Academic Year 2015 - 2016
Fluoroquinolones in children: a review of current literature and directions for future research
Laurens GOEMÉ
Promotor: Prof. Dr. Johan Vande Walle Co-promotor: Dr. Kevin Meesters, Dr. Pauline De Bruyne
Dissertation presented in the 2nd Master year in the programme of
Master of Medicine in Medicine
1 Deze pagina is niet beschikbaar omdat ze persoonsgegevens bevat. Universiteitsbibliotheek Gent, 2021.
This page is not available because it contains personal information. Ghent University, Library, 2021.
Table of contents
Title page Permission for loan Introduction Page 4-6 Methodology Page 6-7 Results Page 7-20 1. Evaluation of found articles Page 7-12 2. Fluoroquinolone characteristics in children Page 12-20
Discussion Page 20-23 Conclusion Page 23-24 Future perspectives Page 24-25 References Page 26-27
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1. Introduction Fluoroquinolones (FQ) are a class of antibiotics, derived from modification of quinolones, that are highly active against both Gram-positive and Gram-negative bacteria. In 1964,naladixic acid was approved by the US Food and Drug Administration (FDA) as first quinolone (1). Chemical modifications of naladixic acid resulted in the first generation of FQ. The antimicrobial spectrum of FQ is broader when compared to quinolones and the tissue penetration of FQ is significantly deeper (1). The main FQ agents are summed up in table 1. FQ owe its antimicrobial effect to inhibition of the enzymes bacterial gyrase and topoisomerase IV which have essential and distinct roles in DNA replication. The antimicrobial spectrum of FQ include Enterobacteriacae, Haemophilus spp., Moraxella catarrhalis, Neiserria spp. and Pseudomonas aeruginosa (1). And FQ usually have a weak activity against methicillin-resistant Staphylococcus aureus (MRSA). Newer compounds of FQ have higher activity against anaerobes than older compounds (2,3).
FQ are rapidly absorbed in the gut after oral administration . They usually penetrate deep into the tissues and diffuse easily in intracellular spaces as concentrations in lung, bile and urine can exceed serum concentration (1). FQ concentrations in saliva, bone and cerebral spinal fluid (CSF) is usually lower than plasma. Nevertheless, the concentration of FQ in CSF is often sufficient for the treatment of meningitis (4,5).
FQ are typically excreted unmetabolized in urine or via the bile where some enterohepatic circulation is possible. Oral administration of FQ generally results in high bioavailability (80- 90%), with norfloxacin being an exception as its bioavailability is significantly less (10-30%) (1,4–6).
As for safety, there are a number of adverse effects associated with FQ use. two patients reported arthralgia, about 8 years after the introduction of FQ, during treatment with nalidixic acid. This led to studies in beagle dogs with nalidixic, oxolinic and pipemedic acid that showed changes in immature cartilage of weight-bearing joints. This finding prompted the FDA to issue a class label warning for FQ use in children and caused pediatric clinical trials in children to halt. The latter has made FQ administration to children controversial until today, as is reflected in the limited number of labeled pediatric FQ indications (24,25).
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Table 1 shows the main FQ agents per generation
First Generation cinoxacin nalidixic
rosoxacin Second Generation ciprofloxacin enoxacin
nadifloxacin norfloxacin ofloxacin
Third Generation* balofloxacin
tosufloxacin Fourth Generation** clinafloxacin
prulifloxacin * Also active against Streptococci **Act at DNA gyrase and topoisomerase IV. This dual action slows development of resistance
The only FDA-labeled pediatric indications for ciprofloxacin are complicated urinary tract infection (UTI) and post exposure to anthrax (25). The European Medicines Agency (EMA) labels FQ in children for complicated UTI, post-antrax expose and for broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa and for ´severe infections in children and adolescents when this is considered to be necessary, as initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.´ (24).
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Bacterial resistance to FQ is a rapidly growing problem. During the last years, resistance to FQ has remained very high among MRSA, Pseudomonas aeruginosa and anaerobes. More worrisome are recent reports of an overall increase in FQ resistance among bacteria causing community-acquired infections, such as E. coli and Neiserria gonorrhea (3). FQ resistance rates are probably due to incorrect prescription practices and the absence of specific pediatric drug studies (2).
Despite the limited number of labeled pediatric indications for FQ prescription, FQ are regularly prescribed to children (15). In this review I will summarize currently available literature regarding indications, pharmacokinetics, safety and antimicrobial resistance of FQ in children. I will review arthropathy in more depth in discussing adverse effects since this specific adverse effect is considered most drastic. I will give recommendations for clinical use and future research as well.
