Emergence of Resistance Mutations in Salmonella enterica Serovar Typhi Against Fluoroquinolones

Takashi Matono; Masatomo Morita; Koji Yahara; Ken-Ichi Lee; Hidemasa Izumiya; Mitsuo Kaku; Makoto Ohnishi

doi:10.1093/ofid/ofx230

Emergence of Resistance Mutations in Salmonella enterica Serovar Typhi Against Fluoroquinolones

Open Forum Infect Dis. 2017 Nov 2;4(4):ofx230. doi: 10.1093/ofid/ofx230. eCollection 2017 Fall.

Authors

Takashi Matono^{1

2}, Masatomo Morita¹, Koji Yahara³, Ken-Ichi Lee¹, Hidemasa Izumiya¹, Mitsuo Kaku², Makoto Ohnishi¹

Affiliations

¹ Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
² Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
³ Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo, Japan.

Abstract

Background: Little is known about the evolutionary process and emergence time of resistance mutations to fluoroquinolone in Salmonella enterica serovar Typhi.

Methods: We analyzed S. Typhi isolates collected from returned travelers between 2001 and 2016. Based on ciprofloxacin susceptibility, isolates were categorized as highly resistant (minimum inhibitory concentration [MIC] ≥ 4 μg/mL [CIP^HR]), resistant (MIC = 1-2 μg/mL [CIP^R]), intermediate susceptible (MIC = 0.12-0.5 μg/mL [CIP^I]), and susceptible (MIC ≤ 0.06 μg/mL [CIP^S]).

Results: A total of 107 isolates (33 CIP^HR, 14 CIP^R, 30 CIP^I, and 30 CIP^S) were analyzed by whole-genome sequencing; 2461 single nucleotide polymorphisms (SNPs) were identified. CIP^S had no mutations in the gyrA or parC genes, while each CIP^I had 1 of 3 single mutations in gyrA (encoding Ser83Phe [63.3%], Ser83Tyr [33.3%], or Asp87Asn [3.3%]). CIP^HR had the same 3 mutations: 2 SNPs in gyrA (encoding Ser83Phe and Asp87Asn) and a third in parC (encoding Ser80Ile). CIP^HR shared a common ancestor with CIP^R and CIP^I isolates harboring a single mutation in gyrA encoding Ser83Phe, suggesting that CIP^HR emerged 16 to 23 years ago.

Conclusions: Three SNPs-2 in gyrA and 1 in parC-are present in S. Typhi strains highly resistant to fluoroquinolone, which were found to have evolved in 1993-2000, approximately 10 years after the beginning of the ciprofloxacin era. Highly resistant strains with survival advantages arose from strains harboring a single mutation in gyrA encoding Ser83Phe. Judicious use of fluoroquinolones is warranted to prevent acceleration of such resistance mechanisms in the future.

Keywords: Salmonella enterica serovar Typhi; evolution; fluoroquinolone resistance; molecular.