How do fluoroquinolones (FQs), such as levofloxacin, ciprofloxacin (Cipro), and moxifloxacin, rank in terms of risk for tendonopathy, neuropathy, and aortic aneurysm?

Ranking Fluoroquinolones by Risk for Tendonopathy, Neuropathy, and Aortic Aneurysm

Based on the most recent and highest quality evidence, levofloxacin (and its parent compound ofloxacin) poses the greatest risk for tendonopathy, while all fluoroquinolones carry similar risks for neuropathy and aortic aneurysm/dissection, with no clear differentiation between individual agents for these latter two complications. 1, 2, 3

Tendonopathy Risk Ranking

Highest Risk: Levofloxacin and Ofloxacin

• Levofloxacin and ofloxacin demonstrate the highest propensity for tendon damage across in vitro studies, animal models, patient-level analyses, and large surveillance reports compared to other fluoroquinolones 2
• The risk with these agents is exposure-dependent, with higher doses and longer treatment durations most commonly associated with tendinopathy 2
• In pediatric studies, ciprofloxacin showed arthropathy rates of 21% in US populations versus 11% in comparators, with the study design unable to demonstrate non-inferiority for musculoskeletal safety 4

Moderate Risk: Ciprofloxacin

• Ciprofloxacin demonstrates intermediate risk for tendon complications 4
• The absolute increase in Achilles tendon rupture risk is approximately 12 cases per 100,000 persons within 90 days of fluoroquinolone treatment 5, 6
• Current use increases the odds ratio for Achilles tendon rupture to 4.1 5, 6

Lower Risk: Moxifloxacin

• Moxifloxacin appears to have a relatively lower tendon toxicity profile compared to levofloxacin and ofloxacin 2
• However, moxifloxacin carries the FDA black box warning for tendon rupture, with symptoms occurring within hours to weeks after starting therapy 1
• Permanent discontinuation due to adverse events occurred in only 3.5% of patients treated with moxifloxacin 4

Neuropathy Risk Ranking

All Fluoroquinolones: Equivalent High Risk

• No significant differentiation exists between individual fluoroquinolones for peripheral neuropathy risk 1, 3
• All fluoroquinolones are associated with sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons, resulting in paresthesias, hypoesthesias, dysesthesias, and weakness 1
• Symptoms may occur within hours of the first dose and can be irreversible in some patients 1
• Neuropsychiatric toxicity can occur after one dose or several months after fluoroquinolone exposure 3
• In pediatric comparative studies, ciprofloxacin showed 3% neurologic adverse events versus 2% in comparators, with no clinically significant difference 4

Aortic Aneurysm/Dissection Risk Ranking

All Fluoroquinolones: Equivalent High Risk

• All fluoroquinolones demonstrate a consistently increased risk of aortic aneurysm and dissection with no clear agent-specific differences 7, 3, 8, 9
• The risk shows a 2-fold increase over background rates within 60-90 days of fluoroquinolone exposure 7, 8
• Data mining of FDA adverse event reports from 2004-2016 found all three major fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) associated with aortic aneurysm 9
• Levofloxacin specifically showed association with aortic dissection in pharmacovigilance data 9
• The annual background risk is approximately 300 events per 100,000 persons in highest-risk populations (age >85 years) 7
• Oral administration appears more likely to produce these adverse events than intravenous formulations 9

Risk Amplification Factors (Apply to All Agents)

Age-Related Risk

• Patients over 60 years have 4 times higher risk of Achilles tendon rupture compared to general population 5, 6
• Elderly patients are at greater risk for aortic aneurysm and dissection 7
• Geriatric patients using intravenous moxifloxacin may be more susceptible to QT prolongation 1

Corticosteroid Co-Administration

• Concomitant corticosteroid use dramatically increases tendon rupture risk with an odds ratio of 43.2 5, 6
• This represents approximately 1 in 979 patients experiencing Achilles tendon rupture when fluoroquinolones are combined with corticosteroids 5

Other High-Risk Conditions

• Renal dysfunction/failure increases tendon rupture risk 4, 2
• History of solid organ transplantation (kidney, heart, or lung) 4, 2
• Pre-existing tendon disorders including rheumatoid arthritis 4
• Known aortic aneurysm or conditions predisposing to aneurysms 7
• Strenuous physical activity or sports participation 4, 5

Clinical Implications

When Fluoroquinolones Must Be Used

• Moxifloxacin represents the safest choice for tendon-related concerns when a fluoroquinolone is absolutely necessary 2
• Avoid levofloxacin and ofloxacin in patients with tendon disorder risk factors (age >60, corticosteroid use, athletes, history of tendinopathy) 5, 2
• All fluoroquinolones carry equivalent risk for neuropathy and aortic complications, so agent selection should not be based on these outcomes 1, 3

Monitoring and Prevention

• Consider magnesium supplementation during fluoroquinolone treatment if no contraindications exist 6
• Antioxidant supplementation with vitamin E or coenzyme Q10 may provide protective effects against tendon damage 6
• Discontinue immediately at first signs of tendon pain, swelling, or inflammation 1
• Symptoms of tendinopathy typically occur within 1 week (median 6 days) but can appear as early as 2 hours or as late as 6 months after discontinuation 5, 6
• Monitor for bilateral involvement, which occurs in more than half of cases 6

Absolute Contraindications

• History of fluoroquinolone-associated tendon disorders 1
• Previous peripheral neuropathy from any cause 1
• Known aortic aneurysm when alternative antibiotics are available 7
• Myasthenia gravis (risk of respiratory failure) 1

Common Pitfall

The most critical error is prescribing fluoroquinolones for uncomplicated acute urinary tract infections, sinusitis, or bronchitis when other antibiotics are appropriate first-line options, as risks outweigh benefits in these settings 3, 10