Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines Geneva, 29 September to 3 October 2008 Fluoroquinolones in children WHO Model List of Essential Medicines for Children lists one fluoroquinolone, ciprofloxacin (250 mg tablet) and is for the treatment of shigella infections only. Hence a review was requested on the appropriate use of fluoroquinolones in children Summary Fluoroquinolones have important antibacterial and pharmacological properties favorable for treating several infections in children. There is no definite evidence to show that they induce sustained injury to developing joints in children. Hence there is no reason to avoid their use when specific indications exist. There are many indications in children and shigellosis is just one of them. However, bacterial resistance to this group is increasing rapidly. Since the probability of adverse events cannot be excluded totally and the danger of resistance emerging is real, these agents should not be considered as first line therapy where other options exist. Currently ciprofloxacin has the most evidence for safety and efficacy in children. BNF C 2006 recommends ciprofloxacin and cautions that expert advice should be sought if other fluorquinolones are to be used. It is suitable for use in most conditions where fluoroquinolones are indicated. However, newer fluoroquinolones are being evaluated and limited data show these to be effective and safe in children. This needs to be reviewed when more data becomes available. Recommendations: Only ciprofloxacin to be included in the EML C Shift ciprofloxacin to complementary list Delete the statement regarding shigella infections Spectrum Fluoroquinolones have a very good spectrum of activity [1, 2]. They are active against several clinically important aerobic Gram negative bacilli like those belonging to 1 enterobacteriaceae (eg E coli) and Pseudomonas aeruginosa. They are also active against Gram positive cocci like S pneumoniae, S aureus and beta haemolytic streptococci. H influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumoniae are also susceptible. Anaerobic cover is limited. Pharmacokinetics This group of drugs is well absorbed from the gastrointestinal tract and all except norfloxacin, penetrate well into tissues. Bioavailability ranges from 10-30% for norfloxacin to 80 -90% for ofloxacin [2]. Elimination is mostly through kidneys, unchanged. Newer fluoroquinolones have improved properties like longer serum half life, higher peak levels and bioavailability and extensive tissue penetration [1]. Because of intracellular penetration, they are useful for treating infections due to Mycobacteria and salmonella [1, 2]. Pharmacokinetic data in children is limited. Studies show that systemic elimination is more rapid in children and so larger doses are required [2]. A recent study showed that the newer fluoroquinolone gatifloxacin is rapidly absorbed in infants and children and allows once a day dosing [3]. Formulations suitable for oral and parenteral use and also for local applications in ear and eye infections are available. Because of these reasons, fluoroquinolones are used in adults for a variety of indications including UTI, respiratory tract infections, skin and soft tissue infections, bone and joint infections and infections in the ear and eyes [2]. However, their use in children is limited since animal studies have shown possible joint/cartilage toxicity. Recent evidence shows that fluoroquinolones are useful for several indications in children and that arthropathy associated with its use is rare [1, 2, 4]. Although there is no compelling evidence supporting the occurrence of sustained injury to developing joints in humans by a fluoroquinolone, the possibility that it occurs infrequently has not been excluded[4]. Adverse events Most frequent adverse events are GI related and occur in up to 4% of those treated [1, 2, 5] Prolongation of QT interval and CNS manifestations like head ache, insomnia, seizures are reported. Transient and reversible eosinopilia, neutropenia, elevated transaminases can occur. Rashes and photosensitivity are also reported. Fluoroquiolones with serious adverse events were withdrawn from clinical use [2, 5]. 2 In young animals, arthropathy [1, 2] with typical histopathological changes, but reversible following drug withdrawal and immobilisation, is recorded. Mild to moderate arthralgia occurred during 31/2030 (1.5%) ciprofloxacin therapy in 1795 children [1]. This is similar to that seen in adults and resolved without interventions. Another review of 31 reports on use of ciprofloxacin, ofloxacin or nalidixic acid in more than 7000 children and adolescents concluded that concern regarding chondrotoxicity is not justified [6]. In a prospective observational study, overall, adverse events occurred in 18% children with 3.8% musculo skeletal events. This was significantly higher than in controls (0.4%) [7], but were transient. Drug differences in cartilage effect exist [1] Label information on Cipro (Bayer) [5] states that ciprofloxacin (335 children) was compared with cephalosporin (349 children) in children aged 1-17 yrs with complicated UTI in a multicentric study involving centers in the US, Canada, South America, Germany and South Africa. Duration of therapy was for 10-21 days with a mean of 11 days. An independent Pediatric Safety Committee reviewed all cases. Findings are summarised in the table. Findings involving joint and periarticular tissue as reported in Bayer label [5] Problems subsided spontaneously after stopping therapy. Neurological events like dizziness, insomina, nervousness and somnolence occurred in 3% of ciprofloxacin treated group versus 2% in the comparator group. In this trial, overall 41% in the ciprofloxacin group and 31% in the comparator group reported adverse events. The most frequent was gastrointestinal. Serious events occurred in 7.5% ciprofloxacin and 5.7% control patients. Drug was discontinued in 3% and 1.4% respectively. 