gms | German Medical Science

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

Objective: To assess risk of 8 ADRs associated with newly prescribed FQs for different groups of patients.

Methods: This cohort study included all adult patients from the German statutory health insurance AOK during the years 2013 to 2019 with ≥ 1 systemic antibiotic prescription and without a history of the respective 8 ADRs of interest. In an active comparator new user design, 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). ADRs observed were 1.) aortic aneurysm/dissection, 2.) cardiac arrhythmia/sudden cardiac death, 3.) acute toxic liver injuries/acute liver failure, 4.) all-cause mortality, 5.) depression and other neuropsychiatric disorders/symptoms, 6.) polyneuropathy/other peripheral nervous system-related diseases, 7.) non-traumatic injuries of muscle/tendon/synovial, and 8.) retinal detachment. 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 AC agents, and dosage.

Results: FQ episodes were associated with an increased risk for ADRs 1-6, but not for ADRs 7-8. This association was robust in all sensitivity analyses. The risk was highest within 30-92 days after index. ADR-specific differences in age and gender were observed. The risk of FQ-associated aortic aneurysm/dissection and all-cause mortality was highest in young females (18-39 years old; aHR=1.47 [95% CI 1.04;2.08] and aHR=1.34 [1.25;1.43]). The risk of FQ-associated acute toxic liver injury/acute liver failure was highest in females aged 40-69 years (aHR=1.32 [1.23;1.42]). For young males the risk of polyneuropathy and other peripheral nervous system-related diseases was highest (aHR=1.24 [1.14;1.36]), and the risk of cardiac arrhythmia/sudden cardiac death was elevated (aHR=1.12 [1.07;1.17]). The risk of FQ-associated depression and other affective disorders was elevated for males aged ≥ 70 years (aHR=1.14 [1.11;1.16]), whereas the risk of FQ-associated somnolence/stupor/coma was increased for young females (aHR=1.26 [1.13;1.42]). FQ episodes were associated with increased risk especially compared to amoxicillin, azithromycin, clindamycin, and doxycycline. Compared to amoxicillin-clavulanic acid, FQ episodes had a smaller risk for cardiac arrhythmia/sudden cardiac death, all-cause mortality, polyneuropathy/other peripheral nervous system-related diseases, and somnolence/stupor/coma. Moreover, a dose-effect relationship was present, especially for acute toxic liver injury/acute liver failure.

Conclusion: FQ were associated with several serious ADRs. Young adults and females were high risk groups. Stratified for single AC agents, the risk of FQ episodes differs. Therefore, confounding by indication should be explored in further studies.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.