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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

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.

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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

oxolinic acid

piromidic acid

pipemidic acid

rosoxacin

Second Generation ciprofloxacin

enoxacin

fleroxacin

lomefloxacin

nadifloxacin

norfloxacin

ofloxacin

pefloxacin

rufloxacin

Third Generation* balofloxacin

levofloxacin

pazufloxacin

sparfloxacin

tosufloxacin

Fourth Generation** clinafloxacin

gemifloxacin

moxifloxacin

sitafloxacin

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

duration

Cumulati

ve dosage

Articular

evaluation

Beagle-dog (3

months)

oxolinic acid

500mg/kg/day

14 days 7g/kg macroscopic

lesions

Beagle-dog (3

months)

oxolinic acid

100mg/kg/day

14 days 1,4g/kg microscopic

lesions

Beagle-dog (3

months)

pipemidic acid

500mg/kg/day

14 days 7g/kg macroscopic

lesions (more than

oxolinic acid

500mg/d)

Beagle-dog(3

months)

pipemidic acid

100mg/kg/day

14 days 1,4g/kg microscopic

lesions

Toxicological studies on pipemidic acid.

Effect on diarthrodial joints of

experimental animals (10)

Subject Compound/dosage Treatment

duration

Cumulati

ve dosage

Articular

evaluation

Spitz-dog (2maand) pipemidic acid

1000mg/kg/day

4 days 4g/kg macroscopic

lesions

Rat (3 weeks) pipemidic acid

1000mg/kg/day

20 days 20g/kg no lesions

Rabbit (4 weeks) pipemidic acid

300mg/kg/day or

less

30 days 9g/kg no lesions

Monkey (5-10

years)

pipemidic acid

1000mg/kg/day

30 days 30g/kg no lesions

Beagle dog (<2

weeks or >3

months)

pipemidic acid

100mg/kg/day

14 days 1,4g/kg no lesions

10

Monkey (5-10

months)

pipemidic acid

1000mg/kg/day

30 days 30g/kg no lesions

Children as a special population at risk –

quinolones as an example for xenobiotics

exhibiting skeletal toxicity (20)

Subject Compound/dosage Treatment

duration

Cumulative

dosage

Articular

evaluation

Rat (juvenile) ofloxacin

600/1200mg/kg/day 1 day

600mg/

1200mg

macroscopic

lesions

Rat (juvenile) ofloxacin

<300mg/kg/day 1 day <300mg/kg no lesions

Rat (juvenile) ofloxacin

100mg/kg/day 5 days 500mg/kg no lesions

Rat (juvenile) ciprofloxacin

1200mg/kg/day 1 day 1200mg/kg no lesions

Rat (juvenile) ciprofloxacin

600mg/kg/day 5 days 3000mg/kg no lesions

Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters,

use of urinary and and absorbed fraction metabolite data to estimate first-pass effect (11)

Subject Compound/dosage Treatment

duration

Cumulative

dosage

Articular

evaluation

Horse (adult) enrofloxacin 2-

5mg/kg/day 1 day 2-5mg/kg no lesions

Horse (adult) marbofloxacin 2-

5mg/kg/day 1day 2-5mg/kg no lesions

Effect of long-term treatment with

therapeutic doses of enrofloxacin on

chicken articular cartilage (22)

Subject Compound/dosage Treatment

duration

Cumulative

dosage

Articular

evaluation

Chicken (21 days) enrofloxacin

10mg/kg/day 35 days 350mg/kg no lesions

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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

weeks)

Chicken Rabbit

(4

weeks)

Beagle-

dog (3

months)

Monkey Horse Human

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

weeks)

Chicken Rabbit

(4

weeks)

Beagle-

dog (3

months)

Monkey Horse Human

Min (mg/kg) 300 0 6000 1700 15000 2 0

Max (mg/kg) 30000 350 9000 7000 30000 5 25

Natural life span

(year)

2 8 8 15 25 30 80

Min total cumulative

dosage/natural life

span (mg/year)

150 0 750 113 600 0 0

Max total

cumulative

dosage/natural life

span (mg/year)

15000 44 1125 467 1200 0,17 0,31

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Chart 1 shows the variation of dosage (mg/kg) per animal species compared to those in

humans. Doses vary significantly between species.

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

300 0

6000

1700

15000

2 0

30000

350

9000

7000

30000

5 250

5000

10000

15000

20000

25000

30000

35000

Rat (3weeks)

Chicken Rabbit (4weeks)

Beagle-dog(3 months)

Monkey Horse Human

Min (mg/kg)

Max (mg/kg)

150 0750 113 600 0 0

15000

441125 467 1200

0,17 0,31

0

2000

4000

6000

8000

10000

12000

14000

16000

Min total cumulative dosage/naturallife span (mg/year)

Max total cumulativedosage/natural life span (mg/year)

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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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1st generation

2nd generation

3rd generation

4th generation

Gram-negative organisms: Enterobacteriaceae

Pseudomonas aeruginosa,

Gram-positive organisms

Streptococcus pneumoniae

Mycobacterium tuberculosis

anaerobes

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).

Figure 1. Classification and antimicrobial activity of FQ. Adapted from Choi S-H et al (21).

nalaxid

acid

ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, pefloxacin

gatifloxacin, gemifloxacin, sparfloxacin

moxifloxacin

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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

Infections Urinary tract infections Acute otitis media and sinusitis Multidrug-resistant 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

Oral 20–40 mg/kg/day, every 12 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)

Intravenous 20–30 mg/kg/day, every 8 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

21

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

22

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.

23

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.

24

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

25

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.

26

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