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| Equipe de Pediatria - HMD |
| Quinolonas em pediatria: |
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| PEDIATRIC USE OF QUINOLONES Urs B. Schaad, M.D. University Children's Hospital, Basel, Switzerland THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 1999;18:469-470 Since the mid-1980s, there has been dramatic development of new derivatives of nalidixic acid, the fluoroquinolones, which now comprise an established class of antimicrobials. These antibiotics are rapidly bactericidal and have an extended antimicrobial spectrum, which includes Pseudomonas, Gram-positive cocci, and intracellular pathogens. They also have advantageous pharmacokinetic properties such as absorption from the gastrointestinal tract, excellent penetration into many tissues, and good intracellular diffusion. Use of fluoroquinolones in children has been limited because of their potential to induce arthropathy in juvenile animals.1 This extraordinary form of age-related drug toxicity has been demonstrated with all fluoroquinolones tested thus far. Their use thus has been considered contraindicated in children, in growing adolescents, and during pregnancy and lactation. Nevertheless, over 10,000 children have received treatment with fluoroquinolones, mainly ciprofloxacin, world-wide.2 Safety Clinical adverse effects associated with fluoroquinolone use occur in 5 to 15% of adult and pediatric patients and necessitate discontinuation of treatment in 1 to 2%.3 The most frequent reactions are gastrointestinal, followed by minor CNS disorders, and allergic skin rashes. More severe but rare adverse effects include seizures, nephrotoxicity and anaphylaxis. These adverse effects are reversible. A recent comprehensive review of published data on quinolone arthropathy concluded that there is no unequivocal quinolone-induced arthropathy in humans.4 The clinical events temporally related to quinolone use are reversible episodes of arthralgia, with and without effusions, that resolve without sequelae when treatment is discontinued. Pharmacokinetics and Dosages Knowledge of the pharmacokinetics of fluoroquinolones in pediatric patients is limited and is only anecdotal in newborns. Results of the available studies, most of which were conducted in patients with cystic fibrosis, indicate that systemic clearance is increased in young children.5,6 Although fluoroquinolones are rapidly absorbed from the gastrointestinal tract, bioavailability ranges from as low as 10 to 30% for norfloxacin to as high as 80 to 90% for ofloxacin. All of the newer compounds except norfloxacin have excellent tissue and intracellular penetration at the recommended therapeutic doses. Some quinolones are excreted predominantly in the urine, often as the parent compound. Others are excreted through the bile, and some of these undergo enterohepatic recirculation. Table 1 summarizes the current dosage recommendations. Based on data from animal models and clinical trials, the efficacy of fluoroquinolones correlates best with the 24-hour AUC/MIC ratio.7 This would be expected from the quinolones' properties of concentration-dependent killing and prolonged post-antibiotic effect, and suggests that large doses given at relatively infrequent intervals would be most efficacious. Studied Indications During the last 10 years, fluoroquinolones have been used in pediatric patients primarily in circumstances where they were the only antimicrobial choice for infections caused by multiply-resistant organisms. These included pseudomonal infections in children with cystic fibrosis,8 complicated urinary tract infections,9 enteric infections in developing countries10, and chronic ear infections.11 Results of controlled clinical trials have shown comparable efficacy of the fluoroquinolones and conventional regimens. Preliminary experience in pediatric patients also indicates that the fluoroquinolones are effective and safe for the prevention and/or therapy of infections in neutropenic cancer patients,12 and for the eradication of nasopharyngeal carriage of meningococci.2 Future Indications Ongoing research on chemical modifications of the quinolones is aimed at (1) more potent derivatives, (2) less frequent resistance, (3) better penetration into CSF and CNS, and (4) improved patient tolerability. Some of the newer compounds have achieved many of these goals. Of major interest for pediatricians are the effective CSF penetration and the excellent in vitro activity of the fluoroquinolones against the pathogens that commonly cause bacterial meningitis in children older than 3 months of age, including strains of S. pneumoniae resistant to betalactams and to other antibiotics. Based on efficacy data both in experimental animals and in clinical trials, trovafloxacin presently is regarded as the most promising fluoroquinolone candidate for treatment of childhood bacterial meningitis.4,13 The newer fluoroquinolones