Wise Use of Antibiotics

What’s the Fuss with Fluoroquinolones?

Author: Ann Wirtz, PharmD, BCPPS | Clinical Pharmacy Specialist, Infectious Diseases and Antimicrobial Stewardship | Co-Director, Antimicrobial Stewardship Program, Children's Mercy Kansas City

Column Editor: Rana El Feghaly, MD, MSCI | Director, Clinical Services; Director, Outpatient Antibiotic Stewardship Program; Associate Professor of Pediatrics, UMKC School of Medicine

Fluoroquinolones, including ciprofloxacin, levofloxacin, moxifloxacin, and newly approved delafloxacin, are broad-spectrum antibiotics targeting a variety of gram-positive and gram-negative bacteria. Systemic use of fluoroquinolones in pediatric patients varies across different age categories and indications. Recently, an 18-year retrospective cohort study identified low outpatient prescription fill rates for fluoroquinolones in pediatrics when compared to adults and to broad-spectrum oral beta-lactams (i.e., amoxicillin/clavulanate), sulfamethoxazole/trimethoprim and nitrofurantoin. Additionally, fluoroquinolone prescribing in pediatrics decreased following publication of FDA warnings with fluoroquinolones, including risks of tendon rupture, suggesting pediatric prescribers have concerns for antibiotic-related harm.¹ Confusion exists regarding how these warnings apply to children and when fluoroquinolones should be prescribed.

What FDA warnings exist with fluoroquinolones?

Shortly after approval of fluoroquinolones in the 1960s, concerns were raised regarding cartilage toxicity observed in the weight-bearing joints of immature animals during testing.² Severity was dependent on the type of fluoroquinolone used as well as the animal tested. In 2008, concerns for additional musculoskeletal adverse effects were identified with publication of an FDA boxed warning associating fluoroquinolone exposure with an increased risk of tendinitis and tendon rupture. Additional boxed warnings in 2013 and 2016 targeted risk of peripheral neuropathy and a generalized statement suggesting fluoroquinolone use only when alternatives do not exist. Further warnings for glucose regulation issues, neurological abnormalities and aortic dissection were acknowledged in 2018.³

How do these warnings apply to pediatric patients?

Despite animal data suggesting cartilage toxicity with fluoroquinolones, large pediatric studies have failed to demonstrate a significant increase in musculoskeletal adverse effects with fluoroquinolones. A slight increase in musculoskeletal adverse effects was observed in pediatric patients receiving levofloxacin versus other antibiotics at 2 months (2.1% vs. 0.9%, p=.038) and 1 year (3.4% vs. 1.8%, P=.025); of those, arthralgias were most common. No long-term musculoskeletal sequalae or growth abnormalities were identified at the end of a five-year follow-up period for select patients. Of note, fluoroquinolone-associated Achilles tendon rupture is extremely rare in pediatric patients.⁴

Additional side effects, including peripheral neuropathy, glucose regulation issues, neurologic adverse effects, QTc prolongation and aortic dissection are rare and more likely to occur in adults than children. Specific underlying risk factors (i.e., diabetes, psychiatric illness, seizures, hypertension, QTc prolongation), or concomitant medications may increase risk of these effects.³

When should I consider prescribing fluoroquinolones?

The American Academy of Pediatrics published a policy statement in 2016 outlining appropriate prescribing practices for fluoroquinolones.² There are certain infections where systemic fluoroquinolones are the best antibiotic option due to lack of other oral alternatives, bacterial resistance or patient allergies. Use should be limited to the shortest duration possible. For example, fluoroquinolones are the only oral antibiotics which treat Pseudomonas aeruginosa infections and must be used to avoid unnecessary IV therapy. Additionally, treatment options for multidrug-resistant gram-negative or resistant pneumococcus may be limited and require the use of a fluoroquinolone. Patients with severe (i.e., anaphylaxis) beta-lactam allergies may receive levofloxacin as an alternative treatment for pneumonia or sinusitis. Finally, fluoroquinolones can be used to treat specific gastrointestinal pathogens (i.e., Salmonella species) or as neutropenia prophylaxis in patients with malignancies.²

What counseling points should I provide patients and caregivers about fluoroquinolones?

Prescribers should be comfortable explaining the FDA warnings with fluoroquinolones and their application to pediatric patients and caregivers. To optimize absorption, fluoroquinolone administration should be spaced away from products containing calcium, magnesium, zinc, aluminum and iron. This includes OTC medications such as multivitamins, calcium carbonate or iron supplements. The absorption of oral ciprofloxacin may be reduced when administered with foods or drinks containing high amounts of calcium, including dairy products or calcium-fortified juices; however, usual dietary intake of calcium likely does not impact absorption. Additionally, patients may experience gastrointestinal adverse effects, and should contact the prescriber if diarrhea is severe or bloody due to concern for infection with Clostridioides difficile.

In summary, despite the perceived fear from fluoroquinolones in pediatrics, these antibiotics are necessary for certain conditions, and can be used safely in most children, as long as side effects are discussed and monitored.

References:

1. Ross RK, Gerber JS, Willis ZI, Hersh AL, Kinlaw AC. Outpatient fluoroquinolone use in children, 2000-2018. J Pediatric Infect Dis Soc. 2020;piaa156. doi:10.1093/jpids/piaa156.
2. Jackson MA, Schutze GE, Committee on Infectious Diseases. The use of systemic and topical fluoroquinolones. Pediatrics. 2016;138(5):e20162706.
3. FDA In Brief: FDA warns that fluoroquinolone antibiotics can cause aortic aneurysm in certain patients. 2018. Available at: https://www.fda.gov/news-events/fda-brief/fda-brief-fda-warns-fluoroquinolone-antibiotics-can-cause-aortic-aneurysm-certain-patients. Accessed March 10, 2021.
4. Patel K, Goldman JL. Safety concerns surrounding quinolone use in children. J Clin Pharmacol. 2016;56(9):1060-1075.