2. Methodology To review available literature of FQ metabolism, safety and antimicrobial resistance in children, I searched through PubMed and Google Schoolar using the following queries: ‘FQ arthropathy’,‘quinolone arthropathy in children’,‘FQ pharmacokinetics’ , ‘FQ pharmacokinetics in children’ ,‘FQ resistance’. To further understand the traditional fears for cartilage tissue damage during FQ treatment in children, I searched for studies conducted on juvenile animals as well using the query ‘FQ in juvenile animals’ on both PubMed and Google Scholar. In selecting articles for inclusion in this thesis, I included review articles published after 1980 and written in either English or Dutch for articles regarding indications and pharmacokinetics. In summarizing available literature I will focus rather on systemic use than topical use.
All articles were first screened on their titles and secondly on their abstract. This allowed for an effective selection of potential studies. Hereafter, the full text was judged and only after this step I finally concluded whether or not an article should be included in my thesis.
Articles were judged based on their level of evidence (GRADE), including as many review articles as possible. I will review results of my search in the following section in a qualitative way.
As a literature study imposes certain difficulties in the acquisition and selection of articles it is worth noting that studies listed on Embase are not included as they have not received a peer
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review before being published. This means that several potentially valuable articles have not been included in this study. This also applies to studies that have not (yet) been published and studies that were missed due to the limitations faced when using variable search terms. These search terms may mismatch with the keywords used to classify studies in databases such as PubMed. However, a valiant effort has been made to minimize the impact of the latter on the in- and exclusion of articles in this study.
3. Results
3.1 Evaluation of found articles
3.1.1 Analysis of search results A total of 21 articles were selected through various searches on PubMed and Google Scholar. Articles were selected based on overall relevance, date of publication, language, study type (cohort, case-control, cross-sectional or experimental designs) , and journal of publication.
The query ‘FQ in children’ on PubMed returned 1702 results, among those, 1 suggested study (7) which assessed 740 patients with febrile neutropenia treated with ciprofloxacin and reports excellent treatment outcomes with high rates of success and no cases of mortality among patients.
The same query also returned a more recent article (8) that monitored which FQ was used to treat certain infections. Ciprofloxacin was prescribed for 382 patients (96% of FQ prescriptions). Febrile neutropenia was by far the most common indication for FQ use. Other common indications include complicated IBD (inflammatory bowel disease), septicemia and UTI.
The query ‘FQ in juvenile animals’ lead to the inclusion of three articles (9–11). Selection was also based on which type of animal species was examined, aiming to include a variety of animal species in order to further understand the reasoning behind the current doses for children.
The query ‘FQ arthropathy’ resulted in 328 articles. One article (12) was included, hypothezising pathogenetic mechanisms for FQ-induced arthropathy, while also providing data of these lesions in immature rats. Later another article (13) was found using the query ‘quinolone arthropathy in children’ on PubMed after finding no relevant articles with the same query on Google Scholar. The authors of this article (13) performed a literature search
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on FQ arthropathy in animals versus children and concluded quinolone arthropathy is to date not convincingly correlated with use of these compounds in children and adolescents.
The query ‘FQ pharmacokinetics’ resulted in 3895 articles and the query ‘FQ pharmacokinetics in children’ 105. Most articles were discarded due to irrelevant patient group or deemed out of date. Three articles (4,6,14) were included. Article (4) evaluated one specific compound (ciprofloxacin-based ear drops, CIPRODEX ®) and was included because chronic otitis media in children is commonly treated with FQ.
Article (6) evaluated single-dose and steady-state pharmacokinetics in 16 patients (aged 0.3 to 7.1 years) of an oral suspension of ciprofloxacin. Article (14) evaluated 16 patients aged between 5 weeks and 5 ½ years after a single oral dose ciprofloxacin 15mg/kg. The results of this study indicate that ‘there are great differences between the pharmacokinetics of ciprofloxacin in different age groups, even between infants and children.’.
The query ‘FQ resistance’ returned 9263 articles, most of them evaluating mechanisms of resistance of one particular bacterium to FQ. Two (3,15) articles were included. Article (3) provided a general evaluation of clinical and practical implications for FQ resistance, while (15) provided insights in the methods of FQ resistance specifically to Salmonella species.
The snowball method was used to find any other relevant articles (1,2,5,16–20). Most of these were found using citations in review articles (1,18,21).
