Quinolones-Induced Musculoskeletal, Neurological, and Psychiatric ADRs: A Pharmacovigilance Study Based on Data From the Italian Spontaneous Reporting System.

Cristina Scavone,Liberato Berrino,Concetta Rafaniello,Annalisa Capuano,Liberata Sportiello,Annamaria Mascolo,Rosanna Ruggiero

doi:10.3389/fphar.2020.00428

Cristina Scavone, Liberato Berrino + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2020.00428

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Abstract

BackgroundThe use of quinolones has been associated with the development of serious and persistent adverse drug reaction (ADR) mainly affecting muscles, joints and the nervous system. This risk has led the European Medicines Agency (EMA) to endorse some restrictions on the use of this class of antibiotic. Therefore, we performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data.MethodsWe retrieved Individual Case Safety Reports (ICSRs) with a quinolone as suspected drug among those reported through the Campania spontaneous reporting system from January 1st, 2001 to April 30th 2019. Moreover, we retrieved national aggregated safety data from the online public report system (RAM system) for the period from January 1st, 2002 to March 31st, 2019. Risk factors were classified as “age greater than 60 years,” “therapeutic indication,” “renal failure,” “organ transplantation,” “use of corticosteroid,” and “history of side effects”. Reporting odds ratio (ROR) was computed to evaluate the reporting probability of musculoskeletal, neurological, or psychiatric events among quinolones generations.ResultsA total of 87 ICSRs with a quinolone as suspected drug that reported at least one musculoskeletal, neurological, and psychiatric adverse event were identified in the Campania spontaneous reporting system. Forty-nine (56.3%) ICSRs reported risk factors (total risk factors 59). The most reported risk factor was “age greater than 60 years” (69.5%), followed by “therapeutic indication” (16.9%), “renal failure” (5.1%), “organ transplantation” (3.4%), “use of corticosteroid” (3.4%), and “history of side effects” (1.7%). Second-generation quinolones were associated with a lower reporting probability of musculoskeletal (ROR 0.70; 95% CI 0.63–0.79), neurological (ROR 0.81; 95% CI 0.73–0.90), and psychiatric (ROR 0.55; 95% CI 0.44–0.63) ADRs compared to the third generation of quinolones.ConclusionsOur findings showed that third-generation quinolones were always associated with a higher reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the second generation ones. Moreover, we described risk factors in more than half of our cases suggesting that the inappropriate use of quinolones is a phenomenon that may frequently predispose patients to the occurrence of these ADRs.

Highlights

Quinolones represent a large group of broad-spectrum bactericides
A higher number of musculoskeletal and neurological adverse drug reactions (ADRs) were found compared to psychiatric ones (1,681 ADRs belonging to the System Organ Class (SOC) “Musculoskeletal and connective tissue disorders” and 1,619 ADRs belonging to the SOC “Nervous system disorders” vs. 1,118 ADRs belonging to the SOC “Psychiatric disorders”) and some differences were noticed among quinolone generations
Reporting odds ratio (ROR) showed that second-generation quinolones were associated with a lower reporting probability of musculoskeletal, neurological, and psychiatric ADRs compared to the third generation of quinolones

Summary

Introduction

Quinolones represent a large group of broad-spectrum bactericides. These antimicrobial agents are characterized by the presence of a bicyclic core structure related to the compound 4-quinolone; those containing a fluorine atom are defined as fluoroquinolones (Walker and Wright, 1991). Quinolones inhibit DNA synthesis through the inhibition of the bacterial DNA gyrase or topoisomerase IV (Oliphant and Green, 2002) Based on their antimicrobial activity, they are classified into four generations: the first-generation agents (cinoxacin, nalidixic acid, pipemidic acid) which show moderate gram-negative activity; the second-generation quinolones (ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin, rufloxacin), that have expanded gram-negative activity; the third-generation quinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, pefloxacin, sparfloxacin, temafloxacin) which show extended gramnegative and improved gram-positive coverage; the fourthgeneration quinolones (clinafloxacin, gemifloxacin, prulifloxacin, trovafloxacin) which have expanded activity against gram-positive, gram-negative, and anaerobic bacteria (Oliphant and Green, 2002). Data from premarketing clinical trials showed that quinolones are generally well tolerated and commonly related to the occurrence of gastrointestinal ADRs, mainly represented by nausea, vomiting, diarrhea, and constipation Less frequently, these antibiotics can induce the occurrence of the central nervous system and dermatologic ADRs, blood toxicities, renal disorders, and skin hypersensitivity. We performed a study to primary estimate the reporting probability of musculoskeletal, neurological, and psychiatric ADRs among quinolone generations using national data

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