Use Of Fluoroquinolones In Children Research Articles

Novel Bacterial Topoisomerase Inhibitor Gepotidacin Demonstrates Absence of Fluoroquinolone-Like Arthropathy in Juvenile Rats.

Fluoroquinolone use in children is limited due to its potential toxicity and negative effects on skeletal development, but the actual effects/risks of fluoroquinolones on bone growth and the mechanisms behind fluoroquinolone-driven arthropathy remain unknown. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic with a unique mechanism of action that is not anticipated to have the same risks to bone growth as those of fluoroquinolones. Gepotidacin is in phase III clinical development for uncomplicated urinary tract infections (ClinicalTrials.gov identifiers NCT04020341 and NCT04187144) and urogenital gonorrhea (ClinicalTrials.gov identifier NCT04010539) in adults and adolescents ≥12 years of age. To inform arthropathy and other potential toxicity risks of gepotidacin in pediatric studies, this nonclinical study assessed oral gepotidacin toxicity in juvenile rats from postnatal day (PND) 4 to PND 32/35 (approximately equivalent to human ages from newborn to 11 years), using both in-life assessments (tolerability, toxicity, and toxicokinetics) and terminal assessments (necropsy with macroscopic and microscopic skeletal femoral head and/or stifle joint examinations). Gepotidacin doses of ≤300 mg/kg of body weight/day were well tolerated from PND 4 to PND 21, and higher doses of ≤1,250 mg/kg/day were well tolerated from PND 22 when the dose levels were escalated to maintain systemic exposure levels up to PND 35, with no observed treatment-related clinical signs, effects on mean body weight gain, or macroscopic findings on articular surfaces. A dose of 1,000 mg/kg/day was not tolerated during the dosing period from PND 4 to 21, with effects on body weight gain, fecal consistency, and body condition. Microscopic effects on articular surfaces were evaluated after 32 days of gepotidacin treatment at the highest tolerated dose. After 32 days of treatment with the highest tolerated gepotidacin dose of 300/1,250 mg/kg/day (systemic concentrations [area under the curve {AUC} values] of 93.7 μg · h/mL [males] and 121 μg · h/mL [females]), no skeletal effects on articular surfaces of the femoral head or stifle joint were observed. The absence of treatment-related clinical signs and arthropathy in juvenile rats provides evidence to support the potential future use of gepotidacin in children.

Outpatient Fluoroquinolone Use in Children, 2000-2018.

While fluoroquinolones are commonly used in adults, the use in children has been low. Since 2000, there were 3 US Food and Drug Administration (FDA) Boxed warnings regarding fluoroquinolones (2008, 2013, and 2016). Our objective was to describe the use of fluoroquinolones in children and assess the impact of 3 recent FDA warnings on fluoroquinolone use. From 2000 to 2018, we assessed claims for all outpatient prescription fills to measure the use of systemic fluoroquinolones and other broad-spectrum antibiotics in children less than 18 years old in the MarketScan Commercial Claims and Encounters database. We describe demographics, indication for antibiotic, and clinical characteristics. To assess the impact of FDA warnings on fill rates, we conducted an interrupted time-series analysis. The cohort included 34.6 million unique beneficiaries less than 18 years old with 441 062 fluoroquinolone fills (5.5 fills per 1000 person-years). The fluoroquinolone fill rate was highest among children > 11 years old. Urinary tract infection was the most common associated diagnosis (21.8%). Since 2008, the fluoroquinolone fill rate has declined. By the end of the study period in December 2018, in the (counterfactual) absence of the FDA warnings, fluoroquinolone fill rate would have been 7.5 (95% confidence interval [CI]: 5.2-9.7); however, the corresponding rate in observed data was 2.8 (95% CI: 1.7-3.9). Fluoroquinolone use was low compared with other common broad-spectrum antibiotics and declining trends over time were associated with FDA warnings, even though these warnings were not pediatric specific. Future work should assess the adverse events at issue in these warnings in children.

Assessment of the risk of musculoskeletal adverse events associated with fluoroquinolone use in children: A meta-analysis.

