Detection of decreasedin vitro susceptibility to ciprofloxacin in Salmonella enterica serotypes Typhi and Paratyphi A

Sir, Ciprofloxacin is now the first-line drug for the treatment of enteric fever and at the PHLS Laboratory of Enteric Pathogens (LEP) all strains of Salmonella enterica serotypes Typhi and Paratyphi A, B and C are tested for resistance to ciprofloxacin using an agar dilution breakpoint method.1 The levels of ciprofloxacin incorporated into the media are 0.125 and 1 mg/L. Strains resistant at 0.125 mg/L but susceptible at 1 mg/L are regarded as exhibiting low-level resistance or decreased susceptibility to this antimicrobial (CpL), whereas those resistant at 1 mg/L are regarded as showing high-level resistance (CpH). Since 1994, an increasing number of strains of S. Typhi from patients in the UK have exhibited CpL, often in addition to resistance to chloramphenicol, ampicillin and trimethoprim. In 1999, 23% of 179 strains exhibited CpL, of which 59% were also resistant to chloramphenicol, ampicillin and trimethoprim.2 In 2000 the proportion of CpL isolates had again increased, with 36% of 194 S. Typhi isolates exhibiting such resistance. Of these, 52% were additionally resistant to chloramphenicol, ampicillin and trimethoprim. CpL was particularly common in strains of Vi-phage type E1, but was also identified in five other phage types, including A, E9, UVS, DVS and Vi-negative. A similar increase in CpL isolates has also been observed in S. Paratyphi A, with 33 of the 148 (22%) strains isolated in 2000 exhibiting CpL. Of these CpL isolates, 5% were also resistant to chloramphenicol, ampicillin and trimethoprim. In contrast, in 1999 only 12 of 162 (7%) isolates exhibited decreased susceptibility to ciprofloxacin. None of these isolates was resistant to other antimicrobials. When studied by breakpoint with doubling concentrations of ciprofloxacin incorporated into the agar, the MICs for isolates of both CpLS. Typhi and S. Paratyphi A ranged from 0.25 to 1 mg/L. The majority of such strains also exhibited high-level resistance to nalidixic acid (MIC > 256 mg/L).2 As yet no strains of either serotype with CpH have been identified. The most common method of testing for resistance to ciprofloxacin in clinical laboratories is by disc diffusion, using discs with concentrations of ciprofloxacin ranging from 1 to 5 mg/L. As a consequence of this, in several cases decreased susceptibility to ciprofloxacin has not been detected and treatment failures have been reported.2,3 This has been particularly evident when nalidixic acid has not been included in the antimicrobials tested. Since 1999, the policy of the LEP has been to use the Etest for the determination of levels of resistance to ciprofloxacin in strains of S. Typhi and S. Paratyphi A resistant to nalidixic acid and with resistance to ciprofloxacin at 0.125 mg/L by breakpoint. A total of 81 strains of S. Typhi (30 in 1999, 51 in 2000) and 34 strains of S. Paratyphi A (eight in 1999, 26 in 2000) with CpL have now been studied by this method (Table). The results are interesting in that they demonstrate a substantial difference in MIC range between the two serotypes, with the most common MIC for S. Typhi being 0.25 mg/L and that for S. Paratyphi A being 0.5 mg/L. The primary mechanism of resistance to nalidixic acid and ciprofloxacin commonly involves a single nucleotide mutation of the gyrA gene. Mutations in gyrA for the two serotypes are currently under investigation. Strains of CpLS. Typhi and S. Paratyphi A are now endemic in many countries in the Indian subcontinent.2,4 As the majority of infections with these serotypes in the UK are in patients returning from such areas, the number of such cases is increasing. The use of the Etest has provided us with a rapid and sensitive method for informing clinicians of the exact MICs of ciprofloxacin. In several cases this has been instrumental in changes of therapy, ceftriaxone being a favoured alternative when patients infected with CpL strains have not responded to treatment with ciprofloxacin. In Enterobacteriaceae, testing for resistance to ciprofloxacin is based on BSAC and NCCLS breakpoints of 1 mg/L (low) or 4 mg/L (BSAC)5/5 mg/L (NCCLS) (high).6 Because of the increasing incidence of treatment failures in cases of infections with S. Typhi and S. Paratyphi A with MICs of <1 mg/L by Etest, a rethink of these levels may be justified. Table. Ciprofloxacin MICs by Etest for strains of S. Typhi and S. Paratyphi A with decreased susceptibility, as determined by a breakpoint method, 1999–2000 Table. Ciprofloxacin MICs by Etest for strains of S. Typhi and S. Paratyphi A with decreased susceptibility, as determined by a breakpoint method, 1999–2000