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Antimicrobial Agents and Chemotherapy, October 2006, p. 3516-3517, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00667-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Multidrug-Resistant Salmonella enterica Serovar Typhi Isolates with High-Level Resistance to Ciprofloxacin in Dhaka, Bangladesh

Top Letter References

 
Typhoid fever due to multidrug-resistant Salmonella enterica serovar Typhi is a global public health problem, with an estimated 30 million cases and 600,000 deaths annually (7). Since the beginning of the 1990s, there has been an increasing prevalence of multidrug resistance to the first-line antimicrobials, such as chloramphenicol, ampicillin, and co-trimoxazole, shifting the drug of choice for the treatment of typhoid fever to fluoroquinolones on the Indian subcontinent (4, 5). Several clinical failures due to infection with isolates of S. enterica serovar Typhi with decreased susceptibilities to fluoroquinolones but resistance to nalidixic acid, and their emergence, incidence, and spread have been reported from other developing countries (2, 3). The purpose of this report was to investigate whether such isolates were present in Bangladesh during the period between January and December 2005 by retrospective analysis of the data for blood cultures and antimicrobial susceptibility tests performed in the Clinical Microbiology Laboratory of the International Centre for Health and Population Research, Bangladesh (ICDDR,B). This is the first report to document the prevalence of isolates of S. enterica serovar Typhi expressing high-level resistance to ciprofloxacin in Bangladesh.

S. enterica serovar Typhi strains were isolated by blood culture by using the BactAlert 3D system (BioMerieux, Marcy l'Etoile, France). Antimicrobial susceptibility was determined by the standard disk diffusion method of the Clinical and Laboratory Standards Institute (CLSI), and the highly resistant isolates were subjected to MIC determination by Etest (AB Biodisk, Solna, Sweden). In 2005, 9,600 blood cultures were processed and S. enterica serovar Typhi was isolated from 428 patients (4.5%). Of these, 388 isolates (90.7%) of S. enterica serovar Typhi showed resistance to nalidixic acid. The ciprofloxacin susceptibilities of these isolates varied; 50 isolates (11.7%) had ciprofloxacin zone diameters of 21 mm (regarded as susceptible by CLSI), 368 (88.3%) had zone diameters of 16 to 20 mm (regarded as intermediate by CLSI), and 10 isolates (2.3%) had zone diameters of 15 mm or less (regarded as resistant by CLSI). On repeat testing, these 10 resistant isolates did not show any zone of inhibition by the disk diffusion method. The phenotypic pattern of resistance showed that 91.4% of the isolates were multidrug resistant (Table 1). The ciprofloxacin MICs of the 10 resistant isolates were also high and varied between 6.0 and 16.0 µg/ml, thus exceeding the CLSI resistance breakpoint of 4 µg/ml. The levels of resistance to nalidixic acid expressed by all 10 ciprofloxacin-resistant isolates were even higher (>256 µg/ml). All isolates, including the 10 highly resistant isolates, however, were susceptible to ceftriaxone, with zone diameters of 21 mm (regarded as susceptible by CLSI).

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TABLE 1. Resistance phenotype and MICs of ciprofloxacin and nalidixic acid for Salmonella enterica serovar Typhi (n = 428), January to December 2005

In the mid-1990s, the emergence of S. enterica serovar Typhi and S. enterica serovar Paratyphi A strains with decreased susceptibilities to fluoroquinolones was reported from the Indian subcontinent and southeast and central Asia. Disk diffusion testing revealed that these isolates were resistant to nalidixic acid but sensitive to ciprofloxacin, according to the current CLSI interpretive criteria. However, the MICs of ciprofloxacin increased from 0.25 to 4 µg/ml, which are 10- to 100-fold higher than those for the usual nalidixic acid-susceptible isolates, but these isolates were still categorized as "susceptible" by current CLSI criteria. This "susceptible" reporting prompted clinicians to use ciprofloxacin, which resulted in delayed clinical responses or treatment failures in the ciprofloxacin-treated cases of typhoid fever caused by these isolates. Accordingly, the CLSI currently recommends the routine use of disk diffusion testing of nalidixic acid as a marker for the detection of reduced susceptibility of Salmonella spp. to fluoroquinolones. Resistance to nalidixic acid in S. enterica serovar Typhi has been reported to be mediated by a single point mutation at the quinolone resistance-determining region of the gyrA gene. Complete resistance to fluoroquinolones is usually associated with a double mutation in gyrA, but multiple mutations with the involvement of other genes have also been mentioned (1). The injudicious administration and rampant use of quinolones in Bangladesh probably contributed to the high prevalence of reduced susceptibility (>88%) and the emergence of very high level or complete resistance (>4 µg/ml) of isolates of S. enterica serovar Typhi to fluoroquinolones. The prevalence of multidrug resistance (resistance to two or more drugs) is also high (91.4%). Alternative effective drugs available for treatment of these resistant isolates are ceftriaxone and cefixime, but they are expensive and one ceftriaxone-resistant case of S. enterica serovar Typhi infection has been reported (6). We therefore face the imminent prospect of encountering untreatable typhoid fever in the near future. A national guideline on the proper usage of antibiotics is required for urgent implementation in Bangladesh. In addition, a reevaluation of the MIC breakpoint criteria by the CLSI is necessary, as the current reference standards are unable to differentiate between fully susceptible isolates and isolates showing reduce susceptibility.

