Letter to the Editor: Consideration on “An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin- association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency” by Bennett et al.

We read with great interest the paper by Bennett et al. published in Expert Opinion on Drug Safety [1] and appreciated the authors’ attempt to provide a comprehensive overview of the adverse events produced by fluoroquinolones (FQs). Adverse events including tendonitis and tendon ruptures, retinal detachment, peripheral neuropathy, neuropsychological impairment, prolongation of QT interval, perforation of the tympanic membrane and aortic aneurysms/dissections have been observed following administration [2]. Bennett et al. reviewed all FQ-related safety notifications contained in Food and Drug Administration (FDA) and the European Medicine Agency (EMA) databases from 2013 to 2019. The authors warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis or bronchitis unless other possible choices are tried first as the risks outweigh the benefits in these settings. However, we believe that other severe collagen-associated adverse events are also possible. We recently diagnosed a case of asymptomatic pneumothorax a few days after the administration of levofloxacin for a pulmonary inflammation in an as-yet untreated patient with local advanced retroperitoneal sarcoma. We performed a search of PubMed and learned of one other case of pneumothorax following the use of levofloxacin reported by Facciolongo et al. [3]. The authors initially administered levofloxacin at a dosage of 750 mg daily, increasing it after a wash-out period to 1500 mg daily in association with other drugs (piperacillin/tazobactam 13.5 g daily, clarithromycin 1 g, rifampicin 900 mg daily, fluconazole 800 mg daily, methylprednisolone 120 mg daily). In vitro and in vivo research shows that FQs upregulate the matrix metalloproteinase enzyme that degrades collagen, especially collagen I and III [4,5]. As collagen and elastin fibers are the main components of lung connective tissue, it is plausible that FQs are correlated with pneumothorax. Spontaneous pneumothoraces are defined by air in the pleural spaces arising from neither trauma nor a iatrogenic cause. A potential limitation of our consideration is that spontaneous pneumothorax is also a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated, mainly involving metastatic osteogenic or soft-tissue sarcomas, especially in cytotoxic chemotherapy or radiotherapy settings [6]. A second potential limitation is that spontaneous pneumothorax may have a genetic or familial origin [7]. We fear that the existence of spontaneous pneumothorax may reduce the likelihood of a clinician hypothesizing a potential correlation with FQs. We believe that high-quality adverse drug reaction reports are essential for monitoring drug safety through pharmacovigilance, but also that improvements in the quality and availability of these reports are urgently needed. The main reason for the underreporting of adverse drug reactions stems from medical professionals’ limited knowledge of pharmacovigilance. Training and follow-up activities organized by authorities such as the National Pharmacovigilance Network and based on the needs of healthcare operators could help to redress this situation. We thus call on the scientific community to bear in mind the possibility that a spontaneous pneumothorax may have been caused by the use of FQs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.