The Fluoroquinolone Toxicity Research Foundation

 
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Fluoroquinolones in Complicated Pediatric Urinary Tract Infections: A Review of the Literature
Raffaella Mormile, MD, Laura Cuzzolin, MD, Vassilios Fanos, MD
Infect Urol 15(3):3-8, 2002. © 2002 Cliggott Publishing, Division of SCP Communications
Posted 09/10/2002
Abstract and Introduction
Abstract
As pressure to use fluoroquinolones for infections in pediatric patients increases, physicians look to current data to assess their options. Because of the restricted use of these agents, little has been published, particularly in the urologic area. We review the information available on the use of fluoroquinolones for urinary tract infections in children and look at their potential for management of complicated infections.
Introduction
To date, use of fluoroquinolones in children has been restricted, on a compassionate basis, to the management of pulmonary infections in patients with cystic fibrosis and in patients with epidemic shigellosis and salmonellosis in developing countries. Although prolonged therapy has been well tolerated and there is no significant evidence of chondrotoxicity in children,[1] cautious use has been suggested because of arthropathy seen in young animals[2] and fear that resistant bacterial strains would emerge if the agents were used routinely for common infections.[3]
The International Society of Chemotherapy[4] suggests that fluoroquinolones may be used in pediatric patients in the following conditions when alternative safe and effective therapy is not available:
 Bronchopulmonary exacerbations of cystic fibrosis caused by Pseudomonas aeruginosa.
 Urinary tract infections (UTIs).
 Chronic suppurative otitis media.
 Epidemic shigellosis or invasive salmonellosis.
 Osteomyelitis.
 Prophylaxis in neutropenia and meningococcal infections.
 Drug-resistant mycobacterial disease (in combination regimens).
Here we review how fluoroquinolones have been used in pediatric patients with UTIs and also report our experience with ciprofloxacin administration in 3 children with recurrent, multidrug-resistant, and complicated infections caused by P aeruginosa.
Fluoroquinolone Safety in the Pediatric Population
The restriction of fluoroquinolone use in children has limited the safety data in this population. The most frequent adverse effects in pediatric patients involve the GI tract and skin, but arthralgia and arthropathy are the main concerns.[5,6]
All fluoroquinolones tested cause arthropathic effects in immature animals in a dose-dependent manner and at varying rates in different species.[7] To date, however, the experimentally induced cartilage damage has not been confirmed in human juvenile joints. More than 31 reports from various multipatient studies have described the use of nalidixic acid, ciprofloxacin, norfloxacin, or ofloxacin in more than 7000 skeletally immature patients without negative effects on linear growth.[1] Exceptions are children who have cystic fibrosis, but in these patients it is difficult to distinguish arthralgias that are a consequence of drug treatment from those that are the result of the natural history of the disease.
Nalidixic acid has been used in children for more than 2 decades, often for prolonged periods, but follow-up studies have failed to detect any joint pathology.[8] In a randomized double-blind clinical trial in which norfloxacin was compared with nalidixic acid for the management of shigellosis in 59 children,[9] no joint problem was encountered at up to 4 months' follow-up.
Since clinical trials of ciprofloxacin began in the early 1980s, this antibiotic has been administered to children, despite restrictions. A review of 202 patients (younger than 1 year to 17 years) from the United Kingdom revealed arthralgias in only 5 patients, but 4 of these children had cystic fibrosis.[10] Hampel and colleagues,[11] confirming results from a previous study of 634 patients,[12] summarized the safety data available on 1795 children; they reported that reversible arthralgia occurred in 31 children, including 28 with cystic fibrosis.
A rigorous surveillance study of 13 prepubertal patients who received oral ciprofloxacin (30 mg/kg/d divided in 2 doses) for 3 months was performed.[13] At the end of therapy and at follow-up (4 to 6 months later), the study revealed no evidence of arthrogenic effects or effects on growth in any of the patients.
Other investigators conducted a retrospective cohort study to estimate the risk of musculoskeletal disorders associated with exposure to ciprofloxacin in more than 1700 pediatric patients.[14] They did not find any diagnosis of acute arthritis or joint toxicity that was associated with the drug.
To assess the potential for fluoroquinolones to produce fetal toxicity, Loebstein and coworkers[15] evaluated fetal outcomes of 200 pregnancies in women who received fluoroquinolones. They concluded that the use of these antibiotics during embryogenesis was not associated with an increased risk of major malformations or musculoskeletal dysfunction. The investigators indicated that in cases of infection with resistant micropathogens or for complicated UTIs during pregnancy, the benefits of fluoroquinolones to the mother outweighed the risks to the fetus.
