Molecular characterization of ciprofloxacin-resistant Salmonella enterica serovar Typhi and Paratyphi A causing enteric fever in India

J Antimicrob Chemother. 2006 Dec;58(6):1139-44. doi: 10.1093/jac/dkl391. Epub 2006 Oct 28.

Abstract

Objectives: To define the genetic characteristics and resistance mechanisms of clinical isolates of Salmonella enterica serovar Typhi (S. Typhi) and S. enterica serovar Paratyphi A (S. Paratyphi A) exhibiting high-level fluoroquinolones resistance.

Methods: Three S. Typhi and two S. Paratyphi A ciprofloxacin-resistant isolates (MICs > 4 mg/L) were compared with isolates with reduced susceptibility to ciprofloxacin (MICs 0.125-1 mg/L) by PFGE, plasmid analysis, presence of integrons and nucleotide changes in topoisomerase genes.

Results: In S. Typhi and Paratyphi A, a single gyrA mutation (Ser-83-->Phe or Ser-83-->Tyr) was associated with reduced susceptibility to ciprofloxacin (MICs 0.125-1 mg/L); an additional mutation in parC (Ser-80-->Ile, Ser-80-->Arg, Asp-69-->Glu or Gly-78-->Asp) was accompanied by an increase in ciprofloxacin MIC (> or = 0.5 mg/L). Three mutations conferred ciprofloxacin resistance: two in gyrA (Ser-83-->Phe and Asp-87-->Asn or Asp-87-->Gly) and one in parC. This is the first report of parC mutations in S. Typhi. Ciprofloxacin-resistant S. Typhi and S. Paratyphi A differed in their MICs and mutations in gyrA and parC. Moreover S. Typhi harboured a 50 kb transferable plasmid carrying a class 1 integron (dfrA15/aadA1) that confers resistance to co-trimoxazole and tetracycline but not to ciprofloxacin. PFGE revealed undistinguishable XbaI fragment patterns in ciprofloxacin-resistant S. Typhi as well as in S. Paratyphi A isolates and showed that ciprofloxacin-resistant S. Typhi have emerged from a clonally related isolate with reduced susceptibility to ciprofloxacin after sequential acquisition of a second mutation in gyrA.

Conclusions: To our knowledge this is the first report of molecular characterization of S. Typhi with full resistance to ciprofloxacin. Notably, the presence of a plasmid-borne integron in ciprofloxacin-resistant S. Typhi may lead to a situation of untreatable enteric fever.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Anti-Bacterial Agents / pharmacology*
  • Ciprofloxacin / pharmacology*
  • DNA Gyrase / genetics
  • DNA Topoisomerase IV / genetics
  • DNA Topoisomerases
  • DNA, Bacterial / genetics
  • Deoxyribonucleases, Type II Site-Specific / metabolism
  • Drug Resistance, Bacterial / genetics*
  • Electrophoresis, Gel, Pulsed-Field
  • Humans
  • India
  • Integrons
  • Microbial Sensitivity Tests
  • Mutation, Missense
  • Paratyphoid Fever / microbiology*
  • Plasmids
  • Salmonella paratyphi A / drug effects*
  • Salmonella paratyphi A / genetics
  • Salmonella paratyphi A / isolation & purification
  • Salmonella typhi / drug effects*
  • Salmonella typhi / genetics
  • Salmonella typhi / isolation & purification
  • Sequence Analysis, DNA
  • Tetracycline / pharmacology
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacology
  • Typhoid Fever / microbiology*

Substances

  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Ciprofloxacin
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • endodeoxyribonuclease XBAI
  • Deoxyribonucleases, Type II Site-Specific
  • DNA Topoisomerase IV
  • DNA Topoisomerases
  • DNA Gyrase
  • Tetracycline