Fluoroquinolone antibiotics have found widespread use in adults because of a favorable safety record, ease of administration (oral and intravenous forms available), and activity against a broad spectrum of gramnegative and gram-positive bacteria. Fluoroquinolones are derived from the first-generation quinolone. nalidixic acid, introduced into clinical practice in the 1960s (see Table 1, see page 338). The addition of a fluorine to the quinolones created the second-generation fluoroquinolones, such as ciprofloxacin and levofloxacin.1 These drugs have a broader spectrum of antimicrobial activity compared with nalidixic acid, particularly against gram-negative bacteria, and improved pharmacokinetics. Further chemical modification resulted in the third- and fourth-generation quinolones, such as moxifloxacin, with expanded coverage to include gram-positive and anaerobic organisms. The classification of certain quinolones as either third- or fourth-generation is somewhat arbitrary and varies among references.
Fluoroquinolones act by inhibiting bacterial DNA gyrase and DNA topoisomerase IV important for DNA synthesis. However, every fluoroquinolone tested in immature animals has resulted in damage to developing cartilage.1 As a result, fluoroquinolone use in children generally has been avoided, except in circumstances where alternative antibiotic choices are limited. Importantly, whether cartilage damage to immature animals translates to the developing musculoskeletal system of children continues to be a topic of debate. Many studies examining fluoroquinolone safety and efficacy in children have failed to document significant musculoskeletal abnormalities.
Certain pediatric pathogens, such as Haemophilus influenzae and Streptococcus pneumoniae, have become increasingly resistant to commonly used classes of antibiotics such as penicillins.3 Therefore, some practitioners have favored expanding the current generally accepted indications for pediatric fluoroquinolone administration to include diseases such as recurrent otitis media.4 Others have been reluctant to endorse increased pediatric fluoroquinolone administration because of concerns that these common pediatric pathogens also will become increasingly resistant to this class of antibiotics.5 Recently, the American Academy of Pediatrics Committee on Infectious Disease addressed this question, publishing recommendations for pediatric fluoroquinolone administration based upon available data and expert opinion (see Table 1 , page 338, and Table 2, page 34O).6
ARE FLUOROQUINOLONES SAFE FOR CHILDREN?
It is compelling that cartilage damage has been noted in a variety of animal studies, ranging from juvenile mice to dogs, regardless of the fluoroquinolone agent tested. Despite these concerns, evidence that fluoroquinolones result in musculoskeletal abnormalities in children is limited. One pharmaceutical company-sponsored literature review found no evidence of skeletal problems in immature patients when examining more than 30 studies encompassing more than 7,000 patients.2 Another study with pharmaceutical company ties compared skeletal side effects in children younger than 19 years who were given either a fluoroquinolone (ofloxacin, ciprofloxacin, or levofloxacin [total of 6,124 participants]) or azithromycin [15,073 participants]). Joint problems occurred in <1% in both groups.7 A later review of published studies, including the Bayer company's ciprofloxacin clinical trials study database, also found that the incidence of skeletal problems, including arthralgia, was similar in children receiving either ciprofloxacin or a non-quinolone antibiotic.8 However, an open-label, non-blinded, multi-center European study found an increased number of arthralgias and myalgias associated with pediatric ciprofloxacin use.9 These symptoms were reversible and remitted when the antibiotic was discontinued. No objective findings of joint swelling or arthritis were reported.