3.1.2 Summary of information on arthropathy in animal studies When assessing whether or not FQ arthropathy occurs in certain animal species, we found a number of different studies, using a wide range of FQ dosage. Furthermore a wide variety of animal species have been tested. Among other factors, dosage plays a significant role in FQ arthropathy. Table 2 lists some of the finding that these animal studies have found.
FQ arthropathy in juvenile animals is a dreaded complication of FQ use, following findings in these studies.
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Table 2 shows a brief summary of the animal studies, their subjects and the results with certain doses and compounds of FQ.
Juvenile canine drug-induced arthropathy clinicopathological studies on articular lesions caused by oxolinic and pipemidic acid (9) Subject Compound/dosage Treatment Cumulati Articular duration ve dosage evaluation Beagle-dog (3 oxolinic acid 14 days 7g/kg macroscopic months) 500mg/kg/day lesions Beagle-dog (3 oxolinic acid 14 days 1,4g/kg microscopic months) 100mg/kg/day lesions Beagle-dog (3 pipemidic acid 14 days 7g/kg macroscopic months) 500mg/kg/day lesions (more than oxolinic acid 500mg/d) Beagle-dog(3 pipemidic acid 14 days 1,4g/kg microscopic months) 100mg/kg/day lesions Toxicological studies on pipemidic acid. Effect on diarthrodial joints of experimental animals (10) Subject Compound/dosage Treatment Cumulati Articular duration ve dosage evaluation Spitz-dog (2maand) pipemidic acid 4 days 4g/kg macroscopic 1000mg/kg/day lesions Rat (3 weeks) pipemidic acid 20 days 20g/kg no lesions 1000mg/kg/day Rabbit (4 weeks) pipemidic acid 30 days 9g/kg no lesions 300mg/kg/day or less Monkey (5-10 pipemidic acid 30 days 30g/kg no lesions years) 1000mg/kg/day Beagle dog (<2 pipemidic acid 14 days 1,4g/kg no lesions weeks or >3 100mg/kg/day months)
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Monkey (5-10 pipemidic acid 30 days 30g/kg no lesions months) 1000mg/kg/day Children as a special population at risk – quinolones as an example for xenobiotics exhibiting skeletal toxicity (20) Treatment Cumulative Articular Subject Compound/dosage duration dosage evaluation ofloxacin 600mg/ macroscopic Rat (juvenile) 1 day 600/1200mg/kg/day 1200mg lesions ofloxacin Rat (juvenile) 1 day <300mg/kg no lesions <300mg/kg/day ofloxacin Rat (juvenile) 5 days 500mg/kg no lesions 100mg/kg/day ciprofloxacin Rat (juvenile) 1 day 1200mg/kg no lesions 1200mg/kg/day ciprofloxacin Rat (juvenile) 5 days 3000mg/kg no lesions 600mg/kg/day Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters, use of urinary and and absorbed fraction metabolite data to estimate first-pass effect (11) Treatment Cumulative Articular Subject Compound/dosage duration dosage evaluation enrofloxacin 2- Horse (adult) 1 day 2-5mg/kg no lesions 5mg/kg/day marbofloxacin 2- Horse (adult) 1day 2-5mg/kg no lesions 5mg/kg/day Effect of long-term treatment with therapeutic doses of enrofloxacin on chicken articular cartilage (22) Treatment Cumulative Articular Subject Compound/dosage duration dosage evaluation enrofloxacin Chicken (21 days) 35 days 350mg/kg no lesions 10mg/kg/day
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3.1.3 Comparison with human doses A large number of animal studies, evaluating the adverse effects of FQ, were conducted and data from these studies show a great variation in administered dose (mg/kg/d) per animal species. However these doses were usually much higher than usual prescribed doses for children. Subsequently, we observe the same variation when evaluating arthropathy in these animals as table 2 illustrates.
Table 3 shows which quantities of FQ are used in which animals, compared to those in humans.
Daily dosage Rat (3 Chicken Rabbit Beagle- Monkey Horse Human weeks) (4 dog (3 weeks) months) Min (mg/kg/d) 100 0 200 100 500 0 0 Max (mg/k/d) 1200 10 300 500 1000 5 25
Treatment dosage Rat (3 Chicken Rabbit Beagle- Monkey Horse Human weeks) (4 dog (3 weeks) months) Min (mg/kg) 300 0 6000 1700 15000 2 0 Max (mg/kg) 30000 350 9000 7000 30000 5 25 Natural life span 2 8 8 15 25 30 80 (year) Min total cumulative 150 0 750 113 600 0 0 dosage/natural life span (mg/year) Max total 15000 44 1125 467 1200 0,17 0,31 cumulative dosage/natural life span (mg/year)
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35000 30000 30000 30000 25000 20000 15000 Min (mg/kg) 15000 9000 Max (mg/kg) 10000 7000 350 6000 5000 300 0 1700 2 5 0 25 0 Rat (3 Chicken Rabbit (4 Beagle-dog Monkey Horse Human weeks) weeks) (3 months)
Chart 1 shows the variation of dosage (mg/kg) per animal species compared to those in humans. Doses vary significantly between species.
