Implications for fluoroquinolone use in children

March 2001

The fluoroquinolones are a well-known class of antibiotics, perhaps better known to clinicians caring for adults, as none of the fluoroquinolones are approved by the Food and Drug Administration (FDA) for systemic use in children.

Several fluoroquinolones have been approved for topical use in children (eg, ofloxacin [Floxin Otic, Daiichi] and ciprofloxacin-hydrocortisone otic (Cipro HC Otic, Alcon). Even though the fluoroquinolones have not been granted FDA approval for systemic use in children, the literature contains numerous studies evaluating their safety and efficacy in this population.

The fluoroquinolone class of antibiotics includes eleven available agents, while the quinolone class (a chemically similar group) includes two available agents. One of the quinolones, nalidixic acid, has been available since 1962 and is approved for systemic use in children 3 months of age and older to treat urinary tract infections (UTIs). Due to its bothersome adverse event profile and the availability of other safer antibiotics, however, nalidixic acid is uncommonly used by most pediatricians today.

Arthrotoxic events

The basis for the lack of pediatric labeling for the fluoroquinolones stems from studies documenting arthrotoxic effects in juvenile animals.

The fluoroquinolones have several advantages, such as good oral bioavailability, once-daily dosing, broad antibacterial spectrum, and activity toward Pseudomonas aeruginosa from an oral dosage form. These characteristics can be useful in children as well as adults, and because of this, the FDA organized several advisory committees to address this issue. Considerable data were discussed, resulting in committee recommendations for prospective, controlled studies of fluoroquinolone use in children for cystic fibrosis (pulmonary exacerbations), bone marrow transplantation-related infections, meningitis, sepsis, pneumonia, complicated UTIs, recurrent otitis media (OM), chronic suppurative OM and osteomyelitis.

Damage to articular cartilage, particularly in large weight-bearing joints, is the basis for their lack of pediatric approval. The various animals tested differ in their sensitivity to fluoroquinolone-induced cartilage damage, with dogs the most sensitive. The resulting cartilage damage can be described by joint effusion, synovial membrane inflammation and thickening of articular cartilage. Clinically, the arthropathy manifests as swelling and limping, which in dogs, have often resolved, even with continued drug administration. In some studies of dogs and rats, structural changes in the affected joints have not totally resolved in study periods of several months.

Safety studies in children

Despite their lack of FDA approval, the fluoroquinolones have been evaluated in thousands of children. While most of these studies were not controlled or prospective, they still provide valuable information. Some prospective studies have used magnetic resonance imaging (MRI), radiography, or ultra sonography to screen for cartilage damage. Several large uncontrolled studies evaluated ciprofloxacin (Cipro, Bayer) in thousands of patients.

The major indication for ciprofloxacin use was for the pulmonary exacerbations in cystic fibrosis (CF) patients. Arthralgias occurred in 1.5% of treatment courses, which may have been due to disease-related arthropathies known to occur with CF. An additional study (Jick) evaluating treatment courses of ciprofloxacin in a mainly non-CF population concluded that no cases of joint toxicity occurred. Several studies, although hampered by their small patient numbers, used MRI, radiography, or ultrasonography to evaluate ciprofloxacin use in children with CF. No clinically significant changes in joint structure or function were noted to occur in these studies.

Two large reviews of fluoroquinolone use in children have been published. Kubin described studies using ciprofloxacin in children, most of whom were treated for CF. Of 1,113 CF patients treated, 36 cases (3.2%) of reversible arthralgia were reported, which is within the suspected prevalence rate (10%-15%) of CF disease-related arthralgias. When given to patients with infectious processes not related to CF, no arthralgias occurred.

Burkhardt's published review of fluoroquinolone use in children included over 7,000 patients. Although many of the studies reviewed contain methodological flaws, arthropathy due to fluoroquinolone therapy was not reported in a single patient. Burkhardt concluded that specific fluoroquinolones should be prospectively evaluated in children.

Efficacy studies and potential uses

Ciprofloxacin is the fluoroquinolone most studied in children, mostly when used to treat pulmonary exacerbations of CF. Advantages of ciprofloxacin include its availability as an oral dosage form (tablet and suspension), in addition to an intravenous solution. As well, ciprofloxacin is active toward many strains of P. aeruginosa an important pathogen in CF.

The fluoroquinolones have also been evaluated in treating enteric infections, febrile neutropenia, central nervous system infections and UTIs, although not to the extent as in CF. Although they have limitations when given for these uses, their success in treatment has prompted researchers to recommend consideration of their use and further study.

The 2000 Red Book states that cipro floxacin " ... does not appear to cause arthropathy, and is effective as an oral agent for treating a number of diseases that would otherwise require parenteral therapy" and "... in special circumstances after careful assessment of the risks and benefits for the individual patient, use of a fluoroquinolone can be justified."

The Red Book describes these uses as instances where other oral antibiotics are not available or appropriate, such as chronic suppurative otitis media or malignant otitis externa, chronic osteomyelitis, mycobacterial infections, or gram-negative bacterial infections in immunocompromised hosts when prolonged oral therapy is expected.

Even though the fluoroquinolones do not have pediatric labeling, significant evidence exists that arthrotoxicities that have occurred in several animal species do not seem to occur in humans. Results of controlled prospective trials and other studies have indicated that the fluoroquinolones can have important clinical benefits in treating some pediatric infectious diseases. It is quite possible that the FDA will approve pediatric indications for ciprofloxacin and perhaps other fluoroquinolones in the near future.

If pediatricians presently choose to prescribe ciprofloxacin (or other fluoroquinolones), it would be wise to discuss their selected use with the patient and or caregivers. Clinicians should heed caution, however, if and when pediatric labeling is granted (as well as now), for the advantages the fluoroquinolones possess (e.g., once-daily dosing, broad antibacterial spectrum) may cause them to be over-prescribed. It is known that with some bacterial pathogens, resistance to the fluoroquinolones easily develops, thus limiting their potential usefulness. idc

Editor's Note: Several years ago, I wrote a commentary on fluoroquinolones. The bottom line was that until the FDA approves these drugs, it would be foolhardy to use them unless there is no alternative and the parents understand this. After having explained this to the parents, it should be documented in the chart. I saw the drugs used extensively in England where the legal climate is somewhat different. I would not want to give trial lawyers a new "cause." If a child you have treated for otitis develops joint complaints at a later date, I would not like to testify for you in court. - Philip A. Brunell, MD

For more information:

• Edward A. Bell, PharmD, BCPS, is an associate of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.

• Bell EA. Use of the fluoroquinolone antibiotics in the pediatric population. Journal of Pediatric Pharmacy Practice. 2000;5:216-28.
• Jick S. Ciprofloxacin safety in a pediatric population. Pediatr Infect Dis J. 1997;16:130-4.
• Richard DA. Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of anti pseudomonal efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Pediatr Infect Dis J.1997;16:572-8.
• Kubin R. Safety and efficacy of ciprofloxacin in pediatric patients - review. Infection. 1993; 21:413-21.
• Burkhardt JE. Quinolone arthropathy in animals vs. children. Clin Infect Dis. 1997;25:1196-204.
• Church DA. Sequential ciprofloxacin therapy in pediatric cystic fibrosis: comparative study vs. ceftazidime/tobramycin in the treatment of acute pulmonary exacerbations. Pediatr Infect Dis J. 1997;16:97-105.