Unresolved Gustatory, Olfactory and Auditory Adverse Drug Reactions to Antibiotic Drugs: A Signal Detection Analysis on Publicly Accessible Eudravigilance Data

Background/Introduction: Unresolved outcomes are frequently reported for gustatory, olfactory and auditory (GOA) ADRs in spontaneous reporting databases [1, 2]. However, such high volume of unresolved GOA ADRs could reflect an under-investigated clinical issue or an intrinsic difficulty in the outcome assessment [3]. Objective/Aim: The primary aim was to demonstrate that unresolved outcomes are reported more frequently for GOA ADRs than for other ADRs to systemic antibiotics. The secondary aim was to identify potential signals of unresolved GOA ADRs for specific classes of antibiotic drugs and for specific antibiotics. Methods: We extracted the number of ADRs to systemic antibiotics of the Anatomical Therapeutic Chemical (ATC) class J01 from Eudravigilance up to February 2019. We classified ADRs in ‘‘non- GOA ADRs’’ and ‘‘GOA ADRs’’. ADRs were categorised in three groups according to the outcome: defined, persistent/permanent (unresolved) and undetermined ADRs. We performed disproportionality analyses with the case/non-case methodology, by calculating the crude reporting odds ratio (ROR) and 95% confidence interval (CI). Cases were all persistent/permanent ADRs, and non-cases were defined and undetermined ADRs. For the primary aim, index groups were gustatory or olfactory or auditory ADRs, while reference group included all non-GOA ADRs. For the secondary aim, we performed a disproportionality analysis by using the sub-set of GOA ADRs. Index and reference groups varied with subgroups of ATC class, so that each class was compared with the others. We conducted two sensitivity analyses for each analysis by varying case definition. Results: We extracted 748,798 ADRs, including 10,770 GOA ADRs. The primary analysis showed that ROR for unresolved gustatory, olfactory and auditory ADRs was 2.68 (95% CI 2.51–2.85), 5.20 (95% CI 4.66–5.81) and 2.64 (95% CI 2.51–2.79), respectively. The secondary analyses detected signals of unresolved gustatory ADRs to doxycycline (ROR 1.69, 95% CI 1.18–2.41, p\0.05), azithromycin (ROR 2.07, 95% CI 1.58–2.72, p\0.001) and levofloxacin (ROR 1.59, 95% CI 1.22–2.07, p\0.05). Signals of auditory unresolved ADRs were found for doxycycline (ROR 1.52, 95% CI 1.09–2.12, p\0.05), clarithromycin (ROR 1.31, 95% CI 1.09–1.59, p\0.05) and several aminoglycosides (e.g. ROR 3.49, 95% CI 2.23–5.45, p\0.001 for amikacin). Signals of olfactory unresolved ADRs were detected for doxycycline (ROR 2.4, 95% CI 1.26–4.58, p\0.05) and levofloxacin (ROR 1.92, 95% CI 1.28–2.86, p\0.05). Sensitivity analyses mostly confirmed the results of the main analysis. Conclusion: In this study, we tested and used an appropriate expected frequency standard to identify signals of unresolved GOA ADRs. This approach allowed the identification of several signals of potential persistent/permanent GOA reactions for antibiotic drugs in the Eudravigilance database.