title: A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.
abstract: The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure.
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Duy
authors.initials: D
authors.lastname: Pham Thanh
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Karkey
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Sabina
authors.initials: S
authors.lastname: Dongol
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Nhan
authors.initials: N
authors.lastname: Ho Thi
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.|The London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Corinne N
authors.initials: CN
authors.lastname: Thompson
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Maia A
authors.identifier: http://orcid.org/0000-0003-0529-2228
authors.initials: MA
authors.lastname: Rabaa
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Amit
authors.initials: A
authors.lastname: Arjyal
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Holt
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wong
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Nga
authors.initials: N
authors.lastname: Tran Vu Thieu
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Phat
authors.initials: P
authors.lastname: Voong Vinh
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Tuyen
authors.initials: T
authors.lastname: Ha Thanh
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Ashish
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Saroj Kumar
authors.initials: SK
authors.lastname: Shrestha
authors.affiliation: Civil Services Hospital, Kathmandu, Nepal.
authors.forename: Damoder
authors.initials: D
authors.lastname: Gajurel
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Pickard
authors.affiliation: The London School of Hygiene and Tropical Medicine, London, United Kingdom.|School of Tropical Medicine and Global Health, Department of Clinical Research, Nagasaki University, Nagasaki, Japan.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Parry
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.|Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: Christiane
authors.initials: C
authors.lastname: Dolecek
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: Oxford University Clinical Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Buddha
authors.initials: B
authors.lastname: Basnyat
authors.affiliation: The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Oxford University, Oxford, United Kingdom.|The London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015373:Bacterial Typing Techniques; D002443:Ceftriaxone / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000627:therapeutic use*; D000077734:Gatifloxacin; D005838:Genotype; D006801:Humans; D009390:Nepal; D012485:Salmonella typhi / Q000145:classification / Q000187:drug effects* / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D014435:Typhoid Fever / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; D002443:Ceftriaxone; D000077734:Gatifloxacin
keywords: <i>s. enterica</i> serovar typhi; H58; epidemiology; fluoroquinolones; global health; human; infectious disease; microbiology; nepal; randomised controlled trial; treatment failure; typhoid fever