Rationale for Use of Fluoroquinolones in Pediatric UTIs
UTIs during childhood are significant, because these infections may lead to renal parenchymal damage and chronic renal insufficiency.[16] Treatment of pediatric patients with UTIs (whether cystitis or pyelonephritis) calls for rapid administration of antibiotics, assessment of anatomic abnormalities, and prevention of recurrent infections. Prompt empiric therapy is mandated while antibiotic susceptibilities are investigated, because clinical studies have shown that larger cortical defects are associated with delays in instituting treatment.[17] For most patients, initial treatment consists of oral antimicrobials, reserving intravenous antibiotics for children who have high fever plus nausea and vomiting.
After the acute infection resolves, antimicrobial prophylaxis is important for children with proven anatomic abnormalities, such as vesicoureteral reflux and urinary tract obstruction.[18,19] The ideal antimicrobial agent should be inexpensive and should maintain low serum concentrations and high urinary levels.[18] Development of bacterial resistance (those children with a history of multiple infections and treatment courses are particularly at risk) and allergies may limit therapeutic options and make it necessary to consider other drug classes.
Because of their antibacterial spectrum and pharmacokinetic properties, fluoroquinolones may be considered potential candidates for use in pediatric UTIs, particularly in children infected with multidrug-resistant organisms or children with allergies or decreased renal function precluding the choice of aminoglycosides. More than 90% of all UTI pathogens are gram-negative organisms (mainly Enterobacteriaceae, but also P aeruginosa). Fluoroquinolones have excellent activity against these microorganisms,[20,21] with ciprofloxacin the most active compound in vitro.[22] UTIs caused by Pseudomonas species and Staphylococcus species, against which the -lactams and third-generation cephalosporins are ineffective, constitute an excellent indication for the use of fluoroquinolones.[23] In particular, ciprofloxacin is twice as active against P aeruginosa as trovafloxacin and levofloxacin and 4 times as active as ofloxacin.[24] In addition, in complicated infections, when bacteria are often multidrug-resistant,[20] combining quinolones with rifampin, ceftazidime, or cefotaxime may have a synergistic effect against Staphylococcus species, Pseudomonas species, and Escherichia coli, respectively.[22]
The excellent bioavailability of oral fluoroquinolones makes them particularly useful in children, because it allows normal activity and may prevent hospitalization.[20] The newer quinolones with a 7-N-methyl-piperazine ring, as well as many of the naphthyridone derivatives, have long half-lives with once- or twice-daily administration, a high volume of distribution, and good penetration into inflamed or purulent sites. These antibiotics diffuse well into cysts and may achieve adequate concentrations in obstructed urinary tracts.[25] With the exception of trovafloxacin, which is excreted primarily through bile,[26] ciprofloxacin, norfloxacin, ofloxacin,[27] and gatifloxacin are excreted mainly in the urine, making them excellent agents to manage UTIs.
Finally, their different mode of action, primarily through inhibition of bacteria-specific DNA gyrase and topoisomerases IV, makes fluoroquinolones an effective alternative therapy when resistance to -lactam agents is encountered. Several researchers have shown that to give rise to a fluoroquinolone-resistant bacterium, multiple mutations in several genes are required.[28] Resistance to fluoroquinolones, however, is being seen more frequently and corresponds to their increasing use.[29]
In some patients, hospital-acquired UTIs with renal involvement are caused by P aeruginosa that is resistant to ciprofloxacin. The newer fluoroquinolones, which are more active against gram-positive pathogens, remain as equally potent as ciprofloxacin against gram-negative pathogens. They are also ineffective against most ciprofloxacin-resistant aerobic gram-negative rods, so their introduction has not altered the potential choices for the management of UTIs in these patients.[24]
A Review of Clinical Studies of Pediatric UTI Treatment
Because clinical experience with fluoroquinolones for the treatment of pediatric patients with UTIs is limited, only a few retrospective studies have been published, as shown in the Table. In one Japanese study, the reported efficacy was 98% in 108 pediatric patients who had documented UTI and were treated with oral norfloxacin (6 to 16 mg/kg/d divided in 3 doses)30; however, no details regarding the bacteriology were provided. In a study from the Netherlands,[31] 40 patients, aged 5 months to 19 years, with UTIs caused by multidrug-resistant pathogens (22 with complicated UTIs) were treated with norfloxacin (9 to 14 mg/kg/d divided in 2 doses) followed by prophylaxis (2.6 mg/kg once daily). All patients had a successful outcome, despite the fact that during the prophylaxis period a superinfection caused by Enterococcus species developed in 18% and 1 child experienced urosepsis caused by Pseudomonas species.
