1. health and fitness
2. therapy

18th Expert Committee on the Selection and Use of Essential Medicines
(2011)
Fluoroquinolone Use in Paediatrics:
Focus on Safety and Place in Therapy
Jennifer A. Goldman, M.D. 1,2,
Gregory L. Kearns, Pharm.D., Ph.D. 1,3,4
Departments of Pediatrics 1 and Pharmacology 3, University of Missouri – Kansas City and
the Divisions of Pediatric Infectious Disease 2 and Clinical Pharmacology and Medical
Toxicology, 4 Children’s Mercy Hospital, Kansas City, MO, USA
Commissioned work for the Guidelines Group for the Revision of the “Guidance for National
Tuberculosis Programmes on the Management of Tuberculosis in Children”, World Health
Organization, 30-31 March 2010, Geneva, Switzerland
1
I. Introduction
The first quinolone, nalidixic acid, was developed in the 1960s and was used (offlabel) in pediatric therapeutics without restriction. Consequent to their broad spectrum of
antimicrobial (including anti-mycobacterial) effect and perceived excellent safety profile,
there was considerable hope and expectation that this class of antibiotics would find an
important place in pediatric therapeutics. However, reports of quinolone-associated injury in
weight bearing joints of juvenile animals resulted not only in an apparent contraindication to
their use in human infants and children but also, completely derailed their formal
development by pharmaceutical companies for use in pediatrics. While this situation resulted
from a genuine concern for safety seemingly supported by relevant experimental findings, it
served initially to remove a potentially useful class of antimicrobial agents from pediatric use.
Despite the concerns associated with fluoroquinolone use in children, the favorable
characteristics of this drug class (eg., excellent oral bioavailability and tissue penetration,
broad antimicrobial spectrum, well characterized and predictable concentration-effect
relationships, relative low incidence of development of microbial resistance) resulted in their
increasing use in infants and children; initially as secondary or tertiary antimicrobial choices
and three decades later, as a potential first line modality of treatment recommended in
standard pediatric compendia used throughout the world (eg., ciprofloxacin monographs in
Medicines for Children, Royal College of Paediatrics and Child Health and Neonatal and
Paediatric Pharmacists Group, 2003; Pediatric Dosage Handbook, 16th edition, Lexicomp
Corporation, 2009). For example, previous recommendations from the American Academy of
Pediatrics (Red Book, 28th edition, American Academy of Pediatrics, 2009) indicate that
fluoroquinolones may be useful for treating infections in pediatric patients where no other
(appropriate) oral agent is available, the infection is caused by a multidrug-resistant pathogen
(such as Pseudomonas sp. and Mycobacterium strains) or prolonged oral treatment of gramnegative bacterial infections (eg., chronic osteomyelitis, exacerbations in patients with cystic
fibrosis, infections in immunocompromised patients) is needed. Consequently, there appears
to now be a real place in the pediatric therapeutic armamentarium for this class of
antimicrobial agents. However, an overriding caveat for their use in children continues to
entail a critical assessment of the risk vs. benefit ratio where adverse event data derived from
animal models may not be completely/accurately extrapolated to developing humans.
The purpose of this review of the fluoroquinolones is to synthesize available
information of pertinence with respect to their use in children. The pharmacokinetics and
pharmacodynamics of the drugs will be discussed as well as their general safety profile and
the current and potential future roles for representative agents in this class in treating serious
infections that can commonly occur in infants and children.
