Identification of patient groups at high risk of fluoroquinolone-associated potentially life-threatening adverse events in German routine care: a population-based cohort study

Background: Fluoroquinolones (FQ) are associated with several serious adverse drug reactions (ADR), but they are highly effective broad-spectrum reserve antibiotic agents. For the advancement of drug therapy safety, it is important to know which patient subgroups may be especially vulnerable to ADRs of FQ.

Objectives: To assess risk of potentially life-threatening ADRs associated with newly prescribed FQs for different groups of patients.

Methods: Episodes of FQ use were compared with use of other antibiotics (active comparators (AC): amoxicillin, amoxicillin-clavulanic acid, azithromycin, cefuroxime, cephalexin, clindamycin, sulfonamethoxazole-trimethoprim and doxycycline) in an active comparator new user design. The cohort included all adult patients from the German statutory health insurance AOK during the years 2013 to 2019 with ≥ 1 prescription and without a history of the respective ADRs aortic aneurysm/dissection (AAD), cardiac arrhythmia/sudden cardiac death (CASCD), acute toxic liver injuries/acute liver failure (ATLI/ALF), and all-cause mortality. Relative risks of ADRs were estimated by piece-wise exponential additive mixed models (PAMM) with smooth non-linear effects for person-time and age and adjusted for comorbidities, year, and quarter at index prescription. Sensitivity analyses regarding selection criteria, ADR assessment, propensity score matching and censoring were conducted. Moreover, the analyses were stratified by age, gender, follow-up time, specific active comparator drugs and dosage.

Results: FQ episodes were associated with all four ADRs within 365 days after index. This association was robust in all sensitivity analyses. The risk for FQ-associated AAD, CASCD and ATLI/ALF was highest within 30 days, and for all-cause mortality within 92 days. The relative risk of FQ-associated all-cause mortality was highest in young females (18-39 years old; aHR=1.77 [1.55;2.03]). The risk of FQ-associated ATLI/ALF was highest in females aged 40-69 years (aHR=1.42 [1.32;1.53]), and the risk of CASCD was elevated in young males (aHR=1.14 [1.08;1.20]). For aortic aneurysm/dissection a nominally increased risk for < 40-year-old females was found (aHR=1.42 [0.96;2.11]), although 95% CI indicates that a small risk reduction is also supported by the data. FQ episodes were associated with increased risk for all four ADRs compared to amoxicillin, azithromycin, clindamycin, and doxycycline, as well as compared to cefuroxime, except for CASCD. Compared to amoxicillin-clavulanic acid, FQ episodes had a smaller risk for CASCD and all-cause mortality. Moreover, a dose-effect relationship was present for all ADRs, especially for ATLI/ALF.

Conclusions: Young adults and females were high risk groups for FQ-associated potentially life-threatening ADRs, but this association differed for specific AC agents. Therefore, confounding by indication should be explored in further studies.