16000 15000 14000 12000 10000 8000 6000 Min total cumulative dosage/natural 4000 life span (mg/year) 1125 467 1200 44 750 0,17 0,31 2000 150 0 113 600 0 0 Max total cumulative 0 dosage/natural life span (mg/year)
Chart 2 shows the cumulative dosage per natural life span year (mg/year).
3.2 Fluoroquinolone characteristics in children
3.2.1 Pharmacokinetics As a class, FQ are rapidly absorbed from the small intestine and their bioavailability is generally high, ranging from 70 to 95% (an exception being norfloxacin which has a bioavailability of 10-30%). Peak plasma concentrations of later generation agents (eg., gatifloxacin, levofloxacin, moxifloxacin) are generally attained between one and two hours after oral administration and their bioavailability does not appear to be markedly impacted by
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concurrent ingestion with food with the exception of concurrent strontium renalate, aluminum-, calcium-and magnesiumsalts consumption which is suspected to cause lower uptake due to the formation of complexes. (4–6). The oral bioavailability of ciprofloxacin in younger children has been reported to lower when compared to older children and young adults (4-6).
FQ demonstrate low binding to circulating plasma proteins and as a result of their excellent penetration into tissue (intracellular working), they have apparent volumes of distribution which far exceed the total body water space (eg., average apparent volume of distribution for ciprofloxacin ~ 2.3 L/kg) (5,6).
The metabolization of the FQ is drug dependent with many of the early generation compounds (eg., ciprofloxacin) being extensively metabolized in the liver when compared to later generation compounds (eg., levofloxacin, gatifloxacin, gemifloxacin) which are predominantly excreted unchanged in the urine. Ciprofloxacin and norfloxacine inhibit CYP1A2, with possible pharmacokinetic interactions of other ingested drugs (4–6).
When compared to early generation compounds, the newer FQ (i.e. gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) generally have longer elimination half-lives which facilitates the use of longer dosing intervals (5,6). Systemic clearance of FQ may be increased in young children due to increased renal excretion however this seems to be compound dependent (4,5). The average elimination half-life of ciprofloxacin in children appears to be shorter than reported from studies in adults and consequently, supporting a need for three times daily dosing (however current guidelines recommend once or twice daily admission). In contrast, the elimination half-life of ciprofloxacin in infants has been reported to be prolonged relative to data from older children and associated with a higher plasma area under the curve (AUC) (ie., higher systemic exposure from a given dose which infers reduced plasma clearance). Similar to ciprofloxacin, the pharmacokinetics of levofloxacin appear to be age dependent (4,5).
3.2.2 Indications All indications listed here are for with systemic (oral, intravenous) FQ, with the exception of chronic otitis media and conjunctivitis, where topical FQ are applied.
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Since the introduction of naladixic acid in 1962 there have been many new FQ compounds, sometimes more or less potent against specific bacterial species. Therefore, there are different indications for different generations of FQ as figure 1 shows.
FQ have extensive antimicrobial activity against gram-negative organisms, gram-positive organisms, and atypical bacteria. Early-generation FQ predominantly target gram-negative pathogens, especially the Enterobacteriaceae family. Second generation FQ have even greater gram-negative coverage, with additional activity against Pseudomonas aeruginosa. New- generation generation FQ have enhanced activity against Staphylococci, Streptococci, and anaerobes. Moxifloxacin, a fourth-generation FQ, has excellent activity against many mycobacteria, including Mycobacterium tuberculosis (21).
1st generation Gram-negative organisms: Enterobacteriaceae nalaxid
acid
2nd generation Pseudomonas aeruginosa, ciprofloxacin, Gram-positive organisms levofloxacin, ofloxacin, norfloxacin, pefloxacin
3rd generation Streptococcus pneumoniae
gatifloxacin, gemifloxacin, sparfloxacin
4th generation Mycobacterium tuberculosis
moxifloxacin anaerobes
Figure 1. Classification and antimicrobial activity of FQ. Adapted from Choi S-H et al (21).
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Table 3 shows which bacteria can be treated with certain FQ compounds and their respective dosage (oral versus intravenous) (17,18,21).
