Fluoroquinolone Use In Children

When you read the Morsel on Perichonditis of the ear last week (or perhaps the Plantar Puncture Morsel from many many many weeks ago) you may have objected because of the mention that, when indicated, fluroquinolones are safe in children. Some of you may have thought to yourself “first the AAP allows tetracycline (Rocky Mountain Spotted Fever) and now they allow fluoroquinolones use in children… what next?!” Historically there have been concerns about the complications of fluoroquinolone use in children, specifically musculoskeletal complications, but are those concerns high enough to remove this important therapeutic option entirely? It would seem that the Fluoroquinolone use in children calls for some myth busting!

Fluoroquinolone Use in Children: Basics

• It has two bacterial drug targets, DNA gyrase and DNA topoisomerase IV.  
• It is active against both Gram-positive and Gram-negative pathogens and can be used in a wide variety of infections. (Jackson 2016)
• Ciprofloxacin was the first fluoroquinolone approved by the FDA in the 1980’s as a broad-spectrum antibiotic. (Rose 2014)
• They are the most frequently prescribed class of medications in adults; however, in children they are the least frequently prescribed class, <2% of antibiotics. (Hersh 2014)

Fluoroquinolone Use in Children: Indications for use

• Let’s keep this simple, Pseudomonas!
  • When there is concern for pseudomonas (ex, perichondritis and plantar puncture wounds), fluoroquinolones are considered first line – there are almost no other oral antibiotic choices.
  • Notably there are a few IV choices if your patient requires IV medications. (Jackson 2016)
• It can also be used in UTIs, but is typically reserved for special cases where the infectious bacteria is found to be multidrug resistant or in complicated UTIs. 
• Prophylaxis or treatment of the plague, Yersinia pestis, as well as Neisseria meningitidis
• Treatment following anthrax exposure
• Complicated pulmonary infections in patients with cystic fibrosis
• Severe multidrug resistant infections as well as multidrug resistant TB
• Fluoroquinolones can be used as an alternative therapy in cases of conjunctivitis, acute otitis externa, acute otitis media, community acquired pneumonia.

Fluoroquinolone Use in Children: A Bad Rep?

Myth #1: Musculoskeletal Adverse Events (MAE)

• This concern is likely the most common reason fluoroquinolones are rarely used in children.
• Musculoskeletal Adverse Events include:
  • Articular cartilage damage causing arthralgias or arthritis,
  • Tendonitis, and
  • Tendon rupture.
• Data was based largely on animal studies in the 1970’s that demonstrated damage to articular cartilage vs epiphyseal plate cartilage in juvenile beagle dogs exposed to high doses. (Hersh 2014)
  • Another study looked at all MAEs in juvenile beagles given either low dose or high dose fluoroquinolone.
  • The low dose range (30 mg/kg) did show sporadic lesions.
  • The high dose range (90 mg/kg) showed much more common lesions which all resolved within the first few weeks of stopping treatment. (Binz 2015)
  • Remember, dogs grow 18 times as fast an infant in the first year of life. This could greatly augment the effects of Fluoroquinolones on growing joints and tendons. (Binz 2015)
  • More recent lamb studies have been performed, where the growth more closely approximates a human child. This showed no abnormalities on examination of the cartilage (Jackson 2016)

• Multiple studies in children have analyzed the effects of fluoroquinolone use to MAEs. 
  • Gatifloxacin use was evaluated in 867 children, which resulted in 12 (1.4%) of children having transient arthritis which resolved within 2 weeks (Pichichero 2005)
  • Ciprofloxacin was compared to Cephalospoin for the treatment of complicated UTI’s in children. Arthropathy was seen in 13.7% of the Ciprofloxacin group vs 9.5% in the Cephalosporin group. (Jackson 2016)
  • A systematic review of safety data for over 16000 pediatric patients did show MAEs were the most frequently reported event. Which is a risk of 1 event for 62.5 patients; however, all cases resolved or improved with medical management or withdrawal of the medication. (Jackson 2016) 
  • Levofloxacin vs a non-fluoroquinolone for community-acquired pneumonia in children and acute otitis media was evaluated. There were 2523 children included. Number of adverse effects was similar between the groups, however in the Levofloxacin group 85% of MSK complaints were arthralgias. None of the patients were documented to have joint disease at follow up. (Noel 2007)
  • In a very robust, recent multicenter, randomized, double-blind controlled study Moxifloxacin was compared to a comparator drug (IV ertapenem followed by PO Augmentin) for complex intraabdominal infections. 451 pediatric patients were included. The incidence of MAEs was comparable between the treatment arms. (Wirth 2018) 
  • One study including 4.4 million adolescents evaluated for tendon injuries including rupture (Achilles, quadriceps, patellar or tibia) and tendonitis.  There was an increased risk of tendon rupture (1.9 per 100,000) when compared to comparison antibiotic. The risk of tendonitis was similarly very small. These were overall still very rare events. (Ross 2021)

• Predisposing risk factors including older age, trauma to tendons or joints, and a family history of MAEs. (Binz 2015). 

This myth is: BUSTED-ish. The studies aren’t conclusive, but mostly lean away from harm. Children may rarely experience MAEs with fluroquinolone use, but other antibiotic classes may also cause MAEs. Even when MAEs occur, they seem to be self-resolving. So, in the right clinical situtation, the benefits of the fluoroquinolone use in children may outweigh the risk. 