The use of fluoroquinolone antibiotics has been restricted in children because of their potential to cause adverse musculoskeletal events. This study was performed to systematically evaluate whether there is a difference between fluoroquinolone and non-fluoroquinolone antibiotics in terms of their associated risk of adverse musculoskeletal events in children. Cochrane Library, Embase, and PubMed databases were used to retrieve studies related to fluoroquinolone and non-fluoroquinolone-induced musculoskeletal adverse events in children. A meta-analysis was performed using Stata 11. A total of 10 studies were included in the analysis. The combined results showed that there was no statistical difference between fluoroquinolone and non-fluoroquinolone groups in terms of musculoskeletal adverse events in children (risk ratio = 1.145, 95% confidence interval = 0.974 - 1.345, P = .101). Subgroup analysis was performed using a random-effects model. Here, the effects on the trovafloxacin and levofloxacin groups were significantly different from that of the control group. However, musculoskeletal adverse events due to either drug was not reported after long-term follow-up. The results showed that fluoroquinolone and non-fluoroquinolone antibiotics were not different in terms of their ability to cause musculoskeletal adverse events in children. For this reason, fluoroquinolone antibiotics can be used in children as appropriate. CRD42019133900.

Oral Fluoroquinolone Prescribing to Children in the United States From 2006 to 2015.

Fluoroquinolone (FQ) prescription rates have increased over the last 10 years despite recent warnings of serious adverse effects such as peripheral neuropathy and tendinopathy. Currently, there are no published data on the extent or appropriateness of FQ prescribing in children. Drug prescription data from the PharMetrics Plus health claims database (United States) were analyzed to examine dispensing of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, or gemifloxacin to children from 2006 to 2015. Based on American Academy of Pediatrics recommendations, an algorithm was created to quantify inappropriate FQ prescriptions, which was further stratified by age and FQ type. Among a cohort of 2,754,431 children, 372,357 prescriptions for an oral FQ were dispensed between 2006 and 2015. An increase was observed in FQ prescriptions from 2006 to 2013, with numbers coming down in 2014 and 2015. Ciprofloxacin was the most frequently prescribed FQ (334,268 prescriptions) followed by levofloxacin (19,386), moxifloxacin (18,434) and combined ofloxacin/gemifloxacin prescriptions (369). Of the FQ prescriptions in children, 48% were prescribed to those 10 years of age or younger, and 22% were deemed inappropriate. Our study suggests an increase in the prescribing of FQs, mostly ciprofloxacin, over a 10-year period, although numbers have decreased slightly in 2014 and 2015. At least 1 in 5 prescriptions were deemed unnecessary. In light of recent FQ safety warnings and lack of long-term safety data with FQ use in children and potential risk of increasing antibiotic resistance, clinicians are advised to refrain from using FQs for uncomplicated community-acquired infections.

Pediatric fluoroquinolone prescription in South Korea before and after a regulatory intervention: A nationwide study, 2007-2015

ObjectiveTo investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents.MethodsData collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred.ResultsA total of 505,859 children received systemic fluoroquinolone during the study period—297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs.ConclusionThe dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Safety Concerns Surrounding Quinolone Use in Children

Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long-term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics, resulting in the development of drug-resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing.

Fluoroquinolones in children: update of the literature

The use of fluoroquinolones (FQ), antibiotics, which have excellent pharmacokinetic and pharmacodynamic characteristics and a broad spectrum of action, has increased dramatically in recent years, both in adults and children. Numerous safety and efficacy data are now available on FQ use in children, particularly regarding the treatment of complicated infections of the urinary tract, typhoid fever, pneumonia, acute external otitis, acute media otitis, meningoencephalitis, sepsis in neutropenic children and multidrug-resistant tuberculosis (MDR-TB), though sometimes studies have the limitations that they were conducted in selected populations, such as children with cystic fibrosis. Despite available safety data are encouraging, there is still an open debate on the toxicity of this class of antibiotics on weight-bearing joints in children. Not being able to exclude the possibility that, in rare cases, this event is likely to occur, their use in children should be limited to cases where the cost-benefit has been carefully examined, for example, in the case of sepsis or other severe infections from multi-resistant bacteria and not responsive to other classes of drugs. Furthermore, considering the increased use of FQ in children, it is possible that there is an increase in the incidence of infections from resistant germs (such as Escherichia coli, and pneumococci), as occurred in adults. In order to limit the diffusion of resistance, a judicious and appropriate use of this class of drugs is recommended.