Selected Quinolones: Current Uses*
Neonates exposed to fluoroquinolones also have been studied for potential skeletal problems. One study reviewed 28 pre-term neonates treated with fluoroquinolones because of infection with multidrug resistant gram-negative bacilli species.10 The authors found no significant side effects except for dental dyschromia (change in tooth color) in two patients. In another study, neonates born at <33 weeks' gestation receiving ciprofloxacin (n=48) were compared with those receiving other classes of antibiotics (n=66). Eighty percent of ciprofloxacin-exposed babies had either normal or minor neurodevelopmental impairment at followup, compared with 74% of the control group. No joint abnormalities were reported, and no imaging studies to evaluate joint development were performed in this study. An important limitation of this study was that a large proportion of neonates were either lost to follow-up or had incomplete follow-up.11
There are also limited data regarding the outcome of neonates exposed to fluoroquinolones in utero. One multi-center prospective trial looked at the outcomes of neonates of 200 mothers exposed to fluoroquinolones.12 These authors did not find that neonates had an increased risk of joint defects or other abnormalities attributable to maternal fluoroquinolone administration. A second study found no overall increase in congenital malformations after fluoroquinolone exposure.13 However, there was a trend toward increased bone malformations (prevalence ratio 2.2, 95% confidence interval 0.7 to 6.7) when the fluoroquinolone was administered either within 30 days of conception or during the first trimester. This study was limited by the small number of enrolled patients and lack of statistical power.
Importantly, cartilage toxicity is not the only potential side effect associated with quinolone use. A number of quinolones are no longer available (see Table 1, see page 338), and each drug has its own set of potential side effects. Recent studies demonstrated the efficacy of gatifloxacin in children with recurrent acute otitis media (AOM).14 The conclusion of this study was that gatifloxacin was an efficacious and safe alternative for children with difficult-to-treat AOM. However, a side effect observed in adults has been abnormalities in blood glucose levels.15·16 Gatifloxacin was voluntarily withdrawn from the market in the spring of 2006 and is no longer available in the United States. Other relatively rare but serious toxicities associated with fluoroquinolone use include spontaneous Achilles tendon rupture, seizures, prolonged QTc (the corrected QT electrocardiogram interval), photosensitivity, and acute liver failure (see Table 1, page 338). U6 Prolonged QTc tends to occur in adults with a history of previous cardiovascular disease. Trovafloxacin was introduced to treat a variety of infections but was withdrawn after several deaths related to acute liver failure were associated with the drug. Ciprofloxacin has been implicated as predisposing to pseudomembranous colitis, and one child administered levofloxacin for AOM had bloody diarrhea likely related to antibiotic exposure.1718 More common and less serious side effects include gastrointestinal symptoms in 2% to 20% of patients depending on the administered drug and central nervous system problems such as headache or dizziness in 1 % to 2% of patients.16
In summary, despite the reported fluoroquinolone-induced musculoskeletal toxicity in juvenile animals, these adverse events have not been confirmed as occurring in children. When arthralgias have been reported, they resolve with discontinuation of the drug. However, quinolone use in adults has been associated with rare but serious side effects, and a number of these antibiotics are no longer available.
Finally, it is important that each fluoroquinolone be considered individually, as the potential toxicity profile of each agent differs. The trovafloxacin and, more recenüy, the gatifloxacin experiences are important lessons that newer fluoroquinolones should be used with caution, especially in children, until a substantial amount of clinical evidence confirms their safety. Current available data regarding the safety of pediatric fluoroquinolone administration suggests that they may be used in selected clinical situations. To our knowledge a bunded, prospective study to definitively resolve the question of pediatric safety and fluoroquinolone use has not been performed. Therefore, because the data remain incomplete, children receiving fluoroquinolones, such as ciprofloxacin or levofloxacin, should be monitored closely for side-effects.
ARE CONCERNS ABOUT FLUOROQUINOLONE RESISTANCE JUSTIFIED?
As the safety of pediatric fluoroquinolone use has become more widely accepted, some infectious diseases specialists have raised concerns that increasing pediatric administration of ciprofloxacin and levofloxacin will lead to higher fluoroquinolone resistance in important pathogens, especially 5. pneumoniae.5 There are several different mechanisms by which bacteria develop resistance to fluoroquinolones.19 The first is by chromosomal mutations in the genes encoding the DNA topoisomerase IV and DNA gyrase that likely alter the affinity of the antibiotic for its target. These occur primarily in the gyrase gene gyrA in gramnegative bacteria and in the topoisomerase gene parC in gram-positive bacteria. Secondly, both gram-negative and grampositive bacteria may possess a drug-efflux pump that facilitates expulsion of the antibiotic. Recently, a plasmid has been identified that carries a gene, qnrA, that confers a form of low-level fluoroquinolone resistance. This plasmid has been found in clinical Salmonella isolates from the United States with increased ciprofloxacin minimum inhibitory concentrations (MICs).20 This is particularly concerning because plasmids are often transmissible between bacterial species and can facilitate spread of resistance.