 
This study was funded by the ICDDR,B Centre for Health and Population Research and its donors, who provide unrestricted support to the center for its operations and research. Current donors providing unrestricted support include the Australian International Development Agency; the Canadian International Development Agency; Department for International Development, United Kingdom; the government of Bangladesh; the government of Japan; the government of Sri Lanka; the government of The Netherlands; the Swedish International Development Cooperative Agency; and the Swiss Development Cooperation. We gratefully acknowledge these donors for their support and commitment to the center's research efforts.

Top Letter References

 

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1. Hirose, K., A. Hashimoto, K. Tamura, Y. Kawamura, T. Ezaki, H. Sagara, and H. Watanabe. 2002. DNA sequence analysis of DNA gyrase and DNA topoisomerase IV quinolone resistance-determining regions of Salmonella enterica serovar Typhi and serovar Paratyphi A. Antimicrob. Agents Chemother. 46:3249-3252.[Abstract/Free Full Text]
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2. Lee, K., D. Yong, J. H. Yum, Y. S. Lim, H. S. Kim, B. K. Lee, and Y. Chong. 2004. Emergence of multidrug resistant Salmonella enterica serovar Typhi in Korea. Antimicrob. Agents Chemother. 48:4130-4135.[Abstract/Free Full Text]
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3. Murdoch, D. A., N. A. Banatvala, A. Bone, B. I. Shoismatulloev, L. R. Ward, and E. J. Threlfall. 1998. Epidemic ciprofloxacin-resistant Salmonella typhi in Tajikistan. Lancet 351:339.[CrossRef][Medline]
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4. Rahman, M. M., J. A. Haq, M. A. Morshed, and M. A. Rahman. 2005. Salmonella enterica serovar Typhi with decreased susceptibility to ciprofloxacin—an emerging problem in Bangladesh. Int. J. Antimicrob. Agents 25:345-346.[CrossRef][Medline]
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5. Renuka, K., S. Sood, B. K. Das, and A. Kapil. 2005. High-level ciprofloxacin resistance in Salmonella enterica serotype Typhi in India. J. Med. Microbiol. 54:999-1000.[Free Full Text]
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6. Saha, S. K., S. Y. Talukder, M. Islam, and S. Saha. 1999. A highly ceftriaxone-resistant Salmonella typhi in Bangladesh. Pediatr. Infect. Dis. J. 18:387.[CrossRef][Medline]
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7. World Health Organization. 1998. Typhoid fever. Wkly. Epidemiol. Rec. 73:284.

						Dilruba Ahmed Liton T. D'Costa Khorshed Alam G. Balakrish Nair M. Anowar Hossain* Clinical Laboratory Services Laboratory Sciences Division ICDDR,B Centre for Health and Population Research Dhaka, Bangladesh
						* Phone: 880-2-8826391, Fax: 880-2-8812529, E-mail: anowar{at}icddrb.org

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Antimicrobial Agents and Chemotherapy, October 2006, p. 3516-3517, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00667-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Thaver, D., Zaidi, A. K M, Critchley, J., Azmatullah, A., Madni, S. A., Bhutta, Z. A (2009). A comparison of fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis. BMJ 338: b1865-b1865 [Abstract] [Full Text]  
• Dimitrov, T., Dashti, A. A., Albaksami, O., Udo, E. E., Jadaon, M. M., Albert, M. J. (2009). Ciprofloxacin-Resistant Salmonella enterica Serovar Typhi from Kuwait with Novel Mutations in gyrA and parC Genes. J. Clin. Microbiol. 47: 208-211 [Abstract] [Full Text]  

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