have increased activity against staphylococci, including methicillin-resistant strains, against streptococci, including multiple-drug resistant pneumococci, and against Mycoplasma and Chlamydia. Recommendations Based on available data demonstrating both the safety and efficacy of the fluoroquinolones, selected pediatric patients should not be deprived of the therapeutic advantages that these agents have to offer. However, the quinolones should never be used in pediatrics for routine treatment when alternative safe and effective antimicrobials are known. To date, potential pediatric indications for the fluoroquinolones include bronchopulmonary exacerbation in cystic fibrosis, complicated urinary tract infection, invasive gastrointestinal infection, and chronic ear infection. [Ed. Note: Fluoroquinolone use has been associated with tendonopathies. Foot and Ankle Intern 17:496-8, 1996.] References Christ W et al. Rev Infect Dis 1988;10:S141-6. Schaad UB et al. Pediatr Infect Dis J 1995;14:1-9. Norrby SR. Eur J Clin Microbiol Infect Dis 1991;10:378-83. Burkhardt JE et al. Clin Infect Dis 1997;25:1196-204. Peltola H et al. Antimicrob Agents Chemother 1992;36:1086-90. Schaefer HG et al. Antimicrob Agents Chemother 1996;40:29-34. Craig WA. Clin Infect Dis 1998;26:1-12. Richard DA et al. Pediatr Infect Dis J 1997;16:572-8. Fujii R. Adv Antimicrob Antineopl Chemother 1992;11:219-32. Green S et al. Pediatr Infect Dis J 1997;16:150-9. Lang R et al. Pediatr Infect Dis J 1992;11:925-9. Freifeld A et al. Pediatr Infect Dis J 1997;16:140-6. Paris MM et al. Antimicrob Agents Chemother 1995;39:1243-6. Pediatr Infect Dis J 1999 May;18(5):469-470 Copyright © 1999 Lippincott Williams & Wilkins All rights reserved |
| Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use-safety report BARBARA HAMPEL, MD; RAINER HULLMANN, MS; HEIKE SCHMIDT, AD From Bayer AG, Wuppertal, Germany. THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 1997;16:127-129 Background. Quinolone-induced cartilage toxicity has been observed in experimental juvenile animal studies and is species- and dose-specific. Accordingly these findings have led to the contraindication of fluoroquinolones in children. Previous data in 634 adolescents and children treated with compassionate use ciprofloxacin demonstrated low rates of reversible arthralgia and a safety profile similar to that for adult patients. Objective. This report describes the safety findings in 1795 children who received 2030 treatment courses of intravenous or oral ciprofloxacin. Results. The average doses of intravenous and oral ciprofloxacin in the study population were 8 and 25 mg/kg/day, respectively. Treatment-associated events were reported in 10.9% of children receiving oral ciprofloxacin compared with 18.9% among intravenous recipients. Overall arthralgia occurred during 31 ciprofloxacin treatment courses (1.5%) and the majority of events were of mild to moderate severity and resolved without intervention. More than 60% of arthralgia episodes were in children with cystic fibrosis. Conclusion. The adverse event pattern in children receiving ciprofloxacin in this analysis was similar to that observed in adults. Rates of reversible arthralgia were low and unchanged from previously published surveillance data in children. Key words: Ciprofloxacin; pediatrics; safety; arthropathy; arthralgia. INTRODUCTION Quinolone cartilage toxicity was initially observed in experimental investigations in juvenile animals. The first histopathologic findings of articular cartilage damage in immature dogs induced by nalidixic, oxolinic and pipemidic acids were reported by Ingham et al.1 in 1977. Specifically the cartilage showed characteristic lesions including blisters and erosions.2 Furthermore the role of mechanical pressure, determined by the fact that clinical arthropathy and blister formations appear only in weight-bearing joints, was confirmed by several investigators.3, 4 Since these first reports articular cartilage toxicity has been observed in juvenile animals with all fluoroquinolones tested. In addition arthrotoxic manifestations were found to be species- and dosage-dependent. For example cartilage damage have been observed with ciprofloxacin, but at larger dosages compared with nalidixic acid. The hips, knees and shoulder joints are mainly affected which signifies that clinical arthropathy occurs only in weight-bearing joints. Although the mechanism of arthrotoxicity is still unknown, this potential risk led to important restrictions in the use of quinolones. However, the experimentally induced cartilage damage has not been confirmed in human juvenile joints. Nalidixic acid has been used in children for more than two decades, often for prolonged periods. Follow-up studies have failed to detect any joint pathology.5 After the initiation of ciprofloxacin clinical trials in the early 1980s, ciprofloxacin has been administered to children despite restrictions. The first