II. Clinical Pharmacology
Fluoroquinolones are a class of antimicrobials that selectively target the action of
bacterial topoisomerase II and IV. Inhibition of the activity of these enzymes disables DNA
replication which in turn, inhibits bacterial replication. Presently, four generations of
fluoroquinolone antibiotics exist as illustrated by the following table:
2
First generation
nalidixic acid
Second generation
ciprofloxacin, levofloxacin, enoxacin, fleroxacin, ofloxacin,
lomefloxacin, norfloxacin
Third generation
gatifloxacin, gemifloxacin, grepafloxacin, sparfloxacin
Fourth generation
moxifloxacin, trovafloxacin
Of these agents, ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin are the most
widely used.8 The mechanism of action for the fluoroquinolones conveys activity that is
bactericidal in nature. They have activity against a broad range of gram positive and negative
organisms. The drugs in this class are uniformly active against the Enterobacteriaceae, and
many strains of Listeria, Chlamydia, and mycobacteria. The newer quinolones have enhanced
activity against staphylococci, streptococci and anaerobes.23 In general, the older generation
compounds have more activity against gram negative bacteria and provide less gram positive
coverage. The converse is true with 3rd and 4th generation fluoroquinolones which
demonstrate an expanded spectrum against gram positive organisms. In regards to their
activity against Mycobacterium tuberculosis, moxifloxacin and gatifloxacin demonstrate more
potent in vitro activity than ciprofloxacin or levofloxacin.24
Expanded use of the fluoroquinolones brings with it increasing concern for the
development of microbial resistance. There are several potential mechanisms for the
development of resistance. These include the development of mutations in the genes that
encode bacterial topioisomerase II and IV (which result in altered binding affinity of the drug
and reduced action) and the development of bacterial efflux transporters (which reduce
intracellular drug exposure). A plasmid carrying the gene qnrA has also been discovered
which leads to an inherent mechanism of resistance.14
As with most antimicrobial agents, a primary determinant of fluoroquinolone efficacy
resides with obtaining a sufficient exposure of the offending pathogen to the drug for a
sufficient time for it to have its intrinsic biological effects. Thus, the application of
pharmacodynamic principles (eg., the relationship between drug intrinsic activity, attained
concentration-time profile and host factors) has become an important tool when selecting
antibiotics.23 This is especially true for the fluoroquinolones as reflected by in vivo studies
which have examined the exposure-response relationship using the pharmacodynamic
surrogate of the ration of the area under the plasma concentration vs. time curve (AUC, a
parameter reflecting general systemic exposure) and the minimum inhibitory concentration
(MIC).
In studies examining the pharmacodynamics of ciprofloxacin in seriously ill patients,
investigators determined that an AUC/MIC below 125 was associated with inadequate
antibacterial activity, a ratio between 125-250 was associated with “acceptable” activity and
that an AUC/MIC between 250-500 produced optimal antibacterial activity.9 Also, the
attainment of peak serum concentration to MIC ratios of ≥ 10:1 for fluoroquinolones has
been shown to increase the probability of successful treatment outcomes as well as reduce the
frequency of emerging resistant pathogens during therapy. While the aforementioned
pharmacodynamic optima (ie. AUC/MIC of > 125 and Cmax:MIC ratio of ≥ 10:1) appear
reasonable based on data from critically ill adult patients with gram negative respiratory
infection, they appear to be different for other conditions where fluoroquinolones might be
used. For example, in adult outpatients with community acquired respiratory infections
caused by Streptococcus pneumoniae, an AUC/MIC ratio of ≥ 25 appears predictive of
3
bacterial eradication.16 Thus, treatment strategies and the prospective design of
fluoroquinolone dosing regimens are best accomplished using a target exposure strategy
which is based upon pharmacodynamic principles, knowledge of both host factors and
microbial susceptibility and an understanding of the pharmacokinetic properties of a given
agent.
The pharmacokinetics of many of the available fluoroquinolone antibiotics have been
previously characterized in both adult and pediatric patient populations.16 As a class, these
agents are rapidly absorbed from the small intestine and their bioavailability is quite high,
ranging from 70 to 95%. 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
concurrent ingestion with food. They demonstrate relatively low binding to circulating
plasma proteins and as a result of their excellent penetration into tissue, 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).11 The biotransformation of the
fluoroquinolones is drug dependent with many of the early generation compounds (eg.,
ciprofloxacin) being extensively metabolized in the liver as compared to later generation
compounds (eg., levofloxacin, gatifloxacin, gemifloxacin) which are predominantly excreted
unchanged in the urine.24 As compared to early generation compounds, the newer
fluoroquinolones (i.e. gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) generally have
longer elimination half lives 16 which facilitates the use of longer dosing intervals.
As a direct result of their relatively restricted use in pediatric patients, there is a
relative paucity of pharmacokinetic data for the fluoroquinolones generated from populations
of infants and children with the exception of studies conducted in patients with cystic fibrosis.
A previous review concerning the clinical pharmacology of the fluoroquinolones in pediatric
patients has denoted that the systemic clearance of drugs within this class may be increased in
young children.19 This phenomenon appears to be quite compound dependent. As reviewed
by Algasham and Nahata, 1 the average elimination half life of ciprofloxacin in children
appears to be shorter than reported from studies in adults and consequently, supported a need
for thrice daily dosing. 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 AUC (ie., higher systemic exposure from a given dose which infers reduced plasma
clearance). As well, the oral bioavailability of ciprofloxacin in younger children has been
reported to be reduced as compared to older children and young adults. 1
Similar to ciprofloxacin, the pharmacokinetics of levofloxacin appear to be age
dependent. As reported by Chien, et al. 6, levofloxacin elimination (as reflected by apparent
elimination half life plasma clearance) in children aged five years and younger appeared to be
significantly different from values obtained in older children and from historical data
generated in an adult cohort. The summary data are presented in the following table:
Summary of Levofloxacin Pharmacokinetic Estimates in Pediatric and Adult Subjects
Receiving a Single Intravenous Dose (7 mg/kg) of Levofloxacin [adapted from Chien S, et al.
