title: A Multicountry Molecular Analysis of Salmonella enterica Serovar Typhi With Reduced Susceptibility to Ciprofloxacin in Sub-Saharan Africa.
abstract: BACKGROUND
  Salmonella enterica serovar Typhi is a predominant cause of bloodstream infections in sub-Saharan Africa (SSA). Increasing numbers of S. Typhi with resistance to ciprofloxacin have been reported from different parts of the world. However, data from SSA are limited. In this study, we aimed to measure the ciprofloxacin susceptibility of S. Typhi isolated from patients with febrile illness in SSA.
  
  
  METHODS
  Febrile patients from 9 sites within 6 countries in SSA with a body temperature of ≥38.0°C were enrolled in this study. Blood samples were obtained for bacterial culture, and Salmonella isolates were identified biochemically and confirmed by multiplex polymerase chain reaction (PCR). Antimicrobial susceptibility of all Salmonella isolates was performed by disk diffusion test, and minimum inhibitory concentrations (MICs) against ciprofloxacin were measured by Etest. All Salmonella isolates with reduced susceptibility to ciprofloxacin (MIC > 0.06 µg/mL) were screened for mutations in quinolone resistance-determining regions in target genes, and the presence of plasmid-mediated quinolone resistance (PMQR) genes was assessed by PCR.
  
  
  RESULTS
  A total of 8161 blood cultures were performed, and 100 (1.2%) S. Typhi, 2 (<0.1%) Salmonella enterica serovar Paratyphi A, and 27 (0.3%) nontyphoid Salmonella (NTS) were isolated. Multidrug-resistant S. Typhi were isolated in Kenya (79% [n = 38]) and Tanzania (89% [n = 8]) only. Reduced ciprofloxacin-susceptible (22% [n = 11]) S. Typhi were isolated only in Kenya. Among those 11 isolates, all had a Glu133Gly mutation in the gyrA gene combined with either a gyrA (Ser83Phe) or gyrB mutation (Ser464Phe). One Salmonella Paratyphi A isolate with reduced susceptibility to ciprofloxacin was found in Senegal, with 1 mutation in gyrA (Ser83Phe) and a second mutation in parC (Ser57Phe). Mutations in the parE gene and PMQR genes were not detected in any isolate.
  