Myth # 2: Neurologic affects 

• Nervous system adverse events mostly include central concerns (ex, seizures, headaches, dizziness, lightheadedness, sleep disorders, hallucinations) and peripheral neuropathy. (Jackson 2016)
• In one clinical trial, the rate of neurologic events described were similar between ciprofloxacin-treated and comparator-treated children. (Jackson 2016)
• Reported rates of neurologic events in the levofloxacin safety database are similar between fluroquinolone- and comparator- treated children (Jackson 2016)
• One recent case report linked Ciprofloxacin to peripheral neuropathy in a teenager. Symptoms resolved within 24 hours of withdrawal of the medication. This is the 8^th case report which has identified fluoroquinolone-associated peripheral neuropathy in a child. (Morley 2022)

This myth is: BUSTED. When compared with other antibiotics, there appears to be no significant increased risk of developing neurologic effects with Fluoroquinolone use in children. Overall, the serious neurological effects appear to be extremely rare.  

Fluoroquinolone Use in Children: Considerations

Before you start writing ciprofloxacin for every pediatric patient…

• There are multiple studies worldwide showing that despite our low use we may be overprescribing fluoroquinolones outside clinical indications: 
  • The number of oral fluoroquinolone prescriptions in children in the United States between 2006 and 2015 was investigated. Nearly 400,000 prescriptions were written and 22% were found to be inappropriate based on clinical guidelines. (Etminan 2019)
  • In Belgium between 2010 – 2013, of the 262 children treated with fluroquinolones while hospitalized, only 17% were used for labelled indications. (Meesters 2018)
• Resistance is growing (likely from inappropriate / overuse)! From 2001 to 2009, in a pediatric hospital gram negative culture showed a drop in sensitivity to ciprofloxacin from 96% to 93%. This was similarly seen with levofloxacin. (Rose 2014)
• However, resistance has remained overall low in children when compared to adult antibiograms.(Hersh 2014)

Moral of the morsel 

• Nothing comes with no cost/risk. All antibiotics have side effects. Fortunately, for fluoroquinolone, the more serious side effects are comparable to alternative antibiotics in multiple trials.
• Pseudomonas? Then maybe Fluoroquinolone is the answer. Know the indications! Avoid misuse and overuse! Fluroquinolones are good for children when they are clinically indicated, as the benefits outweigh the risk. However, Fluroquinolone resistance is increasing, so they should only be used if absolutely necessary! Nobody wants a pseudomonas superbug becoming prevalent!

References:

• Ross RK, Kinlaw AC, Herzog MM, Funk MJ, Gerber JS. Fluoroquinolone Antibiotics and Tendon Injury in Adolescents. Pediatrics. 2021. 147(6):e202003316. PMID: 33990459
• Binz J, Adler CK, So TY. The risk of Musculosketal Adverse Events with Fluoroquinolones in Children: What is the Verdict Now? Clin Pediatr. 2016. 55(2):107-10. PMID: 26260402
• Etminan M, Guo M, Carleton B. Oral Fluoroquinolone Prescribing to Children in the United States From 2006 to 2015. Pediatr Infect Dis J. 2019. 38 (3):268-270. PMID: 29846302
• Jackson MA, Schutze GE. The Use of Systemic and Topical Fluroquinolones. Pediatrics. 2016 138(5):e20162706. PMID: 27940800
• Hersch AL, Gerber JS, Hicks LA, Pavia AT. Lessons Learned in Antibiotic Stewardship: Fluoroquinolone Use in Pediatrics. J Pediatric Infect Dis Soc. 2015. 4(1):57-9. PMID: 26407358
• Meesters K, Mauel R, Dhont E, Walle JV, De Bruyne P. Systemic Fluoroquinolone Prescriptions for Hospitalized Children in Belgium, Results of a Multicenter Retrospective Drug Utilization Study. BMC Infectious Disease. 2018. 18: 89. PMID: 29471791
• Morley C, Carvalho de Almeida C, Moloney S. Ciprofloxacin-associated Peripheral Neuropathy in a Child: A Case Report and Review of the Literature. Pediatr Infect Dis J. 2022. 41(2):121-122. PMID: 34817415
• Noel GJ, Bradley JS, Kauffman RE. Comparative Safety Profile of Levofloxacin in 2523 Children With a Focus of Four Musculoskeletal Disorders. Pediatric Infect Dis J. 2007. 26(10):879-91. PMID: 17901792
• Pichichero ME, Arguedas A, Dagan R, Sher L, Saez-Llorens X, Hamed K, Echols R. Safety and Efficacy of Gatifloxacin Therapy for Children with Recurrent Acute Otitis Media (AOM) and/or AOM Treatment Failure. Clin Infect Dis. 2005. 41(4):470-8. PMID: 16028153
• Rose L, Coulter MM, Chan S, Hossain J, Di Pentima MC. The Quest for the Best Metric of Antibiotic Use and its Correlation with the Emergence of Fluoroquinolone Resistance in Children. Pediatr Infect Dis J. 2014. 33(6): e158–e161. PMID: 24830523
• Wirth S, Emil S, Engelis A, Digtyar V, Criollo M, DiCasoli C, Stass H, Willmann S, Nkulikiyinka R, Grossmann U. Moxifloxacin in Pediatric Patients with Complicated Intra-abdominal Infections. Pediatr Infect Dis J. 2018. 37(8):e207-e213. PMID: 29356761