Ciprofloxacin Levofloxacin Moxifloxacin Multidrug-resistant Infections Urinary tract infections Acute otitis media and sinusitis tuberculosis Escherichia coli Streptococcus pneumoniae Mycobacterium tuberculosis Pseudomonas aeruginosa Haemophilus influenzae Enterobacter species Pneumonia Citrobacter species Streptococcus pneumoniae Serratia species Mycoplasma pneumoniae Gastrointestinal infections Multidrug-resistant tuberculosis Salmonella species Mycobacterium tuberculosis Shigella species Dose 6 months to 5 years old 20–40 mg/kg/day, every 12 Oral hours 16–20 mg/kg/day, every 12 hours Adolescents: 400 mg once daily (maximum 750 mg/dose) 5 years of age and older 10 mg/kg/day, once daily (maximum 750 mg/dose) 20–30 mg/kg/day, every 8 Intravenous to 12 hours Same as oral dose Adolescents: same as oral dose (maximum 400 mg/dose)
Since the mid-1980s, FQ have been used in pediatric patients predominantly in infections caused by multi-resistant organisms (19,21). FQ have historically been used for treating repiratory tract infections caused by Pseudomonas aeruginosa in children with cystic fibrosis, complicated urinary tract infections, enteric infections in developing countries caused by multidrug-resistant Shigella species, Salmonella species, Vibrio cholerae, or Campylobacter jejuni and chronic otitis media (19,21). Currently, these conditions are still often treated with FQ (not always justified) and a number of uses have been added such as: neonatal meningitis, pneumonia with Streptococcus pneumoniae resistant to β-lactams and to other antibiotics, infections in neutropenic cancer patients and exposure to aerosolized Bacillus anthracis (5,18,19).
Cystic Fibrosis The treatment of Pseudomonas aeruginosa pulmonary superinfections in children with cystic fibrosis by ciprofloxacin has proven to be effective (2,21). The published studies show that
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oral ciprofloxacin is at least as effective as the combination of β-lactams and aminoglycosides, and, in addition, the oral administration of ciprofloxacin improves the child’s quality of life (2). But the absence of new pharmacological studies in children with cystic fibrosis presents a problem: the daily doses must be higher than those used in children without this disease, as blood concentration of ciprofloxacin seen in cystic fibrosis patients are lower compared to those without this disease when the drug is used with a conventional regimen (2). However, the progressive increase in Pseudomonas aeruginosa resistance suggests that the dose may still be inadequate (2).
Salmonellosis/Shigellosis Salmonellosis is a major health problem in developing countries, causing severe morbidity and mortality. It is an endemic disease in Africa, Southeast Asia, the Indian subcontinent, and South and Central America. The emergence of multidrug-resistant Salmonella (MDRS) has further complicated the problem. Since 1987, outbreaks of MDRS (resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole) have been reported in many developing countries. Resistant strains have also been isolated in developed countries, primarily among international travelers. Children, particularly infants, are at higher risk of morbidity and mortality from infection with MDRS .Therapeutic options for MDRS include third-generation cephalosporins and FQ (18,19). In two comparative studies, third-generation cephalosporins (ceftriaxone) were less effective than ciprofloxacin and ofloxacin in the treatment of typhoid fever (18). FQ possess unique properties for treating various gastrointestinal infections. One advantage is that the gastrointestinal absorption of FQ is not affected by diarrhea. In addition, high concentrations of FQ in the intestinal lumen are maintained for several days (1,18).
Treatment and prophylaxis of central nervous system infections FQ penetrate well into the CSF in the presence of inflamed meninges, and the CSF concentrations exceed the minimum inhibitory concentrations (MICs) (1). Meningococcal disease is a life-threatening communicable disease causing morbidity and mortality in many parts of the world. Prophylaxis with rifampin, ceftriaxone, and ciprofloxacin in close contacts of patients with meningococcal meningitis is the primary means for prevention of meningococcal disease. A single oral dose of ciprofloxacin has been used successfully in the eradication of nasopharyngeal carriage of Neiserria meningitidis in adults (1,18,19).
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Urinary tract infection Standard empiric therapy for uncomplicated UTI in the pediatric population continues to be a cephalosporin antibiotic agent (1). FQ remain a potential reserve therapy only in the setting of pyelonephritis or complicated UTI when typically recommended agents are not appropriate on the basis of susceptibility data, allergy, or adverse-event history (1).
Ciprofloxacin may be used as oral therapy for UTI and pyelonephritis caused by Pseudomonas aeruginosa or other multidrug-resistant Gram-negative bacteria in children aged 1 through 17 years (1).
