title: Effects of control interventions on Clostridium difficile infection in England: an observational study.
abstract: BACKGROUND
  The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility.
  
  
  METHODS
  Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998-2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses.
  
  
  RESULTS
  National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations <0·59). Regionally, C difficile decline was driven by elimination of fluoroquinolone-resistant isolates (approximately 67% of Oxfordshire infections in September, 2006, falling to approximately 3% in February, 2013; annual incidence rate ratio 0·52, 95% CI 0·48-0·56 vs fluoroquinolone-susceptible isolates: 1·02, 0·97-1·08). C difficile infections caused by fluoroquinolone-resistant isolates declined in four distinct genotypes (p<0·01). The regions of phylogenies containing fluoroquinolone-resistant isolates were short-branched and geographically structured, consistent with selection and rapid transmission. The importance of fluoroquinolone restriction over infection control was shown by significant declines in inferred secondary (transmitted) cases caused by fluoroquinolone-resistant isolates with or without hospital contact (p<0·0001) versus no change in either group of cases caused by fluoroquinolone-susceptible isolates (p>0·2).
  
  
  CONCLUSIONS
  Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes.
  
  
  BACKGROUND
  UK Clinical Research Collaboration (Medical Research Council, Wellcome Trust, National Institute for Health Research); NIHR Oxford Biomedical Research Centre; NIHR Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (Oxford University in partnership with Public Health England [PHE]), and on Modelling Methodology (Imperial College, London in partnership with PHE); and the Health Innovation Challenge Fund.
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK. Electronic address: kate.dingle@ndcls.ox.ac.uk.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Dingle
authors.affiliation: Department of Infectious Disease Epidemiology, and NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England, Imperial College, London, London, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Didelot
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK.
authors.forename: T Phuong
authors.initials: TP
authors.lastname: Quan
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Eyre
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stoesser
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Golubchik
authors.affiliation: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; Department of Zoology, Oxford University, Oxford, UK.
authors.forename: Rosalind M
authors.initials: RM
authors.lastname: Harding
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Griffiths
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Vaughan
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Finney
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; Public Health England Academic Collaborating Centre, Oxford, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Wyllie
authors.affiliation: Microbiology Department, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Oakley
authors.affiliation: Leeds Teaching Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK.
authors.forename: Warren N
authors.initials: WN
authors.lastname: Fawley
authors.affiliation: Leeds Teaching Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Freeman
authors.affiliation: Leeds Teaching Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Morris
authors.affiliation: Leeds Teaching Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Martin
authors.affiliation: Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Howard
authors.affiliation: Cubist Pharmaceuticals, Lexington, MA, USA; Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Sherwood
authors.initials: S
authors.lastname: Gorbach
authors.affiliation: R M Alden Research Laboratory, Culver City, CA USA.
authors.forename: Ellie J C
authors.initials: EJC
authors.lastname: Goldstein
authors.affiliation: R M Alden Research Laboratory, Culver City, CA USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Citron
authors.affiliation: NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK; Healthcare-Associated Infection, Antimicrobial Resistance and Stewardship and Healthcare-Associated Infections Programme, Public Health England, London, UK; Royal Free London NHS Foundation Trust and Public Health England, London, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Hopkins
authors.affiliation: Department of Healthcare-Associated Infections and Antimicrobial Resistance, Centre for Infectious Disease Surveillance and Control, National Infection Service, Public Health England, London, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Hope
authors.affiliation: NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK; Department of Infectious Disease Epidemiology, and NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England, Imperial College, London, London, UK; Department of Healthcare-Associated Infections and Antimicrobial Resistance, Centre for Infectious Disease Surveillance and Control, National Infection Service, Public Health England, London, UK.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Johnson
authors.affiliation: Leeds Teaching Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wilcox
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK.
authors.forename: Timothy E A
authors.initials: TEA
authors.lastname: Peto
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Health Protection Research Unit in Healthcare Associated Infection and Antimicrobial Resistance at University of Oxford in partnership with Public Health England, Oxford, UK.
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D016360:Clostridioides difficile / Q000235:genetics* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000453:epidemiology* / Q000382:microbiology / Q000635:transmission; D003428:Cross Infection / Q000517:prevention & control*; D004739:England / Q000453:epidemiology; D024841:Fluoroquinolones / Q000600:supply & distribution / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D015994:Incidence; D017053:Infection Control / Q000379:methods*; D058885:Multilocus Sequence Typing / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones