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.

Findings: 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).

Interpretation: 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.

Funding: 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.

Figure 1

National incidence of Clostridium difficile infections and fluoroquinolone prescribing (A) and national antibiotic prescribing overall (B) (A) Mandatory incidence of C difficile infections corresponds to all infections reported for individuals older than 2 years (from 2004 to 2007, infections were only reported for individuals older than 65 years, and are upweighted to provide similar estimates in individuals older than 2 years; appendix). Since mandatory reporting was only introduced in 2004, we have also included voluntary-reported C difficile infections to give an indication of trends before that date. (B) Dotted lines are estimates (appendix).

Figure 2

Incidence of Clostridium difficile infections together with fluoroquinolone and cephalosporin prescribing for Oxfordshire (A) and incidence of C difficile infections by fluoroquinolone susceptibility for Oxfordshire (B) (A) Mandatory incidence of C difficile infections corresponds to all cases reported for individuals older than 2 years (from 2004 to 2007, cases were only reported for individuals older than 65 years, and are upweighted to provide similar estimates in individuals older than 2 years; appendix). Only toxin-positive culture-positive samples were used in the genotype-specific and phylogenetic analyses. (B) C difficile is inherently resistant to most cephalosporins. IRR=annual incidence rate ratio.

Figure 3

Oxfordshire Clostridium difficile IRR by fluoroquinolone resistance and genotype For genotypes with more than 10% resistant isolates (denoted FQR), rates were calculated separately for C difficile infections caused by fluoroquinolone-susceptible and resistant isolates. To show that the difference in IRR for resistant and susceptible isolates is not driven solely by the decline in ST1(027), rates were also calculated for all non-ST1(027) genotypes together, as well as for all genotypes with more than 10% resistant isolates (excluding ST1(027)) and for all genotypes with 10% or less resistant isolates (FQS). Heterogeneity between IRRs in C difficile infections caused by fluoroquinolone-resistant versus fluoroquinolone-susceptible isolates: all p<0·0001, non-ST1 p<0·0001, non-ST1 FQR p<0·0001, ST42 p<0·0001, ST37 p=0·00015, ST3 p=0·00070, ST35 p=0·92, ST11 p=0·0053. The dotted vertical lines separate out the different ways the isolates were divided for the different analyses. The horizontal dotted line represents an IRR of 1. IRR=annual incidence rate ratio.

Figure 4

Contrasting incidence of Clostridium difficile infections (Oxfordshire) and whole-genome sequence phylogenies representing the fluoroquinolone-resistant genotype ST1(027), the mixed resistant and susceptible genotype ST3(001), and the almost entirely fluoroquinolone-susceptible genotype ST8(002) (A) Incidence of C difficile infections by fluoroquinolone susceptibility for genotype ST1(027) in Oxfordshire. Red bars indicate fluoroquinolone-resistant isolates, blue bars indicate fluoroquinolone-susceptible isolates, grey bars indicate resistance not determined. (B) Incidence of C difficile infections by fluoroquinolone susceptibility for genotype ST3(001) in Oxfordshire. (C) Incidence of C difficile infections by fluoroquinolone susceptibility for genotype ST8(002) in Oxfordshire. (D) Time-scaled phylogeny for ST1(027) generated with ClonalFrameML. Every third Oxfordshire isolate (by date) is shown. Phylogenies were scaled to be directly similar post-1990; the grey shaded regions before 1990 represent the regions of the phylogenies that should not be compared because they are not scaled identically. Background colour indicates fluoroquinolone susceptibility; branch colour indicates geographic location. (E) Time-scaled phylogeny for the mixed fluoroquinolone resistant or susceptible genotype, ST3(001), generated using ClonalFrameML. Two fluoroquinolone-resistant areas of the phylogeny are indicated by red shading within the blue susceptible region. Rapid clonal expansion after resistance emergence is supported by significantly lower ED scores for resistant versus susceptible areas. (F) Time-scaled phylogeny for ST8(002) generated using ClonalFrameML. Every second Oxfordshire isolate (by date) is shown. Two fluoroquinolone-resistant isolates are indicated at the bottom of the panel. IRR=annual incidence rate ratio. ED=evolutionary distinctiveness. R=fluoroquinolone resistant. S=fluoroquinolone susceptible.

Figure 5

Incidence trends of inferred secondary Clostridium difficile cases in Oxfordshire from April 2008 to March 2011 Inferred secondary cases are those caused by C difficile isolates that are genetically closely related (≤two single nucleotide variants) to isolates recovered from a previous case, and therefore potentially transmitted. Incidence trends were calculated separately for inferred secondary cases caused by fluoroquinolone-resistant ST1(027), fluoroquinolone-resistant non-ST1(027), and fluoroquinolone-susceptible isolates, stratified by with versus without hospital-based contact. Horizontal dotted line shows an IRR per year of 1 (ie, no change over time) against which the 95% CI bars are compared to determine statistical significance of any change. The p values are a test of the IRR against the null hypothesis of no change over time (IRR=1). IRR=annual incidence rate ratio.