2005]
4
Age Group
Cmax
t1/2
AUC
Vss
CL
CLR
(μg/mL)
(h)
(μg•h/mL)
(L/kg)
(L/h/kg)
(L/h/kg)
Pediatric subjects, Single IV dose, 7 mg/kg
0.5−2 y
(n=6)
5.19±1.26
4.1±1.3
21.5±6.12
1.56±0.30
0.35±0.13
NA
2−5 y
6.02±1.07
4.0±0.8
22.7±4.66
1.50±0.21
0.32±0.08
NA
5−10 y
(n=9)
6.11±0.88
4.8±0.8
29.2±6.40
1.57±0.44
0.25±0.05
0.18±0.07
10–12 y
(n=7)
6.12±1.19
5.4±0.8
39.8±11.3
1.44±0.35
0.19±0.05
0.15±0.06
12−16 y
(n=11)
6.15±1.55
6.0±2.1
40.5±7.56
1.56±0.53
0.18±0.03
0.11±0.04
48.3±5.40
1.27±0.12
0.15±0.02
NA
(n=7)
Adults, Single IV dose, 500 mg*
18–45 y
(n=23)
6.18±1.04
6.0±1.0
NA = Not Available
All data presented as Mean±Standard Deviation
*Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Data on file.
The almost two-fold difference in levofloxacin clearance observed in this study between
infants and children less than five years and those > 12 years of age led the authors to
recommend a dose of 10 mg/kg every 12 hours for infants and young children (as opposed to
a dose of 10 mg/kg daily for adolescents and adults) so as to enable attainment of a systemic
exposure likely to produce desired antimicrobial effect. Finally, this study reported similar
plasma concentration vs. time profiles for levofloxacin in children receiving oral and
intravenous doses of the drug which suggested excellent oral bioavailability of the liquid
formulation in pediatric patients.
In contrast to the previous data on ciprofloxacin and levofloxacin, gatifloxacin does
not appear to have age-dependent pharmacokinetics. In a study of 76 pediatric patients (age
range 0.5 to 16 years) who received a single oral dose of gatifloxacin suspension of 5, 10 or
15 mg/kg (maximum dose 600 mg), Capparelli, et al.4 did not find a statistically significant
association between age and either the apparent oral clearance (mean±SD value = 5.5±2.1
ml/min/kg) or plasma elimination half life (5.1±1.4 hr). As well, these authors reported an
apparent proportional relationship between gatifloxacin dose and AUC, and comparable
relative oral bioavailability of the suspension and tablet formulation of the drug. Data from
this study supported a recommendation for gatifloxacin dosing of 10 mg/kg every 24 hours in
both infants and children to attain potentially therapeutic systemic exposures.
5
III. Data on safety and use of fluoroquinolones in children
Soon after the first generation of quinolones was introduced, preclinical studies
conducted in experimental animals (Beagle dogs) demonstrated damage to articular cartilage
in weight-bearing joints.7 This adverse effect continues to limit fluoroquinolone general use
in pediatric patients consequent to a concern that similar effects (eg., damage to growth plate
cartilage) might occur in growing children. Case reports of tendinitis and tendon rupture have
also been reported in association with fluoroquinolone use. 7, 10, 12
Fluoroquinolone-associated tendon disorders are more likely to occur in the elderly
(>60 years of age) with the Achilles tendon being the most common site affected. The time of
onset of tendon symptoms following the initiation of treatment generally develops during the
first 1-2 weeks following initiation of therapy while tendon rupture occurs within 2-3 weeks.12
In a case-control study by van der Linden et al, 22 the risk of Achilles tendon disorders
associated with fluoroquinolone exposure was found to be relatively rare, with an overall
excess risk of 3.2 cases per 1000 patient years. The concomitant use of corticosteroids appears
to substantially increase the risk.
A review of the literature reveals several large, retrospective studies evaluating the
adverse events observed with fluoroquinolone use in children. Chuen et al. 7 performed a
retrospective, observational study to assess the incidence and relative risk of tendon or joint
disorders that occurred following the use of ofloxacin, levofloxacin, and ciprofloxacin. This
study involved greater than 6000 children < 19 years of age with history of fluoroquinolone
exposure and a “control group” of children exposed to azithromycin, a macrolide antibiotic
which does not have known effects on cartilage, tendons or joints. The calculated risk for
tendon or joint disorders was found to be no different in the children treated with
fluoroquinolones when compared to those prescribed azithromycin.
