Diarrheal Disease Research (ICDDR), Dhaka, Bangladesh,¹¹ The Wellcome Trust Sanger Institute, Cambridge, United Kingdom,¹² Department of Medical Microbiology and Genitourinary Medicine, Duncan Building, University of Liverpool, United Kingdom,¹³ London School of Hygiene and Tropical Medicine, London, United Kingdom,¹⁴ Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait,¹⁵ Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao People's Democratic Republic,¹⁶ An Giang Provincial Hospital, Long Xuyen, An Giang, Vietnam,¹⁷ Dong Thap Provincial Hospital, Cao Lanh, Dong Thap, Vietnam,¹⁸

Received 1 March 2007/ Returned for modification 28 May 2007/ Accepted 24 September 2007

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high 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 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 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 serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring 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 serovar Typhi harboring both the single- and double-amino-acid substitutions.

Published ahead of print on 1 October 2007.