Possible Indications for Pediatric Fluoroquinolone Use
Surveillance studies of adults suggest that fluoroquinolone resistance is indeed on the rise. In Canada, the Bacterial Surveillance Network reported an increase of pneumococcal ciprofloxacin resistance from 1.4% to 2.7% between 2002 and 2004.21 One risk factor for carrying a resistant organism was increasing age. Several studies examined fluoroquinolone resistance in bacterial isolates from both the United States and abroad. A recent study found a pneumococcal ciprofloxacin resistance rate of 4.5%.3 However, virtually all pneumococci from pediatric patients in an earlier study were susceptible to levofloxacin.22 Importantly, in areas of the world where fluoroquinolones are used to treat enteric fever, there have been reports of increased resistance. For example, in a recent report from India, 20% (5/25) Salmonella typhi and 24% (6/25) of Salmonella paratyphi were resistant to ciprofloxacin.23 Another concerning development is the identification of ciprofloxacin-resistant enteric gram-negative bacteria in the stools of children who have never been exposed to the antibiotic.24 This reservoir of resistant bacteria would only be expected to increase with increasing pediatric fluoroquinolone use.
In conclusion, even if fluoroquinolones are generally safe for children, the existing data regarding emerging fluoroquinolone resistance are concerning and should limit their pediatric use.
WHEN IS QUINOLONE USE APPROPRIATE IN CHILDREN?
There have been many proposed clinical indications for pediatric fluoroquinolone administration. The strength of the data to support pediatric fluoroquinolone use varies with the clinical scenario. These have included children with cystic fibrosis and associated pulmonary infection with Pseudomonas aeruginosa, chronic recurrent urinary tract infections, serious infection with drug-resistant gram negative organisms, enteric fever due to Salmonella or Shigella species, chronic recurrent suppurative otitis media, empiric therapy in immunocompromised children with fever and neutropenia, respiratory infections including otitis media, treatment of gram-negative infections in patients with allergies to other classes of antibiotic, bacterial meningitis, and most recently postexposure prophylaxis and therapy against inhalational anthrax (see Table 2).6
The Food and Drug Administration (FDA) has approved the use of fluoroquinolones for children only under the following two circumstances:
Post-exposure treatment for inhalational Bacillus anthracis (anthrax): Although the majority of B. anthracis strains in nature are susceptible to penicillin, the bioterrorist attacks of 2001 raised concerns that B. anthracis could be engineered to become resistant to penicillin. Ciprofloxacin is effective in reducing mortality in rhesus monkey models of postexposure prophylaxis.25 This model is currently considered the best surrogate for human disease, and there are no human data on the efficacy of ciprofloxacin for inhalational anthrax. Therefore, FDA approval was based primarily on the above animal studies. This approval included children because in this clinical situation the potential benefits of ciprofloxacin were believed to outweigh the risks of therapy. It is worth noting that after exposure to anthrax, the recommended length of prophylaxis is at least 45 days, and studies of pediatric fluoroquinolone use have included few children receiving uninterrupted prolonged therapy. It is also important to recognize that both penicillin and doxycycline provided protection to monkeys exposed to inhalational anthrax.25
Complicated urinary tract infection: Data to support the administration of fluoroquinolones to children with urinary tract infections (UTI) are extremely limited.26 Ciprofloxacin is an appealing therapy for UTIs because it can be administered orally, is present in high levels in the urine, and has activity against most of the organisms responsible for UTIs including P aeruginosa. Case series of small numbers of patients suggest that ciprofloxacin is safe and efficacious.26 However, to our knowledge there has not been a large controlled trial that has demonstrated the superiority of ciprofloxacin compared with other antibiotics used to treat complicated UTIs.