In a review of the literature on the use of ciprofloxacin in 28 preterm neonates, ciprofloxacin alone eradicated organisms from various sites of infection, including urine, in 16 low-birth-weight neonates with multidrug-resistant infection.[32] Other investigators conducted a preliminary study of the therapeutic efficacy of ciprofloxacin in 8 children (aged 8 to 14 years) with UTIs that were resistant to classic antibiotics; because of the outcomes, the authors recommended the monitored use of ciprofloxacin in children with multidrug-resistant UTIs.[33]
Alghasham and Nahata,[34] in their review of fluoroquinolone use in children, included their successful use of ciprofloxacin at Children's Hospital in Columbus, Ohio, in the management of UTIs caused by P aeruginosa, transitioning from intravenous to oral therapy and for prophylaxis.
We recently reported on 3 children (aged 15 months to 4 years) who had recurrent, multidrug-resistant infections caused by P aeruginosa.[35] The children had severe, bilateral hydroureteronephrosis; 1 child also had bladder diverticula in association with Menkes syndrome. After treatment with oral ciprofloxacin (25 mg/kg/d for 5 days), the microorganisms were eradicated in all patients without adverse effects.
Conclusions
Until now, fluoroquinolones have been used in children essentially on a compassionate basis, mainly for the treatment of pulmonary infections in cystic fibrosis as well as in salmonellosis and shigellosis. For these reasons, a number of unresolved issues remain about their use in renal infections. Well-defined studies are urgently needed, particularly in patients who have complicated infections, to define the optimal regimens.
Initiation of quinolone therapy in the pediatric population should be done cautiously with full knowledge of the advantages and potential side effects. In fact, some of these side effects in children, such as nephrotoxicity,[36] not described until recently, may only be seen with wider use of these antibiotics in the pediatric population.[37] Parents of children who are receiving quinolones should be made aware of the possible development of arthralgias, so that evaluation of the children can be carried out immediately.
If used judiciously, the new fluoroquinolones, because of their antibacterial spectrum and pharmacokinetic properties, may be considered not only for compassionate use but also for potential administration in children with complicated UTIs. Their use as alternative therapy may help prevent the development of bacterial resistance to standard antimicrobial therapy.
Editorial Comment: Studying the Safety of Fluoroquinolones in Children
Despite class label warnings against the use of fluoroquinolones in children, physicians are increasingly using these antibiotics to manage pediatric infections. Currently, health care providers prescribe almost 14,000 courses of fluoroquinolone antibiotics per year for children younger than 10 years, another 28,000 courses for children between 10 and 14 years, and more than 140,000 courses for children 15 to 17 years.[1] For certain pediatric populations, the broad-spectrum activity of fluoroquinolone antibiotics is especially appealing. These patient populations include:
 Children with cystic fibrosis who are prone to respiratory infections caused by Pseudomonas aeruginosa.
 Children who are immunocompromised from chemotherapy regimens to manage malignancy or to prevent allograft rejection after transplantation.
 Children with complex genitourinary anomalies who are prone to complicated urinary tract infections.
 Children with Salmonella infections.
 Children with severe bacterial infections that fail to respond to initial antibiotic therapy.[2]
Because fluoroquinolones are so effective for the management of P aeruginosa infections, they have also been used on a compassionate basis even when these infections do not occur in a susceptible patient population.
The class label warnings against fluoroquinolone use in children stem from drug studies in juvenile animals in which there was documented joint toxicity, especially to the cartilage of growth plates. This led to labeling precautions against their use in children, except on a compassionate basis.
During the last 15 years, the cumulative number of children treated on a compassionate basis with this class of antibiotics has grown, as has the experience with the adverse effects associated with fluoroquinolones in the pediatric population. Nalidixic acid was the first quinolone agent developed for antibiotic use. Joint toxicity was noted in animal studies with this agent in the 1970s. Since then, all the fluoroquinolone agents, including ciprofloxacin and levofloxacin, have demonstrated joint toxicity in animal studies. Nalidixic acid, however, has been used for decades in children despite its recognized side effects.[3] As a result, nalidixic acid provided the first insight into the adverse-event profile and particularly the effects of this quinolone on pediatric joints. These initial clinical data suggested that there might be significant interspecies differences regarding the incidence and severity of toxicity associated with the use of quinolones.
