Antibiotic prescribing patterns and risk of antibiotic-resistant infections and Clostridium difficile in Warfarin and Direct Oral Anticoagulant users: matched population-based cohort study

Warfarin and Direct Oral Anticoagulant (DOAC) users may have more frequent antibiotic prescriptions than non-users. The aim of this study was to estimate rates of common and resistant infections, and antibiotic prescribing amongst warfarin and DOAC users versus non-users. This matched retrospective cohort study used data from patients registered with General practices in England contributing to the Clinical Practice Research Datalink GOLD. We included 61,750 adults who initiated warfarin or a DOAC between 1st January 2011 and 31st December 2019, matched 1:1 to non-users. We estimated Incident Rate Ratios (IRR) and 95% Confidence Intervals for three common infections and all-cause antibiotic prescribing. We estimated hazard ratios (HRs) and 95% CIs for the risk of methicillin resistance Staphylococcus aureus (MRSA), other antibiotic-resistant organisms, or Clostridium difficile. We assessed the extent to which any of the effect of warfarin and DOAC use on antibiotic resistant infections or Clostridium difficile was mediated by antibiotic prescribing patterns. 37,143 warfarin users and 24,607 DOAC users were matched 1:1 to non-users. Warfarin and DOAC users had greater relative consultation rates for respiratory, urinary, and skin infections. All-cause antibiotic prescribing was greater in warfarin and DOAC users (warfarin; adjusted IRR 1.47, 95% CI 1.45–1.50, DOAC; adjusted IRR 1.66, 95% CI 1.63–1.69). Largest effect sizes were observed for flucloxacillin (adjusted IRR 2.11, 95% CI 2.01–2.20), and erythromycin (adjusted IRR 2.32, 95% CI 2.00–2.70). Warfarin users had significantly higher risk of MRSA (adjusted HR 1.68, 95% CI 1.38–2.05) and hospital admission with antibiotic resistant infections (adjusted HR 1.91, 95% CI 1.11–3.30). DOAC users had significantly higher risk of MRSA (adjusted HR 1.57, 95% CI 1.20–2.06), hospital admission with antibiotic resistant infections (adjusted HR 2.13, 95% CI 1.61–2.82), and Clostridium difficile (adjusted HR 1.45, 95% CI 1.10–1.92). We found little evidence to suggest that the increased risks of studied outcomes were mediated by rates of antibiotic prescription. Warfarin and DOAC use was associated with greater rates of infection consultations, all-cause antibiotic prescribing, antibiotic resistant infections, and Clostridium difficile, but there was little evidence that antibiotic prescribing rates mediated risk of resistant infections or Clostridium difficile.