There are a number of other clinical situations in which although fluoroquinolones have not been approved for children by the FDA, experts generally agree that they are a reasonable choice. There are other suggested indications where fluoroquinolones have been demonstrated to be efficacious but should not be considered first-line therapy because other approved antibiotics remain useful. The American Academy of Pediatrics Committee on Infectious Diseases recently reviewed the safety, resistance, and efficacy data for fluoroquinolone use in children and published recommendations for the appropriate use of ciprofloxacin in children.6
OFF-LABEL APPROPRIATE USE OF FLUOROQUINOLONES (TABLE 2)
In addition to the previously mentioned situations, there are several general clinical situations where ciprofloxacin is an appropriate first line therapy. These include infections with P. aeruginosa when oral therapy is desired or appropriate. The best studied example of this is for pulmonary exacerbations due to P. aeruginosa in children with cystic fibrosis. Ciprofloxacin is also indicated for a variety of infections with multidrug resistant gram-negative organisms where alternative antibiotic choices are limited. Ciprofloxacin has been used as first line therapy for enteric fever in areas where Salmonella species are endemic because of their resistance to other classes of antibiotics. As previously noted, fluoroquinolone resistance amongst these organisms is also increasing, so the susceptibility of the organism to ciprofloxacin and/or levofloxacin should be confirmed. Finally, patients with allergies to other antibiotics are appropriate candidates for fluoroquinolones when they have an infection caused by a fluoroquinolone-susceptible organism.
There are certain situations, such as fever and neutropenia in immunocompromised children, for which alternative intravenous antibiotics are similar in efficacy to oral ciprofloxacin.27 Substitution of an oral agent for intravenous therapy has obvious advantages, and these benefits must be compared against the potential safety risks regarding fluoroquinolones and resistance previously discussed. Adults with fever and neutropenia who are considered to be low risk are frequently managed with oral fluoroquinolones. In general, empiric therapy with a fluoroquinolone is not recommended when a causative organism has not been isolated.
Levofloxacin has recently been found to be efficacious for the treatment of recurrent otitis media.18 However, the majority of bacteria that cause AOM remain susceptible to other agents such as ceftriaxone.3 Therefore, unless an organism is isolated that is resistant to multiple antibiotics, fluoroquinolones should be infrequently recommended for treating acute otitis media and respiratory infections in children.
Current data, although incomplete, suggest that pediatric administration of a fluoroquinolone, especially the best-studied ciprofloxacin, is safe. However, many experts have raised concerns regarding the emergence of fluoroquinolone-resistant pathogens such as pneumococcus if more children are treated with fluoroquinolones. Examination of the available data suggests that these concerns remain valid. Therefore, most experts continue to advise against expanded pediatric use of fluoroquinolones, except in those selected clinical situations where the benefits clearly outweigh the risks of therapy and there are few other antibiotic choices.
1. Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect. 2005; 1 1(4):256-280.
2. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone arthropathy in animals versus children. Clin infect Dis. 1997;25(5): 1 196-1204.
3. Fedler KA, Biedenbach DJ, Jones RN. Assessment of pathogen frequency and resistance patterns among pediatric patient isolates:
Report from the 2004 SENTRY Antimicrobial Surveillance Program on 3 continents. Diagn Microbiol Infect Dis. 2006;56(4):427-436.\
4. Echols R, Hamed K, Arguedas A, et al. Gatifloxacin therapy for children: turn on the light. CUn Infect Dis. 2005:41(12): 1824-1825.
5. Mandell LA, Peterson LR, Wise R, et al. The battle against emerging antibiotic resistance: should fluoroquinolones be used to treat children? Clin Infect Dis. 2002;35(6):72 1-727.
6. Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics. 2006;1 1 8(3): 1287-1 292.
7. Yee CL, Duffy C, Gerbino PG, Stryker S, Noel GJ. Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin. Pediatr Infect Dis J. 2002;21(6):525-529.
8. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003;22(12):1 128-1 132.
9. Chalumeau M, Tonnelier S, D'Athis P, et al, and the Pediatric Fluoroquinolone Safety Study Investigators. Fluoroquinolone safety in pediatric patients: a prospective, multicenter, comparative cohort study in France. Pediatrics 2003;lll(6Ptl):e714-7I9.