report from a child treated with ciprofloxacin was in May, 1983.6 Since that time ciprofloxacin has been continuously used in children and adolescents when conventional therapy failed or was not available. This report summarizes the safety data available from patients, in the international Bayer clinical data pool, who received ciprofloxacin on a compassionate use basis. PATIENTS AND METHODS Safety data were accrued from two sources involving pediatric patients. Ciprofloxacin tablets and/or intravenous solution were provided to physicians on request for use in pediatric patients who had failed conventional therapy or for whom no other therapeutic alternative was appropriate. Secondly safety reports were obtained from physicians who chose to use ciprofloxacin in pediatric patients outside of labeling. The first part of these data (634 cases) has been published by Chysky et al.7 Continuing collection of these compassionate use data has resulted in a total of 2030 treatment courses. Documentation of these cases included case report forms used for Phase IV trials as well as case report forms used for postapproval surveillance studies. Physicians, who requested ciprofloxacin on compassionate use basis, were asked to carefully document the safety of the drug with special emphasis on joint evaluation. They were also requested to provide the following information: patients' demographic data; the general status of health; infection diagnosis; causative organisms; accompanying diseases; concomitant medication; ciprofloxacin dosage regimen and route of administration; duration of therapy; and laboratory safety data including hematology, blood chemistry and urinalysis. Because these patients were not part of a study, information is occasionally incomplete. RESULTS Demographic data. By December 31, 1994, a total of 2030 treatment courses with ciprofloxacin in 1795 children and adolescents (up to 17 years) were completed. Of these 1767 received oral treatment, 159 iv treatment and 98 patients sequential iv/oral therapy. Eighty-two patients received more than 1 treatment course. One patient received 14 treatment courses. There was a slight female predominance (54%). The majority of the children treated with ciprofloxacin were between 13 and 17 years old: 1447 or 71.3%. There were 517 treated children (25.5%) between 5 and 12 years and 66 children were younger than 5 years old (3.3%). The respiratory tract was considered the infection site in >65% of the children (1316 cases), followed by skin and skin structure in 155 patients and urinary tract in 153 patients. All other infection sites were of minor importance. In cases with a specific diagnosis, cystic fibrosis followed by pneumonia and bronchitis were the most frequently reported respiratory tract pathologies. The severity of the infection clearly reflected the compassionate use of ciprofloxacin: 36.6% of the infections were considered to be severe; 49.2% were considered moderate; and the infection was mild in only 14.2%. A causative organism was documented in approximately one-third of the patients with respiratory tract infection. The most frequently documented organism from these patients was 358 (54%) isolates of Pseudomonas aeruginosa. In addition 111 (17%) Pseudomonas sp. were cultured. Clearly more than two-thirds of pathogens from the respiratory tract were Pseudomonas sp. This pathogen distribution clearly reflects the predominance of cystic fibrosis patients. The next most frequently isolated pathogen was Staphylococcus sp. which was documented in 93 (14%) cases in the respiratory tract. All other organisms were infrequently documented. DOSAGE AND LENGTH OF TREATMENT The largest group of orally treated patients (n = 649, 36.7%) received 21 to 40 mg/kg body weight per day; 150 patients received 41 to 50 mg/kg/day and 171 patients were treated with 15 to 20 mg/kg/day. The median oral daily dosage was 25 mg/kg. The duration of oral treatment ranged from 1 to 303 days. Thirteen patients received oral ciprofloxacin from 151 to 300 days, but most patients were treated for 15 to 30 days (n = 555, 32.9%). The most often administered iv dosage in mg/kg body weight was 6 to 10 mg/kg/day. The latter iv dosage was also documented for most of the patients receiving sequential iv/oral treatment. Duration of iv treatment ranged from 1 to 72 days. Five patients received iv treatment for 31 to 72 days. Safety. Adverse events (drug-related and non-drug-related), according to the Costart system, were reported in 192 (10.9%) of 1767 patients treated with ciprofloxacin (Fig. 1). The total number of individual adverse events was 270. After iv ciprofloxacin administration 47 adverse events occurred in 30 of 159 patients (18.9%; Fig. 1). The digestive system was the site of most adverse effects, including diarrhea, with nausea and vomiting. In addition headache and abdominal pain were frequently reported. Hypersensitivity, injection site reactions, musculoskeletal