Because of perceived need and because a growing number of children were receiving fluoroquinolone antibiotics, in 1989 the FDA gave permission to study the use of ciprofloxacin in 2 subpopulations who had demonstrated special need for this class of antibiotics: patients with cystic fibrosis and patients with neutropenia undergoing chemotherapy for malignancy. In Europe, similar efforts were under way. Clinical trials took place in the early 1990s and provided preliminary data on the safety and efficacy of fluoroquinolone antibiotics in children.[3]
For children who have taken ciprofloxacin worldwide, Bayer AG requested safety data from the health care providers who used this medication on a compassionate basis. Chysky and associates[4] first reported on this worldwide experience with 634 patients in 1991.
Subsequently, Hampel and colleagues[5] reported clinical data from 1795 children who had taken a total of 2030 treatment courses of ciprofloxacin. More recent data from the Bayer global drug safety database include reports from more than 4.5 million children younger than 18 years.[1] Adverse events compare similarly with those of the adult population. Data from clinical research trials using ciprofloxacin for children also show a remarkably similar side-effect profile for the study group and the control group.[6,7] These studies include trials evaluating the use of ciprofloxacin for diarrheal diseases, for bronchopulmonary infections associated with cystic fibrosis, for bacterial infections in neutropenic patients, for pneumonia, and for children who are asymptomatic carriers of meningococcus.
So, despite concerns about the possible effect of quinolone antibiotics on the developing musculoskeletal system of children, this class of antibiotics has been used to manage infections in this age group. Clinical observations surrounding their use suggest that quinolone antibiotics might be safer in children than in animals. Subsequent clinical research trials incorporating clinical and radiographic outcomes have supported these initial observations so far. In well-defined pediatric populations, fluoroquinolone antibiotics may have a safe and useful role to play.
Richard W. Grady, MD
Assistant Professor of Urology
University of Washington School of Medicine
Pediatric Urologist
The University of Washington Medical Center
Children's Hospital and Regional Medical Center
Seattle
References
1. Grady R. Are quinolones safe for children? Paper presented at: Ciprofloxacin Summer Symposium; 2001; San Diego.
2. Redmond AO. Risk-benefit experience of ciprofloxacin use in pediatric patients in the United Kingdom. Pediatr Infect Dis J. 1997;16:147-149.
3. Echols RM. Historical perspective -- use of ciprofloxacin in children. Pediatr Infect Dis J. 1997;16:89-90.
4. Chysky V, Kapila K, Hullmann R, et al. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use: emphasis on joint evaluation. Infection. 1991;19:289-296.
5. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use: safety report. Pediatr Infect Dis J. 1997;16:127-129.
6. Salam MA, Dhar U, Khan WA, Bennish ML. Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis. Lancet. 1998;352:522-527.
7. Leibovitz E, Janco J, Piglansky L, et al. Oral ciprofloxacin vs intramuscular ceftriaxone as empiric treatment of acute invasive diarrhea in children. Pediatr Infect Dis J. 2000;19:1060-1067.
Tables

Table. Clinical Studies of Fluoroquinolone Use in Pediatric Urinary Tract Infections

Reference Drug Dosage
(mg/kg/d) Number of patients
Fujii[30] Norfloxacin 6 - 16 108
van Wijk[31] Norfloxacin 9 - 14 40
van den Oever[32] Ciprofloxacin 4 - 40 28
Naccari[33] Ciprofloxacin Not indicated 8
Mormile[35] Ciprofloxacin 25 3
References
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3. Jafri HS, McCracken GH Jr. Fluoroquinolones in paediatrics. Drugs. 1999;58(suppl 2):43-48.
4. Schaad UB, abdus Salam M, Aujard Y, et al. Use of fluoroquinolones in pediatrics: consensus report of an International Society of Chemotherapy commission. Pediatr Infect Dis J. 1995;14:1-9.
5. Nelson JD, McCracken GH. Fluoroquinolones in pediatrics. Pediatr Infect Dis J. 1998;17:A1.
6. Lietman PS. Fluoroquinolone toxicities: an update. Drugs. 1995;49(suppl 2):159-163.
7. Schaad UB. Toxicity of quinolones in pediatric patients. Adv Antimicrob Antineopl Chemother. 1992;11:S259-S265.
8. Schaad UB, Wedgwood-Krucko J. Nalidixic acid in children: retrospective matched controlled study for cartilage toxicity. Infection. 1987;15:165-168.
9. Bhattacharya K, Bhattacharya MK, Dutta D, et al. Double-blind, randomized clinical trial for safety and efficacy of norfloxacin for shigellosis in children. Acta Paediatr. 1997;86:319-320.
