Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study.
BACKGROUND
Shigellosis is an acute, severe bacterial colitis that, in high-income countries, is typically associated with travel to high-risk regions (Africa, Asia, and Latin America). Since the 1970s, shigellosis has also been reported as a sexually transmitted infection in men who have sex with men (MSM), in whom transmission is an important component of shigellosis epidemiology in high-income nations. We aimed to use sophisticated subtyping and international sampling to determine factors driving shigellosis emergence in MSM linked to an outbreak in the UK.


METHODS
We did a large-scale, cross-sectional genomic epidemiological study of shigellosis cases collected from 29 countries between December, 1995, and June 8, 2014. Focusing on an ongoing epidemic in the UK, we collected and whole-genome sequenced clinical isolates of Shigella flexneri serotype 3a from high-risk and low-risk regions, including cases associated with travel and sex between men. We examined relationships between geographical, demographic, and clinical patient data with the isolate antimicrobial susceptibility, genetic data, and inferred evolutionary relationships.


RESULTS
We obtained 331 clinical isolates of S flexneri serotype 3a, including 275 from low-risk regions (44 from individuals who travelled to high-risk regions), 52 from high-risk regions, and four outgroup samples (ie, closely related, but genetically distinct isolates used to determine the root of the phylogenetic tree). We identified a recently emerged lineage of S flexneri 3a that has spread intercontinentally in less than 20 years throughout regions traditionally at low risk for shigellosis via sexual transmission in MSM. The lineage had acquired multiple antimicrobial resistance determinants, and prevailing sublineages were strongly associated with resistance to the macrolide azithromycin. Eight (4%) of 206 isolates from the MSM-associated lineage were obtained from patients who had previously provided an isolate; these serial isolations indicated atypical infection patterns (eg, reinfection).


CONCLUSIONS
We identified transmission-facilitating behaviours and atypical course(s) of infection as precipitating factors in shigellosis-affected MSM. The intercontinental spread of antimicrobial-resistant shigella through established transmission routes emphasises the need for new approaches to tackle the public health challenge of sexually transmitted infections in MSM.


BACKGROUND
Wellcome Trust (grant number 098051).
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Kate S
KS
Baker
Gastrointestinal Bacteria Reference Unit, Public Health England, London, UK.
Timothy J
TJ
Dallman
Gastrointestinal Bacteria Reference Unit, Public Health England, London, UK.
Philip M
PM
Ashton
Gastrointestinal Bacteria Reference Unit, Public Health England, London, UK.
Martin
M
Day
Department of HIV and STIs, Centre for Infectious Disease Surveillance and Control, Public Health England, London, UK.
Gwenda
G
Hughes
Field Epidemiology Services, Public Health England, London, UK.
Paul D
PD
Crook
Department of HIV and STIs, Centre for Infectious Disease Surveillance and Control, Public Health England, London, UK.
Victoria L
VL
Gilbart
Public Health Ontario Laboratories, Toronto, ON, Canada.
Sandra
S
Zittermann
Public Health Ontario Laboratories, Toronto, ON, Canada.
Vanessa G
VG
Allen
Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia; Infectious Diseases Department, Austin Health, Heidelberg, VIC, Australia; Department of Microbiology, Monash University, Clayton, VIC, Australia.
Benjamin P
BP
Howden
Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
Takehiro
T
Tomita
Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia.
Mary
M
Valcanis
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Simon R
SR
Harris
Cardiff School of Biosciences, Sir Martin Evans Building, Museum Avenue, Cardiff, UK.
Thomas R
TR
Connor
Marie Bashir Institute for Infectious Diseases and Biosecurity and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Centre for Infectious Diseases and Microbiology-Public Health, Institute of Clinical Pathology and Medical Research-Pathology West, Westmead Hospital, Sydney, NSW, Australia; NSW Enteric Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, NSW, Australia.
Vitali
V
Sintchenko
Centre for Infectious Diseases and Microbiology-Public Health, Institute of Clinical Pathology and Medical Research-Pathology West, Westmead Hospital, Sydney, NSW, Australia; NSW Enteric Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, NSW, Australia.
Peter
P
Howard
NSW Enteric Reference Laboratory, Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research-Pathology West, Sydney, NSW, Australia.
Jeremy D
JD
Brown
The ithree institute, University of Technology Sydney, Sydney, NSW, Australia.
Nicola K
NK
Petty
Institut Pasteur, Unité des Bactéries Pathogènes Entériques, Paris, France.
Malika
M
Gouali
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Duy Pham
DP
Thanh
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Centre for Enteric Diseases, National Institute for Communicable Diseases, Johannesburg, South Africa.
Karen H
KH
Keddy
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Centre for Enteric Diseases, National Institute for Communicable Diseases, Johannesburg, South Africa.
Anthony M
AM
Smith
International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh.
Kaisar A
KA
Talukder
International Centre for Diarrhoeal Disease Research Bangladesh, Dhaka, Bangladesh.
Shah M
SM
Faruque
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
Julian
J
Parkhill
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; The London School of Hygiene & Tropical Medicine, London, UK.
Stephen
S
Baker
Institut Pasteur, Unité des Bactéries Pathogènes Entériques, Paris, France.
François-Xavier
FX
Weill
Gastrointestinal Bacteria Reference Unit, Public Health England, London, UK.
Claire
C
Jenkins
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK; The London School of Hygiene & Tropical Medicine, London, UK. Electronic address: nrt@sanger.ac.uk.
Nicholas R
NR
Thomson
D000293:Adolescent; D000328:Adult; D000368:Aged; D017963:Azithromycin / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004196:Disease Outbreaks; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000453:epidemiology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D012306:Risk; D012749:Sexually Transmitted Diseases / Q000188:drug therapy* / Q000453:epidemiology* / Q000382:microbiology; D012763:Shigella flexneri / Q000187:drug effects; D014195:Travel; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
D017963:Azithromycin