system adverse events, psychiatric disorders and thromboembolism were infrequently reported. Arthralgia. Arthralgia denotes the clinical entity of joint pain and may be associated with signs of inflammation. Arthralgia occurred in 31 of 2030 patients (1.5%). Nineteen patients had documented cystic fibrosis and 9 additional patients' underlying condition was cystic fibrosis. The intensity of the arthralgia was documented in 29 cases and was considered mild in 9 patients, moderate in 16 patients and severe in 4 patients. The total daily dose of oral ciprofloxacin in these patients was 200 to 1500 mg. The median duration of therapy was 23 days. Therapy was permanently discontinued in 9 patients, discontinued temporarily in 5 cases and was not discontinued in 14 patients. In one patient the dosage was reduced and another received remedial therapy. Arthralgia was reported to resolve in 25 patients, including the severely affected patients, 1 patient improved and 1 remained unchanged. In the remaining 4 patients, information regarding resolution is lacking. DISCUSSION The data from the international clinical data pool reflect the spectrum of ciprofloxacin compassionate use in children wherein it was administered most frequently to children with acute pulmonary exacerbation caused by cystic fibrosis. Ciprofloxacin was found to be advantageous when compared with conventional intravenous therapy because of its availability in an oral formulation and its excellent activity against pseudomonal organisms. Of most importance this report emphasized the safety of ciprofloxacin in pediatric patients and confirms the results reported previously in 634 cases.7 Except for arthralgia the adverse event pattern in children was similar compared to that observed in adults.8 The incidence of reversible arthralgia has remained unchanged from a previous report with 1.3%7 and 1.5% from the current report. Arthralgia occurred in 31 patients in this report, including 28 cases among cystic fibrosis patients. Arthropathy has been estimated to occur in 4 to 7% of the cystic fibrosis population.9 Therefore definite diagnosis of quinolone-associated arthropathy in this patient population is often difficult. In a recent literature review of ciprofloxacin use in pediatric patients, there were 36 cases of arthralgia among 1113 children (3.2%) from 12 studies.10 The great majority of patients with joint symptoms were adolescents with cystic fibrosis, which concurs with the current report. In 3 of the 12 studies, where magnetic resonance imaging or plane radiographs were obtained, no cartilage damage was observed. The compassionate data presented herein, as well as data from published trials, indicate that acute courses of ciprofloxacin therapy appear to be safe in children. The incidence of arthropathy is consistent among all available reports, and to date no cases of cartilage damage have been reported. Continued surveillance of ciprofloxacin safety in children will be necessary to confirm these findings, especially if ciprofloxacin is prescribed more widely in the pediatric population. REFERENCES [Click here for reference links. (5 references linked.)] Ingham B, Brentnall DW, Dale EA, McFadzean JA. Arthropathy induced by antibacterial fused N-alkyl-4-pyridone 3-carboxylic acids. Toxicol Lett 1977;1:21-6. Gough A, Barsoum NY, Mitchell L, McGuire EJ, De La Iglesia FA. Juvenile canine drug-induced arthropathy: clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids. Toxicol Appl Pharmacol 1979;51:177-87. Simon C. Im Tierexperiment beobachtete Knorpelsch, digung duch Chinolone. Fortschr Antimikrob Antineoplast Chemother 1984;3:785-8. Stahlmann R, Merker HJ, Hinz N, Chahoud J, Heger W, Neubert D. Ofloxacin in juvenile non-human primates and rats: arthropathia and drug plasma concentrations. Arch Toxicol 1990;64:193-204. Schaad UB, Wedgwood-Krucho J. Nalidixic acid in children: retrospective matched controlled study for cartilage toxicity. Infection 1987;15:165-8. Data on file. Bayer AG, Wuppertal, Germany. Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echols R. Quinolones in clinical use: safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use-emphasis on joint evaluation. Infection 1991;19:289-96. Schacht P, Arcieri G, Branolte J, et al. Worldwide clinical data on efficacy and safety of ciprofloxacin. Infection 1988;16(Suppl. 1):29-43. Phillips BM, David TJ. Pathogenesis and management of arthropathy in cystic fibrosis. J R Soc Med 1986;79(Suppl. 12):44-50. Kubin R. Safety and efficacy of ciprofloxacin in paediatric patients: review. Infection 1993;21:413-21. Address for reprints: Dr. Barbara Hampel, Medical Department Germany, D-51368 Leverkusen, Germany. Fax 49-214-3051469. Proceedings of a symposium; July 28 to 29, 1995; Nantucket, MA Pediatr Infect Dis J 1997 January;16(1):127-129 Copyright © 1997 Lippincott Williams & Wilkins All rights reserved |
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