10. Black A, Redmond AO, Steen HJ, Oborska IT. Tolerance and safety of ciprofloxacin in paediatric patients. J Antimicrob Chemother. 1990;26(suppl F):25-29.
11. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use: safety report. Pediatr Infect Dis J. 1997;16:127-129.
12. Chysky V, Kapila K, Hullmann R, et al. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use: emphasis on joint evaluation. Infection. 1991;19:289-296.
13. Schaad UB, Stoupis C, Wedgwood J, et al. Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. Pediatr Infect Dis J. 1991;10:723-729.
14. Jick S. Ciprofloxacin safety in a pediatric population. Pediatr Infect Dis J. 1997;16:130-134, 160-162.
15. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42:1336-1339.
16. Winberg J, Andersen HJ, Bergstrom T, et al. Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand Suppl. 1974;252:1-20.
17. Jakobsson B, Berg U, Svensson L. Renal scarring after acute pyelonephritis. Arch Dis Child. 1994;70:111-115.
18. Mangiarotti P, Pizzini C, Fanos V. Antibiotic prophylaxis in children with relapsing urinary tract infections: review. J Chemother. 2000;12:115-123.
19. Fanos V, Agostiniani R, Cataldi L. Pyelectasis and hydronephrosis in the newborn and infant. Acta Paediatr. 2000;89:900-904.
20. Dagan R. Fluoroquinolones in paediatrics -- 1995. Drugs. 1995;49(suppl 2):92-99.
21. Fanos V, Khoory BJ. Antimicrobial survey of urinary tract isolates from a pediatric department. J Chemother. 1999;11:255-259.
22. Brun P. Utilization des quinolones dans le traitment des infectiones urinaires de l'enfant. In: Quinolones en Pediatrie. Paris: Flammarion Medicine Sciences; 1992:99-104.
23. Naber KG. Fluoroquinolones in urinary tract infections: proper and improper use. Drugs. 1996;52(suppl 2):27-33.
24. Hoogkamp-Korstanje JA. In vitro activities of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against gram-positive and gram-negative pathogens from respiratory tract infections. J Antimicrob Chemother. 1997;40:427-431.
25. Ronald A. The quinolones and renal infection. Drugs. 1999; 58(suppl 2):96-98.
26. Friedland IR, Lutsar I. New antibiotics. Curr Opin Pediatr. 1998;10:41-45.
27. Hendershot EF. Fluoroquinolones. Infect Dis Clin North Am. 1995;9:715-730.
28. Everett MJ, Jin YF, Ricci V, Piddock LJ. Contributions of individual mechanisms to fluoroquinolone resistance in 36 Escherichia coli strains isolated from humans and animals. Antimicrob Agents Chemother. 1996;40:2380-2386.
29. Smith A, Pennefather PM, Kaye SB, Hart CA. Fluoroquinolones: place in ocular therapy. Drugs. 2001;61:747-761.
30. Fujii R. The use of norfloxacin in children in Japan. Adv Antimicrob Antineopl Chemother. 1992;11(suppl 2):S219-S230.
31. van Wijk JA, de Jong TP, van Gool JD. Using quinolones in urinary tract infections in children. Adv Antimicrob Antineopl Chemother. 1992;11(suppl 2):S157-S161.
32. van den Oever HL, Versteegh FG, Thewessen EA, et al. Ciprofloxacin in preterm neonates: case report and review of the literature. Eur J Pediatr. 1998;157:843-845.
33. Naccari F, Salpietro DC, De Sarro A, et al. Tolerance and pharmacokinetics of ciprofloxacin in the chick: preliminary experience in subjects of pediatric age with urinary tract infections (UTI). Res Commun Mol Pathol Pharmacol. 1998;99:187-192.
34. Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. Ann Pharmacother. 2000;34:347-359.
35. Mormile R. Utilizzo dei fluorchinoloni nelle infezioni delle vie urinarie complicate del bambino: uno scenario che cambia. Descrizione di 3 casi clinici e revisione della letteratura. Proceedings "Incontri Pediatrici Normanni." C.H.S. eds. Aversa. 2000:236-243.
36. Fanos V, Cataldi L. Antibacterial-induced nephrotoxicity in the newborn. Drug Saf. 1999;20:245-267.
37. Fanos V, Cuzzolin L. Fluoroquinolones in pediatrics and their nephrotoxicity in adults: minireview. J Chemother. 2000;12:228-231.


Dr. Mormile is a physician, Dr. Fanos is a senior physician in the pediatric department, and Dr. Cuzzolin is a researcher in the department of medicine and public health, section of pharmacology, at the University of Verona in Italy.