Background
The control of Clostridium difficile infections (CDI) is an international clinical challenge. Uniquely, CDI incidence in England declined by ~80% after 2006, following implementation of national control policies; we investigated their role in this decline. This study tested two hypotheses. First, if CDI declines in England were driven by changes in use of particular antibiotics, then incidence of CDI caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes (defined by multilocus sequence type (ST)). Second, if CDI declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility.
Methods
Regional and national CDI incidence and antimicrobial prescribing data (1998-2014) were combined with whole genome sequences (WGS) from 4045 national and international C. difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from WGS. The incidence of CDI caused by fluoroquinolone-resistant and -susceptible isolates was estimated using negative-binomial regression, overall and per genotype. Selection and transmission were investigated using phylogenetic analyses.
Findings
National fluoroquinolone and cephalosporin prescribing correlated highly with CDI incidence (cross-correlations>0·88), in contrast to total antibiotic prescribing (cross-correlations<0·59). Regionally, CDI decline was driven by elimination of fluoroquinolone-resistant isolates (~67% of Oxfordshire cases in September 2006, ~3% in February 2013; annual incidence rate ratio: 0·52, (95%CI 0·48,0·56), versus fluoroquinolone-susceptible isolates: 1·02, (0·97,1·08)). CDI 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 demonstrated 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).
Interpretation
Restricting fluoroquinolone prescribing appears to explain the decline in CDI incidence, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of CDI control programs.