Bacillus Anthracis FQ may be used post exposure to aerosolized Bacillus anthracis to decrease the incidence or progression of the disease (21).
Mycobacterium Tuberculosis FQ are active in vitro against mycobacteria, including Mycobacterium tuberculosis and many nontuberculous mycobacteria. Increasing multidrug resistance in Mycobacterium tuberculosis has led to the increased use of FQ as part of individualized, multiple-drug treatment regimens; levofloxacin and moxifloxacin have demonstrated greater bactericidal activity than has ciprofloxacin (5).
Treatment regimens that include FQ for 1 to 2 years for multidrug-resistant and extensively drug-resistant tuberculosis have not been prospectively studied in children. However, the benefit of treatment of tuberculosis with an active compound when other active alternatives are not available is considered greater than the potential for arthropathy (1).
Chronic suppurative otitis media Chronic suppurative otitis media (CSOM) is characterized by persistent otorrhea through a perforated tympanic membrane or tympanostomy tube for more than six weeks. Pseudomonas aeruginosa is a predominant pathogen. Potential ototoxicity limits the use of aminoglycosides and antipseudomonal β-lactam antibiotics, which are used most often for the treatment of CSOM (18).
The efficacy, systemic absorption, and safety of ciprofloxacin ear drops were evaluated in children with CSOM unresponsive to other therapies. Ten of 11 infected ears were given ciprofloxacin 0.3% ophthalmic solution 3 drops three times daily for 14 days ototopically. By day 7 of treatment, 10 of 11 patients with infected ears were cured (cessation of drainage) or improved (18).
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Conjunctivitis An increasing number of topical FQ have been investigated and approved by the FDA for treatment of acute conjunctivitis in adults and children older than 12 months, including levofloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and besifloxacin (1). Conjunctival tissue pharmacokinetic evaluation was conducted in healthy adult volunteers; besifloxacin, gatifloxacin, and moxifloxacin were compared by using conjunctival biopsy. All three agents reached peak serum concentrations after 15 minutes. Bacterial eradication and clinical recovery of 447 patients aged 1 through 17 years with culture confirmed bacterial conjunctivitis was evaluated in a post hoc multicenter study that investigated besifloxacin and moxifloxacin ophthalmic drops. Although better clinical and microbiological response was noted for besifloxacin compared with placebo, similar outcomes were noted when compared with moxifloxacin. Both agents were reported to be well tolerated (1).
3.2.3 Adverse effects Safety studies in adult humans have reported tendinopathy in several cases, mostly patients aged 60+ but no cases have been described in children. In most cases the Achilles tendon is affected and symptoms range from tendinitis to tendon rupture. There is an association with simultaneous corticosteroid treatment (1,16,21).
Few trials have evaluated the quality and quantity of adverse effects associated with long-term use of FQ in children but the ones that have been conducted, show FQ are well tolerated in children and show no long-term effects on weight-bearing joints which were affected in juvenile animals. [Table 2] In adults FQ are used to treat many infections such as pneumonia, UTI, skin, bone, ear and eye infections. In this population adverse effects are uncommon and mild. The most frequent adverse effects are gastrointestinal, CNS reactions and skin reactions (1,17–19,21).
Chalumeau et al. (23) reported the most commonly affected systems were the gastrointestinal followed by musculoskeletal (arthralgias of large joints or myalgias but no tendinopathy), skin, and central nervous systems. Adverse musculoskeletal events occurred more frequently in the FQ group than in the controls (3.8% vs. 0.4%); the crude OR for musculoskeletal potential adverse events in the FQ group was 9.3 (95% CI, 1.2 to 195). Although adverse events did occur more frequently with FQ treatment, all cases were transient, and no severe or persistent musculoskeletal injuries were observed at follow-up (21,23).
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Studies showed dogs were more susceptible to articular damage than other species and that damage is also dependent on which FQ compound is used. Recovery of the cartilage damage is usually incomplete and structural changes are at least in part irreversible (1,16). Observations in these animals include blisters, fissures and erosions, accompanied by non- inflammatory joint effusion. The pathophysiology of this problem has not been fully discovered, hypotheses stating that the damage is based on magnesium deficiency in the joint is currently the most plausible. Methods to measure this damage is typically done by either clinical examination, MRI, sonography or histopathology (which remains the gold standard). The fact remains that most of the data gathered in human studies are based on clinical evaluation and not on histopathological findings. It is worth noting that most histopathological findings describing articular damage found in animal experiments did not cause clinical manifestations (1,16,21).
