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.