3 Resistance Inappropriate use of fluoroquinolones in children and adults is associated with rapidly increasing bacterial resistance to these agents. This aspect is probably of greater concern than potential adverse events [4, 8]. Uses The use of fluoroquinolone in a child or adolescent is therefore is restricted to special circumstances after careful assessment of the risks and benefits for the individual patient [4]. Indications in children will include treatment of [4] 1. Infections caused by multidrug-resistant pathogens for which there is no safe or effective alternative or as second line where first line therapy has failed 2. Infections where no other effective oral agent is available and parenteral therapy is not feasible. Specific indications in children BNF C 2006 and Australian Medicines Handbook also list the following indications FDA Approved [4] • Exposure to aerosolized Bacillus anthracis to decrease the incidence or progression of disease • Urinary tract infections caused by multidrug-resistant, Gram-negative bacteria (FDA licensed for complicated Escherichia coli UTI and pyelonephritis in patients 1 to 17 years of age). Increasing resistance to fluoroquinolones among uropathogens is of concern. Fluoroquinolone resistance has appeared among commensals and uropathogens in most parts of the world, but prevalence rates vary [9-12]. Others [1, 2, 4] 1. Exacerbation of pulmonary disease in patients with cystic fibrosis (CF): Potential causative organisms like P. aeruginosa and other bacteria causing respiratory infections in CF patients are susceptible. Oral ciprofloxacin is shown to be as efficacious as betalactam and aminoglycoside combination [1]. Use of oral therapy can avoid hospitalization and can therefore improve quality of life. Longer period of therapy (3-6 months) was well tolerated [2]. There is most agreement for this indication [1]. 4 2. Typhoid and paratyphoid fevers[1]: Oral ciprofloxacin and ofloxacin bring about clinical and bacteriological cure in children. However, evidence for superiority over other drugs is inconclusive. A Cochrane review [13] identified 33 trials of which 3 were exclusively in children. In adults, chloramphenicol was not significantly different from fluoroquinolones in causing clinical or microbiological failure. In trials of hospitalized children, fluoroquinolones were not significantly different from ceftriaxone (60 participants, 1 trial) or cefixime (82 participants, 1 trial). Norfloxacin had more clinical failures than other fluoroquinolones (417 participants, 5 trials). Trials comparing different durations of fluoroquinolone treatment showed no statistically significant differences (693 participants, 8 trials) 3. Gastrointestinal tract infection caused by multidrug-resistant Shigella species[14], Salmonella species, Vibrio cholerae or Campylobacter jejuni. Incidences of such strains have increased considerably in recent years. Ciprofloxacin is clinically useful and safe for GI infections in children [2]. It was used effectively in an out break of shigellosis [15]. Short courses of therapy are usually sufficient. However, suboptimal dosages can lead to rapid emergence of resistance or decreasing susceptibility as is being reported from several countries for Salmonella [16-19], Shigella[20] and Campylobacter [21-23]. Hence careful attention to rational use is necessary, especially for this indication. 4. Chronic suppurative otitis media [2] or malignant otitis externa caused by P. aeruginosa. Oral or topical applications can be used. A Cochrane review [24] identified 9 trials (842 analysed participants or ears). Topical quinolones were better than systemic quinolone and non-quinolone antibiotics at clearing discharge at 1-2 weeks. Role of fluoroquinolones in acute otitis media (AOM) is limited. However, Gatifloxacin or Levofloxacin can be useful in treating complicated AOM failing to respond to initial antibiotic therapy [1] . 5. Gram negative neonatal sepsis/meningitis [2]: Because of the good penetration into CSF and cerebral tissues and activity on Gram negative bacteria, it can be used for treating Gram negative meningitis in the new born. It is suggested that it reduces chance of cerebral abscess formation in the neonates and the immunocompromised [2]. 116 neonates with microbiologically proven/probable sepsis were treated successfully with ciprofloxacin. No short term adverse events were observed. No clinical arthropathy or growth impairment occurred at one year follow up [25] 5 However, since seizures and raised intracranial pressure are listed as adverse events, close monitoring is required. Some others state that it can be used for neonatal sepsis but not for meningitis [26] 6. Gram-negative bacterial infections in immuno-compromised hosts in which oral therapy is desired or resistance to alternative agents is present 7. As second line in bacterial septicemia or meningitis in infants and children in whom therapy with other appropriate antimicrobial agents has failed . 8. Chronic or acute osteomyelitis or osteochondritis [2]: Fluoroquinolones reach high concentrations in the bones and joints and have action against common aetiological agents. It is shown to be clinically effective for those infections caused by P. aeruginosa and so is recommended for this infection. 9. Children with serious allergy to alternative agents and severe infections with fluoroquinolones-susceptible pathogens 10. Mycobacterial infections Among the various fluoroquinolones, Ciprofloxacin is most potent against pseudomonas and most data on safety and efficacy in children are on this drug. It is effective for all indications listed above. Gatifloxacin, levofloxacin, gemifloxacin, moxifloxacin are more recent introductions with better activity against S pneumoniae and other Gram positive bacteria. Limited data shows that gatifloxacin is safe and effective in children and has convenient dosing schedule [2]. However, more evidence is required for their clinical utility and superiority over ciprofloxacin in terms of efficacy and safety for the various indications in children. It is also better to prevent wide spread use of newer fluoroquinolones to minimize development of resistance. 1. Leibovitz, E., The use of fluoroquinolones in children. Curr Opin Pediatr, 2006. 18(1): p. 64-70. 2. Velissariou, I.M., The use of fluoroquinolones in children: recent advances. Expert Rev Anti Infect Ther, 2006. 4(5): p. 853-60. 3. Capparelli, E.V., et al., Pharmacokinetics of gatifloxacin in infants and children. Antimicrob Agents Chemother, 2005. 49(3): p. 1106-12. 4. Committee on Infectious Diseases.The use of systemic fluoroquinolones. Pediatrics, 2006. 118(3): p. 1287-92. 5. Label, Cipro, Bayer Health Care, Bayer Pharmaceuticals corporation. 2007. 6. Burkhardt, J.E., J.N. 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