The risk of drug-induced liver injury associated with flucloxacillin: a nationwide, entropy-balanced cohort study.

Objectives: In this nationwide cohort study in a Scandinavian setting, we aimed to investigate the magnitude of association between flucloxacillin use and drug-induced liver injury (DILI).

Methods: Nationwide cohort study among adults in Sweden, 2006-2018, was conducted. Register data on filled prescriptions, patient characteristics, co-medications, and DILI were linked. All filled prescriptions for flucloxacillin and oral clindamycin, among Swedish adults aged 18-85 years, were identified. Entropy-balancing methods were used to control for confounding. Cox regression was used to estimate hazard ratios (HRs) for a first diagnosis of DILI, defined as admission to hospital, emergency department or specialist care, or death because of DILI, within 45 days from the start of treatment.

Results: Within the main 45-day risk period, there were 219 events of DILI among 1 443 622 flucloxacillin users (incidence rate: 14/10 000 person-years) as compared with nine events among 583 847 oral clindamycin group (incidence rate: 1.4/10 000 person-years). This corresponded to an HR of 7.32 (95% CI: 4.1-13.0). The absolute risk difference for users of flucloxacillin compared with clindamycin in the main period was 11 cases of DILI (95% CI: 5-20) per 100 000 courses. The risk diminished in the subsequent periods, 46-90 days (HR: 4.17; 95% CI: 1.44-12.10), and 91-180 days (HR: 0.72; 95% CI: 0.36-1.44).

Discussion: In this nationwide cohort study, the use of flucloxacillin was associated with a sevenfold increased risk of DILI, predominantly in the first 45 days of exposure.