Acute Bacterial Sinusitis in Children

On the basis of strong research evidence, the pathogenesis of sinusitis involves 3 key factors: sinusostia obstruction, ciliary dysfunction, and thickening of sinus secretions. On the basis of studies of the microbiology of otitis media, H influenzae is playing an increasingly important role in the etiology of sinusitis, exceeding that of S pneumoniae in some areas, and b-lactamase production by H influenzae is increasing in respiratory isolates in the United States. On the basis of some research evidence and consensus,the presentation of acute bacterial sinusitis conforms to 1 of 3 predicable patterns; persistent, severe, and worsening symptoms. On the basis of some research evidence and consensus,the diagnosis of sinusitis should be made by applying strict clinical criteria. This approach will select children with upper respiratory infection symptoms who are most likely to benefit from an antibiotic. On the basis of some research evidence and consensus,imaging is not indicated routinely in the diagnosis of sinusitis. Computed tomography or magnetic resonance imaging provides useful information when complications of sinusitis are suspected. On the basis of some research evidence and consensus,amoxicillin-clavulanate should be considered asa first-line agent for the treatment of sinusitis.

Systemic use of fluoroquinolone in children

Fluoroquinolones are an important class of antibiotics that are widely used in adult patients because of their broad spectrum of activity, good tissue penetration, and oral bioavailability. However, fluoroquinolone use in children is limited because juvenile animals developed arthropathy in previous experiments on fluoroquinolone use. Indications for fluoroquinolone use in patients younger than 18 years, as stated by the U.S. Food and Drug Administration, include treatment of complicated urinary tract infections and postexposure treatment for inhalation anthrax. In Korea, the systemic use of fluoroquinolones has not been approved in children younger than 18 years. Although concerns remain regarding the adverse musculoskeletal effects of fluoroquinolones in children, their use in the pediatric population has increased in many circumstances. While pediatricians should be aware of the indications and adverse effects of fluoroquinolones, recent studies have shown that the risk for musculoskeletal complications in children did not significantly increase following fluoroquinolone treatment. In addition, fluoroquinolones may be particularly helpful in treating multidrug-resistant infections that have not responded to standard antibiotic therapy in immunocompromised patients. In the present article, we provide an updated review on the safety and current recommendations for using fluoroquinolones in children.

The Use of Systemic and Topical Fluoroquinolones

Appropriate prescribing practices for fluoroquinolones are essential as evolving resistance patterns are considered, additional treatment indications are identified, and the toxicity profile of fluoroquinolones in children becomes better defined. Earlier recommendations for systemic therapy remain; expanded uses of fluoroquinolones for the treatment of certain infections are outlined in this report. Although fluoroquinolones are reasonably safe in children, clinicians should be aware of the specific adverse reactions. Use of fluoroquinolones in children should continue to be limited to treatment of infections for which no safe and effective alternative exists.

The use of fluoroquinolone in children

The fluoroquinolones are an important group of antibiotics widely used in the treatment of various infectious diseases in adults, as a result of an excellent spectrum of activity, good tissue penetration and convenient ways of administration. In recent decades, there has been extensive development, clinical investigation, licensure and use of fluoroquinolone antibiotics. However, the use of fluoroquinolones in children has been limited because of their potential to induce arthropathy in juvenile animals. Despite class label warnings against use in children, prescriptions for quinolone antibiotics to treat infections in children have become increasingly prevalent. The main use of fluoroquinolones in pediatrics should be, understandably, in serious life-threatening infections for which other antibiotics therapies are not effective or available. While most of the published studies failed to detect an increased rate of articular adverse effects in children treated with fluoroquinolones, an increase in the use of these compounds, particularly in community-acquired lower respiratory infections, could accelerate the emergence of multidrug-resistant (including fluoroquinolone) pneumococcal strains. This review will discus the main issues related to the use of fluoroquinolones in children, the major problems of resistance developing among these compounds, with special emphasis on the potential side effects and skilled use of these alternative potent drugs in pediatric infection.