  
  CONCLUSIONS
  Salmonella Typhi with reduced susceptibility to ciprofloxacin was not distributed homogenously throughout SSA. Its prevalence was very high in Kenya, and was not observed in other study countries. Continuous monitoring of antimicrobial susceptibility is required to follow the potential spread of antimicrobial-resistant isolates throughout SSA.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine German Center for Infection Research, partner site Hamburg-Borstel-Lübeck, Hamburg, Germany.
authors.forename: Hassan M
authors.initials: HM
authors.lastname: Al-Emran
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine German Center for Infection Research, partner site Hamburg-Borstel-Lübeck, Hamburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eibach
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine German Center for Infection Research, partner site Hamburg-Borstel-Lübeck, Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Krumkamp
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baker
authors.affiliation: Division of Infectious Diseases and International Health, Duke University Medical Center Duke Global Health Institute, Duke University, Durham, North Carolina.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Biggs
authors.affiliation: Bandim Health Project, Bissau, Guinea-Bissau Research Center for Vitamins and Vaccines, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Bjerregaard-Andersen
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Kenya Collaboration, Nairobi Global Health Institute, Emory University, Atlanta, Georgia.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Breiman
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka.
authors.forename: John D
authors.initials: JD
authors.lastname: Clemens
authors.affiliation: Division of Infectious Diseases and International Health, Duke University Medical Center Duke Global Health Institute, Duke University, Durham, North Carolina Kilimanjaro Christian Medical Centre, Moshi, Tanzania Centre for International Health, University of Otago, Dunedin, New Zealand.
authors.forename: John A
authors.initials: JA
authors.lastname: Crump
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Ligia Maria
authors.initials: LM
authors.lastname: Cruz Espinoza
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Jessica
authors.initials: J
authors.lastname: Deerin
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine German Center for Infection Research, partner site Hamburg-Borstel-Lübeck, Hamburg, Germany.
authors.forename: Denise Myriam
authors.initials: DM
authors.lastname: Dekker
authors.affiliation: Institut Pasteur de Dakar, Université Cheikh Anta Diop de Dakar, Senegal.
authors.forename: Amy
authors.initials: A
authors.lastname: Gassama Sow
authors.affiliation: Division of Infectious Diseases and International Health, Duke University Medical Center Duke Global Health Institute, Duke University, Durham, North Carolina.
authors.forename: Julian T
authors.initials: JT
authors.lastname: Hertz
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Justin
authors.initials: J
authors.lastname: Im
authors.affiliation: Ministry of Health.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ibrango
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Vera
authors.initials: V
authors.lastname: von Kalckreuth
authors.affiliation: Schiphra Hospital, Ouagadougou, Burkina Faso.
authors.forename: Leon Parfait
authors.initials: LP
authors.lastname: Kabore
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Frank
authors.initials: F
authors.lastname: Konings
authors.affiliation: Bandim Health Project, Bissau, Guinea-Bissau Research Center for Vitamins and Vaccines, Copenhagen, Denmark.
authors.forename: Sandra Valborg
authors.initials: SV
authors.lastname: Løfberg
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine Institute of Tropical Medicine, Eberhard-Karls University Tübingen, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
authors.affiliation: National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Mintz
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Kenya Collaboration, Nairobi.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Montgomery
authors.affiliation: Kenya Medical Research Institute-Centers for Disease Control and Prevention Kenya Collaboration, Nairobi.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Olack
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Gi Deok
authors.initials: GD
authors.lastname: Pak
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Ursula
authors.initials: U
authors.lastname: Panzner
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: University of Antananarivo, Madagascar.
authors.forename: Jean Luco Tsiriniaina
authors.initials: JL
authors.lastname: Razafindrabe
authors.affiliation: University of Antananarivo, Madagascar.
authors.forename: Henintsoa
authors.initials: H
authors.lastname: Rabezanahary
authors.affiliation: University of Antananarivo, Madagascar.
authors.forename: Jean Philibert
authors.initials: JP
authors.lastname: Rakotondrainiarivelo
authors.affiliation: University of Antananarivo, Madagascar.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rakotozandrindrainy
authors.affiliation: University of Antananarivo, Madagascar.
authors.forename: Tiana Mirana
authors.initials: TM
authors.lastname: Raminosoa
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea Institute of Medical Microbiology, University of Cologne, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Schütt-Gerowitt
authors.affiliation: Institute of Medical Microbiology, University of Cologne, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sampo
authors.affiliation: University of Ouagadougou, Burkina Faso.
authors.forename: Abdramane Bassiahi
authors.initials: AB
authors.lastname: Soura
authors.affiliation: Institut Pasteur de Dakar, Université Cheikh Anta Diop de Dakar, Senegal.
authors.forename: Adama
authors.initials: A
authors.lastname: Tall
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Michelle
authors.initials: M
authors.lastname: Warren
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wierzba
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine German Center for Infection Research, partner site Hamburg-Borstel-Lübeck, Hamburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: May
authors.affiliation: International Vaccine Institute, Seoul, Republic of Korea.
authors.forename: Florian
authors.initials: F
authors.lastname: Marks
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D002939:Ciprofloxacin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008826:Microbial Sensitivity Tests; D017720:Molecular Epidemiology; D012485:Salmonella typhi / Q000187:drug effects* / Q000235:genetics; D014435:Typhoid Fever / Q000453:epidemiology / Q000382:microbiology*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin
keywords: S. Typhi; ciprofloxacin; sub-Saharan Africa; susceptible