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By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.
SYNOPSIS: As a class, fluoroquinolones are some of the most commonly used antibiotics worldwide. Their use carries a significant risk of neurotoxicity, for both the peripheral and central nervous system.
SOURCE: Morales D, Pacurariu A, Slattery J, et al. Association between peripheral neuropathy and exposure to oral fluoroquinolone or amoxicillin-clavulanate therapy. JAMA Neurol 2019;76:827-833.
Fluoroquinolones, commonly used to treat respiratory, gastrointestinal, and urinary tract infections, include (among others) ciprofloxacin (Cipro), levofloxacin (Levaquin), and moxifloxacin (Avelox). Side effects include gastritis, hepatotoxicity, QT interval prolongation, and (among its most common adverse effects) altered mental status and neuropathy, including mononeuropathy, multiple mononeuropathy, and polyneuropathy. What are the risk estimates for polyneuropathy with fluoroquinolone exposure? What factors are associated with this risk?
Using The Health Improvement Network (THIN) database, covering approximately 6% of the United Kingdom population from more than 500 general medical practices, a nested case-control study design was used to evaluate the risk of incident peripheral neuropathy. Investigators included adults who were in the THIN database between Jan. 1, 1999, and Dec. 31, 2015. These adults were ≥ 18 years of age and were issued at least one prescription of oral amoxicillin-clavulanate (controls) or oral fluoroquinolone antibiotic therapy. The authors chose amoxicillin-clavulanate so that controls were sampled from a more representative population prescribed antibiotics. Patients with a history of neuropathy or diabetes were excluded. At least one year of observation prior to cohort entry was required of all participants. Cohort exit was defined as outcome occurrence, death, deregistration from the practice, end of study period, or date of last data collection from the general practice. Cumulative antibiotic exposure was measured as the total number of days of oral fluoroquinolone or oral amoxicillin-clavulanate exposure within each risk window. Cumulative days of exposure was calculated by dividing the prescription quantity information by the standard administration schedules for each antibiotic. Adults with incident peripheral neuropathy were matched with up to four controls using incidence density sampling, selected from a cohort prescribed oral fluoroquinolone or amoxicillin-clavulanate antibiotics. Statistical analysis included conditional logistic regression, sensitivity analyses, and multiple imputation, with a two-sided P < 0.05 considered statistically significant.
Among 1,338,900 adults issued one or more prescriptions of fluoroquinolone (34.3%) or amoxicillin-clavulanate (65.7%) (mean age, 52.8 years; 57% female) without a diagnosis of peripheral neuropathy at cohort entry, 11,224 incident peripheral neuropathy cases were identified and matched to 42,316 controls. Those with diabetes were identified and excluded, leaving 5,357 incident peripheral neuropathy cases (mean age, 65.6 years; 2,809 women) matched to 17,285 controls (mean age, 64.4 years; 9,485 women). Median duration of exposure was 10 days for fluoroquinolone and seven days for amoxicillin-clavulanate, with risk of neuropathy calculated as increased by 3% for each additional day of current fluoroquinolone exposure, the risk persisting for up to 180 days following exposure. No significant increased risk was observed with exposure to oral amoxicillin-clavulanate. Absolute risk with oral fluoroquinolone exposure was 2.4 per 10,000 patients per year of use, with number needed to harm for a 10-day course being 152,083 patients, greatest among men and those > age 60 years.
In use for more than 30 years, and currently among the most widely prescribed antibiotics worldwide (representing 10% of prescriptions per 1,000 population in 2015 in the United States alone), fluoroquinolones have been associated with significant side effects in susceptible individuals. Historically, these have included peripheral neuropathy, photosensitivity, prolonged QT interval, hypoglycemia, and tendon rupture. More recently, the FDA has extended these warnings to include a risk of aortic dissection, thus recommending avoidance of these drugs in patients with peripheral vascular disease, uncontrolled hypertension, vasculitides, and connective tissue disorders (e.g., Ehlers-Danlos syndrome). In addition to tendon rupture, there is an increased risk of tendonitis; myalgia; muscle weakness; arthralgia and joint swelling; neuropsychiatric issues, encompassing psychosis, anxiety, insomnia, depression, hallucinations, suicidal thoughts, confusion; and impairment of vision, hearing, smell, and taste. Transplant recipients, those with renal dysfunction, older patients, and those receiving concomitant corticosteroids, are at higher risk. Lastly, a fibromyalgia-like syndrome, termed fluoroquinolone-associated disability syndrome, has been associated with these antibiotics. However, the risk of fibromyalgia with fluoroquinolone is similar to that with amoxicillin and azithromycin; thus, the antibiotic is not likely causative.1,2
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott, Acadia, Allergan, AstraZeneca, Avadel, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Mylan, and Salix; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Editor Jason Schneider; Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.