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J Med Microbiol 54 (2005), 999-1000; DOI: 10.1099/jmm.0.45966-0
© 2005 Society for General Microbiology
ISSN 0022-2615

High-level ciprofloxacin resistance in Salmonella enterica serotype Typhi in India

K Renuka, Seema Sood, Bimal K Das and Arti Kapil

Department of Microbiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Correspondence: Arti Kapil (akapil_micro{at}yahoo.com)


Enteric fever remains a major public health problem in developing countries. The antimicrobials used for treatment of enteric fever used to be chloramphenicol, trimethoprim-sulfamethoxazole and ampicillin. However, after the development of resistance to these agents, fluoroquinolones, such as ciprofloxacin, became the drug of choice for the treatment of this infection (Eykyn & Williams, 1987; Mandal, 1991). However, there have been several reports, including from India, of therapeutic failure of ciprofloxacin in patients with enteric fever (Aarestrup et al., 2003; Kapil et al., 1999). All these strains were interpreted as ciprofloxacin susceptible by the standard antibiotic susceptibility tests done in a clinical laboratory using the NCCLS guidelines (NCCLS, 2002) but showed a gradual increase in the MIC of ciprofloxacin, although the MIC values were still below the breakpoint of resistance (Jesudason et al., 1996; Kapil et al., 2002). However, recently there has been a report of the isolation of a strain of Salmonella enterica serotype Paratyphi A (S. Paratyphi A) showing resistance to ciprofloxacin with a MIC value of 8 µg ml–1 from Pondicherry, India (Harish et al., 2004). To our knowledge there have been no reports of absolute resistance to ciprofloxacin in S. enterica serotype Typhi (S. Typhi). We report the isolation of a strain of S. Typhi showing high-level resistance to ciprofloxacin.

The strain was isolated from the blood sample of a 19-year-old male presenting with enteric fever at All India Institute of Medical Sciences Hospital, New Delhi, India. The antimicrobial susceptibility was determined by the disc diffusion method as per the NCCLS guidelines. The isolate was found to be resistant to ciprofloxacin, chloramphenicol, ampicillin and co-trimoxazole, and susceptible to ceftriaxone. The MIC of ciprofloxacin as determined by the E-test method (AB Biodisk) was found to be 16 µg ml–1. The gyrA gene of this isolate was amplified and sequenced according to a protocol described previously (Renuka et al., 2004). We found that this strain had two mutations in the quinolone-resistance-determining region (QRDR), namely substitution of phenylalanine for serine at position 83 (Ser83 to Phe) and asparagine for aspartate at position 87 (Asp87 to Asn).

The mechanism of fluoroquinolone resistance in S. Typhi and S. Paratyphi A is not completely understood and there have been only a few studies on fluoroquinolone resistance in these organisms (Table 1). These studies as well as the present study have found that a single mutation in the gyrA gene is sufficient to confer resistance to nalidixic acid and reduced susceptibility to fluoroquinolones, and a second mutation leads to high-level fluoroquinolone resistance (MIC range 8 to >32 µg ml–1). Moreover, the varying levels of the ciprofloxacin MIC in strains with the same type of gyrA mutation suggests that some other mechanism(s) may also be involved in high-level fluoroquinolone resistance in S. Typhi and S. Paratyphi A.


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  		Table 1. Studies reporting gyrA mutations in S. enterica serotype Typhi and S. enterica serotype Paratyphi A
 

Mutations conferring resistance to quinolones occur in a stepwise manner and are demonstrated by a gradual increase in the MIC values. It has been shown in studies involving well-characterized single-step mutants that each mutation affecting quinolone-resistance reduces the susceptibility 4–8-fold (Sanders, 2001). The sudden emergence of a strain of S. Typhi with such a high level of resistance to ciprofloxacin has therefore come as a surprise. Nevertheless, it once again emphasizes the need for continuous surveillance of antimicrobial resistance among clinical isolates of S. Typhi and S. Paratyphi A and leaves us with one question: should fluoroquinolones be considered as the first-line treatment for enteric fever any longer?


   References
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  • Brown, J. C., Shanahan, P. M., Jesudason, M. V., Thomson, C. J. & Amyes S. G. (1996). Mutations responsible for reduced susceptibility to 4-quinolones in clinical isolates of multi-resistant Salmonella typhi in India. J Antimicrob Chemother 37, 891–900.[Abstract/Free Full Text]

  • Eykyn, S. J. & Williams, H. (1987). Treatment of multiresistant Salmonella typhi with oral ciprofloxacin. Lancet ii, 1407–1408.

  • Harish, B. N., Madhulika, U. & Parija, S. C. (2004). Isolated high-level ciprofloxacin resistance in Salmonella enterica subsp.enterica serotype Paratyphi A. J Med Microbiol 53, 819. 819.[Free Full Text]

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