Table 4 shows FQ induced side effects. Similar results were found in other studies (1,16,20,21).
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3.2.4 Mechanism of action/resistance FQ are the only class of antimicrobial agents in clinical use that are direct inhibitors of bacterial DNA synthesis. FQ inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV, which have both essential and distinct roles in DNA replication. The FQ bind to the complex of each of these enzymes with DNA; the resulting topoisomerase-quinolone-DNA ternary complex subsequently leads to the generation of double-stranded breaks in DNA and blocks progress of the DNA replication enzyme complex. Ultimately, this action results in damage to bacterial DNA and bacterial cell death (2,3).
Resistance to FQ occurs by mutation in chromosomal genes that encode the subunits of DNA- gyrase and topoisomerase IV (altered target mechanism), and that regulate the expression of cytoplasmic membrane efflux pumps or proteins that constitute outer membrane diffusion channels (altered permeation mechanism). Furthermore, reduced target expression has been described as another mechanism leading to low level FQ resistance (3). Repair mechanisms are activated as a consequence of inhibition of bacterial type II topoisomerases. Any DNA damage triggers the production of various repair proteins by activating an SOS gene network, further prohibiting the working of FQ (3).
4. Discussion The aim of this thesis was to provide an analysis of currently available knowledge on FQ use in children, what has led to today’s advised dosage and to give recommendations for future research towards appropriate prescription of FQ in children.
After analysis of current literature we found a high off-label use of FQ. In 2002, there were approximately 520,000 FQ prescriptions in the U.S. Over 13,000 of those prescriptions were written for children 2 to 6 years of age and nearly 3000 were prescribed for children younger than 2 years of age (5,23).
There are several possible explanations as to why FQ remain to be widely used among practitioners, despite class label warnings. One possible reason why doctors continue to prescribe FQ is because of their beneficial pharmacokinetic and antimicrobial properties. Another reason might be that doctors are not aware of the risks, both for the patient (articular
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damage) or for the community (resistance). A last reason might be that practitioners are thus familiar with prescribing FQ in adults with UTI that they prescribe them in children as well.
This is surprising as severe adverse effects were observed in animal studies, consequently pediatric trails were cancelled, and safety concerns regarding the use of FQ in children has inhibited both further research and correct present-day use.
4.1 Dose The question remains where current doses and indications of FQ use in children have originated. Currently there are no representative animal models allowing any extrapolation to today’s practice. There has been an extrapolation based on data in adults, however these doses have never been researched in a prospective study and are still subject of discussion. Especially since FQ can have very different pharmacodynamic characteristics in children of different age groups. Furthermore there is no research on how FQ behave in severely ill children, neonates, children with birth defects or children requiring intensive care. We should also keep in mind that while FQ have an excellent bioavailability, there is a well-known interaction with calcium causing a decrease in absorption in the gut which warrants additional care when administering FQ, as young children’s diet often includes milk and milk products.
4.2 Indications Similarly to dosage, there has been very little research in children regarding indications for FQ use. There are a small number of studies evaluating the use of FQ in children with cystic fibrosis suffering from Pseudomonas aeruginosa infection.
A lot of the current-day uses of FQ in children were obtained from experience with FQ in adults. This poses a risk for misuse of FQ in children. Not only could FQ be ineffective in some indications, there could also be a higher risk of resistance, which FQ are very prone to when used incorrectly.
4.3 Safety/Adverse effects A wide variety of animal studies have been conducted attempting to provide insight in the occurrence of FQ arthropathy in children. These studies often assumed a very similar mechanism of adsorption, distribution, metabolism and excretion between animals and
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humans. Another concern is the use of very high doses in the animal studies, compared to those used today in children.
Earlier animal studies have been produced mostly in the 1980-2000s era. Furthermore, these studies were often toxicological in nature, using extremely high and acute doses in order to map the adverse effects that this type of administration caused. A clinical extrapolation to a pediatric model is therefore impossible and these studies do not provide data on the long term effects of physiological doses of FQ.
Currently there are no new, representative animal studies being conducted that would allow extrapolation to a pediatric model. There would have to be new studies on larger animals using doses that are representative of treating schedules used today.
The absence of preclinical trials (so-called labelling studies) in children may be a cause for several safety concerns regarding current FQ use. Studies suggest that younger children have a higher renal clearance, resulting in a quicker than expected decrease in plasma and tissue concentration leading to insufficient FQ working. This mechanism also facilitates the occurrence of bacterial resistance which is currently a major problem when using FQ.
