Abstract
SummaryBackgroundThe 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.MethodsRegional (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.FindingsNational 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).InterpretationRestricting 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.FundingUK 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.
Highlights
If C difficile infection declines in England were driven by reductions in use of particular antibiotics, incidence of C difficile infection caused by resistant isolates should post-interventions decline in C difficile infections reflected the disappearance of fluoroquinolone-resistant isolates, whereas the incidence of C difficile infections caused by fluoroquinolone-susceptible isolates remained unchanged
C difficile infection declines occurred while total antibiotic prescribing was increasing
Between 2005 and 2012, the cross-correlations (CCs) between English incidence of C difficile infection and total English antibiotic prescribing were –0·57 for hospital and community, –0·59 (–0·68 to –0·44) for community, and 0·29 (–0·19 to 0·60) for hospital prescribing
Summary
Clindamycin or fluoroquinolone use has been restricted, and combined with other measures aiming to control localised C difficile infection outbreaks.. Most cases of C difficile infection are temporally associated with health care, reflecting a combination of health-care-associated acquisition, and health-care-related. Department, Oxford University Hospitals NHS Trust, Oxford, UK (S J Oakley MSc); Leeds Teaching. Hospitals and University of Leeds, Department of Microbiology, Leeds General Infirmary, Leeds, UK (W N Fawley PhD, J Freeman PhD, K Morris PhD, J Martin MRCP, Prof M H Wilcox MD); Leeds. Teaching Hospitals NHS Trust, Leeds, UK (P Howard FRPharmS); Cubist Pharmaceuticals, Lexington, MA, USA (Prof S Gorbach MD); Tufts University School of Medicine, Boston, MA, USA (Prof S Gorbach); R M Alden Research Laboratory, Culver.
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