title: Clinical implications of reduced susceptibility to fluoroquinolones in paediatric Shigella sonnei and Shigella flexneri infections.
abstract: OBJECTIVE
  We aimed to quantify the impact of fluoroquinolone resistance on the clinical outcome of paediatric shigellosis patients treated with fluoroquinolones in southern Vietnam. Such information is important to inform therapeutic management for infections caused by this increasingly drug-resistant pathogen, responsible for high morbidity and mortality in young children globally.
  
  
  METHODS
  Clinical information and bacterial isolates were derived from a randomized controlled trial comparing gatifloxacin with ciprofloxacin for the treatment of paediatric shigellosis. Time-kill experiments were performed to evaluate the impact of MIC on the in vitro growth of Shigella and Cox regression modelling was used to compare clinical outcome between treatments and Shigella species.
  
  
  RESULTS
  Shigella flexneri patients treated with gatifloxacin had significantly worse outcomes than those treated with ciprofloxacin. However, the MICs of fluoroquinolones were not significantly associated with poorer outcome. The presence of S83L and A87T mutations in the gyrA gene significantly increased MICs of fluoroquinolones. Finally, elevated MICs and the presence of the qnrS gene allowed Shigella to replicate efficiently in vitro in high concentrations of ciprofloxacin.
  
  
  CONCLUSIONS
  We found that below the CLSI breakpoint, there was no association between MIC and clinical outcome in paediatric shigellosis infections. However, S. flexneri patients had worse clinical outcomes when treated with gatifloxacin in this study regardless of MIC. Additionally, Shigella harbouring the qnrS gene are able to replicate efficiently in high concentrations of ciprofloxacin and we hypothesize that such strains possess a competitive advantage against fluoroquinolone-susceptible strains due to enhanced shedding and transmission.
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, Oxford University, Oxford, UK The London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Corinne N
authors.initials: CN
authors.lastname: Thompson
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nga Tran Vu
authors.initials: NT
authors.lastname: Thieu
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Phat Voong
authors.initials: PV
authors.lastname: Vinh
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Anh Nguyen
authors.initials: AN
authors.lastname: Duc
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, Oxford University, Oxford, UK.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.affiliation: The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Ha
authors.initials: H
authors.lastname: Vinh
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, Oxford University, Oxford, UK.
authors.forename: James I
authors.initials: JI
authors.lastname: Campbell
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Dung Tran Thi
authors.initials: DT
authors.lastname: Ngoc
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Van Minh
authors.initials: NV
authors.lastname: Hoang
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tuyen Ha
authors.initials: TH
authors.lastname: Thanh
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Hao Chung
authors.initials: HC
authors.lastname: The
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: To Nguyen Thi
authors.initials: TN
authors.lastname: Nguyen
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Phu Huong
authors.initials: NP
authors.lastname: Lan
authors.affiliation: The London School of Hygiene and Tropical Medicine, London, UK School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Parry
authors.affiliation: The London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Nguyen Van Vinh
authors.initials: NV
authors.lastname: Chau
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, Oxford University, Oxford, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Thwaites
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Duy Pham
authors.initials: DP
authors.lastname: Thanh
authors.affiliation: Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam Centre for Tropical Medicine, Oxford University, Oxford, UK The London School of Hygiene and Tropical Medicine, London, UK sbaker@oucru.org.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004405:Dysentery, Bacillary / Q000188:drug therapy* / Q000382:microbiology* / Q000473:pathology; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D008826:Microbial Sensitivity Tests; D016032:Randomized Controlled Trials as Topic; D017422:Sequence Analysis, DNA; D012763:Shigella flexneri / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D012764:Shigella sonnei / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D017211:Treatment Failure; D014744:Vietnam
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D024841:Fluoroquinolones