A great variation in administered dose per animal species and great variation when evaluating articular damage has fueled the hypothesis that FQ induced arthropathy is not only dependent on dosage but also shows major differences between species.
Dietary induced magnesium deficiency in juvenile rats caused pathological changes in joint cartilage that could not be distinguished from ofloxacin-induced lesions by histology (12).
While studies in Beagle dogs showed severe articular damage after FQ use, multiple academic post- marketing studies (using mostly observational cohort or retrospective designs) have shown no evidence to suggest permanent articular damage in children due to FQ intake (5,13,20,21).
New, long term studies in pediatric animals could provide new information on the long term effects on developing cartilage after FQ treatment and assess whether or not articular damage also occurs when using lower doses for longer periods of time. These studies would be deemed unethical in healthy children and studies in adults will not provide any data on growth since the cartilage is already full grown.
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Many authors have previously commented on the lack of research on FQ, however no new data has been brought forward. Patents on FQ have expired and there is little interest from the pharmaceutical industry to fund and organize new studies and these types of studies have shown to be difficult to organize in an academic setting, partially due to a lack of funding.
Despite the fact that no labelling studies have been completed FQ remain to be used widely among practitioners and this poses several potential issues. FQ may be erroneously preferred over other antibiotics such as aminoglycosides. Doctors may also use relatively low doses, due to fear of adverse effects, which in turn leads to higher occurrence of bacterial resistance.
4.4 Analysis of available literature Normally, when developing a drug the first step is to test the drug on various (rodent and non- rodent) animal species, preferably those that have similar age (relative to their life expectancy) as the target group. The following step is to conduct labelling studies, these are industry-driven and attempt to obtain data on the safety, working, dosage and indications of a certain drug. The final step is the post-market surveillance, intended to monitor the safety of a drug.
In the case of FQ, only the first step has been completed, a proper labelling study has never been finished. This leaves an important gap in our knowledge on FQ pharmacodynamical properties, indications, safety data and dosage.
5. Conclusion In this thesis, I aimed to investigate the evidence for the off-label use of FQ in children despite their safety warnings.
In 2002, there were approximately 520,000 FQ prescriptions written for children in the U.S. Over 13,000 of those prescriptions were written for children 2 to 6 years of age and nearly 3000 were written for children younger than 2 years of age. The main indications are pulmonary exacerbations in patients with cystic fibrosis, infections associated with complicated urogenital anomalies, immunosuppressed patients, those with infectious diarrheal diseases and patients who develop infections secondary to multi-drug resistant organisms.
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Current FDA and EMA recommended doses in children vary from 10-50mg/kg but there are no prospective studies confirming that these doses are correct. These doses are based on estimates using data from animal studies and studies in adults. The observational studies evaluating the effectiveness and safety of FQ are mostly small and often have a heterogenic group of participants, which makes drawing conclusions from these studies extremely difficult. This also means that current advised doses may be too low, worsening patient outcomes and increasing the risk of bacterial resistance to FQ which is an imminent threat to FQ use worldwide. Additionally, practitioners might prescribe even lower doses of FQ due to fear of adverse effects, further increasing the risk of bacterial resistance.
After finding severe articular damage due to FQ use in Beagle dogs, only a few trials have evaluated if this damage also exists in other animal species after FQ use. Furthermore, most studies employ a toxicological setup and therefore do not use therapeutic doses. There are no long-term studies in large animals that could provide insight on the mechanism of FQ induced arthropathy. These studies also do not allow to predict any adverse effects in children due to the difference in administered dose.
After carefully researching current publication on FQ use in children we have found little to no evidence to support claims that FQ cause irreversible arthropathy in children. However, the lack of long-term follow up studies may lead to a false sense of security when using FQ in children.
FQ in children should be reserved for when no other safe alternative treatment is available. They should be used with caution but in the correct dose to ensure complete eradication of bacteria, preventing resistance.
6. Future perspectives It would be unethical to conduct long term safety studies in healthy children and therefore the safety and adverse effects in children could be approximated by conducting long term studies in larger animal models, using therapeutic doses. This will allow us to evaluate whether or not cartilage damage also occurs under these circumstances.
Pharmacodynamics should be researched in studies in a real-life situation, to account for the possible interaction with calcium. These studies should also be held in children with very severe infections, sepsis, congenital defects and children requiring intensive care as these
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groups can react very different to drugs compared to other children in their age group. An ideal method would be to use a system of continuous monitoring of FQ concentrations in a patient’s blood.
These studies should allow practitioners to prescribe FQ in the appropriate dose for the correct indication.
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