Do fluoroquinolones commonly cause arthropathy in children?

The objective of this paper was to review the relation between fluoroquinolone (FQ) use and arthropathy in children. The biomedical literature from January 1980 to February 2007 was searched using PubMed. Key search terms included fluoroquinolones, arthropathy, tendinopathy and children. Literature was included if it was a clinical trial or meta-analysis examining the use of 1 or more FQs in a pediatric human population and if it had a primary outcome measure of reported incidence of arthropathy or tendinopathy. Articles were excluded if the primary outcome measure was efficacy of an FQ in a particular pediatric disease state, and evaluated safety was a secondary end point. Data was reviewed from 4 large retrospective studies. Three of the 4 studies failed to find a significant link between musculoskeletal injury and FQ treatment. One study reported a correlation between use of pefloxacin and arthropathy, but the authors' conclusions supported the use of FQs in select pediatric cases. Arthropathy that occurs as a result of FQ use in children has not been adequately supported by published data from safety trials in human children. Concerns about arthropathy with FQs should not preclude their use by emergency physicians when appropriate and necessary in pediatric patients.

Gatifloxacin in the Treatment of Recurrent Otitis Media and Otitis Media Treatment Failure in Children

Gatifloxacin is a new fluoroquinolone with different properties, such as excellent activity against otitis media pathogens, less potential for selection of antimicrobial resistance, good middle ear penetration and a prolonged half life. Fluoroquinolone use in children has been limited owing to some concerns of arthrotoxicity based on observations made on juvenile animals. Nevertheless, multiple studies have been published showing that this observation, found only in certain animals, does not necessarily correlate to findings in humans. Results from four clinical (two Phase II and two Phase III) studies involving 1176 children have been published to evaluate the safety and efficacy of gatifloxacin (10 mg/kg once daily for 10 days) in children with complicated to treat otitis media. Three studies included a baseline tympanocentesis and one study included a mandatory, during therapy, tympanocentesis in those children with a positive baseline culture. In the double tympanocentesis study, the bacterial eradication rate was 90% (103/114). Among all clinically evaluated children treated with gatifloxacin, 90% (605/682) were considered to be a clinical success at the end of therapy and 90% by the end of the study. The overall incidence of gatifloxacin-related adverse events observed in the Phase III trials was 2% for both gatifloxacin and the comparator agent, amoxicillin-clavulanate. Among 453 gatifloxacin recipients, the incidence of adverse events was similar for children younger than 2 years old (16%) and older than 2 years (23%). Transitory arthralgia occurred in 1.4% (12/867) of gatifloxacin-treated children. At 1-year safety follow-up, data was collected among 77% of gatifloxacin-treated children and no evidence of arthropathy was reported.

Guidelines for the use of fluoroquinolones in children have been released by the American Academy of Pediatrics (AAP) Committee on Infectious Diseases.

Guidelines for the use of fluoroquinolones in children have been released by the American Academy of Pediatrics (AAP) Committee on Infectious Diseases.

Guidelines for the use of fluoroquinolones in children have been released by the American Academy of Pediatrics (AAP) Committee on Infectious Diseases.

Guidelines for the use of fluoroquinolones in children have been released by the American Academy of Pediatrics (AAP) Committee on Infectious Diseases.

The use of fluoroquinolones in children: recent advances

Fluoroquinolones are an important group of antibiotics that are used widely in the treatment of various infectious diseases in adults as a result of their excellent spectrum of activity, significant tissue penetration and convenient routes of administration. Their use in children, however, has been limited until recently as a result of possible fluoroquinolone-induced joint toxicity. Nevertheless, this group of antibiotics is rapidly gaining consideration for use in children as new agents are emerging with a wide antimicrobial range of action and minimal toxicity, even in young children. This review presents the pharmacokinetics, clinical indications and possible toxicity of fluoroquinolones in children, as well as the newer agents and their safety profile in pediatrics.