10. van den Oever HL, Versteegh FG, Thewessen EA, van den Anker JN, Mouton JW, Neijens HJ. Ciprofloxacin in preterm neonates: case report and review of the literature. Eur J Pediatr. 1998;157(10):843-845.
1 1 . Ahmed AS, Khan NZ, Sana SK, et al. Ciprofloxacin treatment in preterm neonates in Bangladesh: lack of effects on growth and development. Pediatr Infect Dis J. 2006;25( 1 2): 1 1 37- 1 14 1 .
12. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339.
13. Wogelius P, Norgaard M, Gislum M, Pedersen L, Schonheyder HC, Sorensen HT. Further analysis of the risk of adverse birth outcome after maternal use of fluoroquinolones. Ira J Antimicrob Agents. 2005;26(4):323-326.
14. Arguedas A, Sher L, Lopez E, et al. Open label, multicenter study of gatifloxacin treatment of recurrent otitis media and acute otitis media treatment failure. Pediatr Infect Dis J. 2003:22(1 1):949-956.
15. Frothingharn R. Glucose homeostasis abnormalities associated with use of gatifloxacin. Clin Infect Dis. 2005;41(9):1269-I276.
16. Owens RC, Ambrose PG. Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis. 2005;41(Suppl2):144-157.
17. Angel CA, Green J, Swischuk L, Patel J. Severe ciprofloxacin-associated pseudomembranous colitis in an eight-year-old child. J Pediatr Surg. 2004;39(10):1590-I592.
1 8. Arguedas A, Dagan R, Pichichero M, Leibovitz E, Blumer JL, McNeeley DF, et al. An open label, double tympanocentesis study of levofloxacin therapy in children with or at high risk for , recurrent or persistent otitis media. Pediatr Infect Dis J. 2006;25(12):1 102-1 109.
19. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005;41(Suppl 2):120-I26.
20. Gay K, Robicsek A, Strahilevitz J, et al. Plasmid-mediated quinolone resistance in non-Typhi serotypes of Salmonella enterica. Clin infect Dis. 2006;43(3):297-3O4.
21. Powis J, McGeer A, Green K, et al, and the Canadian Bacterial Surveillance Network. In vitro antimicrobial susceptibilities of Streptococcus pneumoniae clinical isolates obtained in Canada in 2002. Antimicrob Agents Chemother. 2004;48(9):3305-3311.
22. Karlowsky JA, Thomsberry C, Critchley IA, Jones ME, Evangelista AT, Noel GJ, et al. Susceptibilities to levofloxacin in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from children: results from 2000-2001 and 2001-2002 TRUST studies in the United States. Antimicrob Agents Chemother. 2003;47(6): 1790-1797.
23. Joshi S, Amamath SK. Fluoroquinolone resistance in Salmonella typhi and S. paratyphi A in Bangalore, India. Trans R Soc Trop Med Hyg. 2007;101(3):308-310.
24. Qin X, Razia Y, Johnson JR, et al. Ciprofloxacin-resistant gram-negative bacilli in the fecal microflora of children. Antimicrob Agents Chemother. 2O06;5O(10):3325-3329.
25. Meyerhoff A, Albrecht R, Meyer JM, Dionne P, Higgins K, Murphy D. U.S. Food and Drug Administration approval of ciprofloxacin hydrochloride for management of postexposure inhalational anthrax. Clin Infect Dis. 2004;39(3):303-308.
26. Koyle MA, Barqawi A, Wild J, Passamaneck M, Fumess PD. Pediatric urinary tract infections: the role of fluoroquinolones. Pediatr Infect Dis J. 2003;22( 1 2): 1 1 33- 1 1 37.
27. Mullen CA. Ciprofloxacin in treatment of fever and neutropenia in pediatric cancer patients. Pediatr Infect Dis J. 2003;22(12): 1 138-1 142.
Selected Quinolones: Current Uses*
Possible Indications for Pediatric Fluoroquinolone Use