Fluoroquinolones in children addressed in AAP policy

For the past two decades, the use of fluoroquinolones in children has been approached with caution and concern by pediatricians and the Food and Drug Administration (FDA). ![Figure][1] Dr. Bradley As more data on the safety and efficacy of this class of antimicrobials in children have

The Use of Systemic Fluoroquinolones

The only indications for which a fluoroquinolone (ie, ciprofloxacin) is licensed by the US Food and Drug Administration for use in patients younger than 18 years are complicated urinary tract infections, pyelonephritis, and postexposure treatment for inhalation anthrax. Nonetheless, approximately 520,000 prescriptions for fluoroquinolones were written in the United States for patients younger than 18 years in 2002; 13,800 were written for infants and children 2 to 6 years of age, and 2750 were written for infants younger than 2 years. Clinical trials of fluoroquinolones in pediatric patients with various diagnoses have been published and are reviewed. Fluoroquinolones cause arthrotoxicity in juvenile animals and have been associated with reversible musculoskeletal events in both children and adults. Other adverse events associated with fluoroquinolones include central nervous system disorders, photosensitivity, disorders of glucose homeostasis, prolongation of QT interval with rare cases of torsade de pointes (often lethal ventricular arrhythmia in patients with long QT syndrome), hepatic dysfunction, and rashes. The increased use of fluoroquinolones in adults has resulted in increased bacterial resistance to this class of antibacterial agents. This report provides specific guidelines for the systemic use of fluoroquinolones in children. Fluoroquinolone use should be restricted to situations in which there is no safe and effective alternative to treat an infection caused by multidrug-resistant bacteria or to provide oral therapy when parenteral therapy is not feasible and no other effective oral agent is available.

The use of fluoroquinolones in children

The fluoroquinolones are an important group of antibiotics widely used in the treatment of various infectious diseases in adults, as a result of an excellent spectrum of activity, good tissue penetration and convenient ways of administration. Their use in children is limited as a result of possible fluoroquinolone-induced joint/cartilage toxicity observed mainly in juvenile animal studies. Fluoroquinolones were successfully used in immunocompromised children and also in those suffering from multidrug-resistant Gram-negative infections (including neonatal infections and multidrug-resistant enteric infections caused by Salmonella and Shigella spp.). The fluoroquinolones were shown to be efficacious and well tolerated in the treatment of complicated cases of acute otitis media. The emergence of Streptococcus pneumoniae with reduced susceptibility to fluoroquinolones has been described worldwide. No arthropathy associated with fluoroquinolone use in children was evident. With the exception of cystic fibrosis and life-endangering infections, the use of fluoroquinolones in pediatrics should be limited to Gram-negative neonatal meningitis, Salmonella and Shigella spp. infections, chronic suppurative otitis media and some cases of complicated acute otitis media. Unskilled use of fluoroquinolones in children, particularly in community-acquired lower respiratory infections, could accelerate the emergence of pneumococcal resistance.

Pharmacodynamics of gatifloxacin in experimental models of pneumococcal meningitis.

The alarming increase of bacterial resistance has had a serious impact on treatment practices for patients with meningitis and has prompted investigation of other possibly effective antibiotic regimens with agents, such as gatifloxacin and trovafloxacin, that have excellent activity against Streptococcus pneumoniae. The use of fluoroquinolones in children has been limited by studies that report chondrotoxicity in young animals. Gatifloxacin, a new fluoroquinolone, was recently tested in a rabbit model of cephalosporin-resistant pneumococcal meningitis. In these studies, animals were infected with a ceftriaxone-resistant (minimal inhibitory concentration [MIC], 4 microg/mL; minimal bactericidal concentration [MBC], 4 microg/mL) and gatifloxacin-susceptible (MIC, 0.125 microg/mL; MBC, 0.25 microg/mL) strain of S. pneumoniae and were treated with either a single- or divided-dose regimen of gatifloxacin. Results from these studies are reviewed and compared with data from other studies that used a similar rabbit model of pneumococcal meningitis. Overall, it was found that the bacteriologic efficacy of gatifloxacin against S. pneumoniae was as effective as that of conventional regimens. Bactericidal activity of gatifloxacin was correlated with the area under the time-concentration curve-to-MBC ratio; maximal activity was achieved when gatifloxacin concentrations exceeded the MBC for the entire dosing interval.