Chalumeau, et al. 5 reported results from a multicenter, observational, cohort study
conducted in France which compared potential adverse events in a pediatric population of 276
pediatric patients who received fluoroquinolones and 249 “control” patients who received an
antimicrobial other than a fluoroquinolone. Although short-term potential adverse events did
occur more frequently in association with fluoroquinolone treatment, all events were transient
and no severe or persistent musculoskeletal lesions were observed. The most common
potential adverse event involved the gastrointestinal tract followed by the musculoskeletal
system, the skin and the CNS. In this patient cohort, musculoskeletal adverse events were
more frequently associated with pefloxacin (18.2%) than ciprofloxacin (3.3%).5 A
comparative study of levofloxacin in the treatment of children with community acquired
pneumonia demonstrated cure rates and safety profiles that were comparable to the other
antibiotics used in the study.3
Noel, et al. 15 examined the comparative safety profile of levofloxacin in a cohort of
2,523 children treated with the drug from three large multi-center efficacy trials. Spontaneous
(un-blinded) reports of one or more musculoskeletal events (arthritis, arthralgias,
tendinopathy, gait abnormality) within sixty days of starting therapy were higher in
levofloxacin-treated children when compared with those treated with non-fluoroquinolone
antibiotics. The majority of musculoskeletal disorders reported were episodes of arthralgias in
weight-bearing joints. Five participants from the levofloxacin group who had musculoskeletal
complaints underwent either CT or MRI which failed to reveal any apparent structural
abnormalities. As well, the data failed to reveal an association with long-term joint
abnormalities or growth impairment and levofloxacin exposure.15
Other relatively rare but serious toxicities have been associated with fluoroquinolone
use including: prolonged QT interval, photosensitivity, and acute liver failure. 14 The
6
frequency of their occurrence in pediatric patients can only be inferred from spontaneous
reports emanating from use of these agents in adults.
IV. Place of therapy for fluoroquinolones in pediatrics
Despite concerns of possible adverse effects, fluoroquinolones are being used in
infants and children. In 2002, there were approximately 520,000 fluoroquinolone
prescriptions written 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.8 In
most instances, the use of fluoroquinolones in pediatric patients is limited to specific clinical
settings where their pharmacologic attributes are felt by the prescriber to outweigh potential
risks for drug-associated adverse events. Examples of clinical settings where these drugs are
felt to have utility include 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.10 Further delineation of fluoroquinolone use in pediatrics has been
provided by the American Academy of Pediatrics through a published policy statement which
recommended that their use be limited to the following: 1) exposure to aerosolized Bacillus
anthracis 2) urinary tract infections caused by Pseudomonas aeruginosa or other multi-drug
resistant, gram-negative bacteria 3) chronic suppurative otitis media or malignant otitis
externa caused by Pseudomonas aeruginosa 4) osteomyelitis or osteochondritis caused by
Pseudomonas aeruginosa 5) exacerbation of pulmonary disease in patients with cystic
fibrosis who have colonization with Pseudomonas aeruginosa and can be treated in an
ambulatory setting 6) mycobacterial infections caused by isolates known to be susceptible to
fluoroquinolones 7) Gram-negative bacterial infections in immunocompromised hosts in
which oral therapy is desired or resistance to alternative agents is present 8) gastrointestinal
tract infection caused by multidrug-resistant Shigella species, Salmonella species, Vibrio
cholerae, or Campylobacter jejuni 9) documented bacterial septicemia or meningitis due to
organisms with in vitro resistance to approved agents or in immunocompromised infants and
children in whom parenteral therapy with other appropriate antimicrobial therapy has failed
and 10) serious infections attributable to fluoroquinolone-susceptible pathogen(s) in children
with life-threatening allergy to alternative agents.8
The clinical use of fluoroquinolones in children has been reviewed by Alghasham and
Nahata.1 As denoted in the summary table below, there is ample evidence to support the
utility of ciprofloxacin in the treatment of acute pulmonary exacerbations in patients with
cystic fibrosis where treatment has been associated with improved clinical outcomes. There
also appears to be a role for this drug as part of maintenance therapy this particular patient
population.
7
* Citations to primary literature available in review by Alghasham and Nahata.1
Several efficacy studies of fluoroquinolones have also been performed in children with
gastrointestinal infections caused by multi-drug resistant salmonellosis or shigellosis.
Summarized results from these previously published studies 1 are contained in the following
table. Collectively, clinical outcome data reveal a very high cure rate without the risk of
relapse.
8
* Citations to primary literature available in review by Alghasham and Nahata.1
Fluoroquinolones penetrate well into the cerebral spinal fluid where the concentration
can exceed 50% of the corresponding plasma drug concentration. This pharmacokinetic
property in addition to the broad spectrum of antimicrobial activity has resulted in the use of
these agents to treat meningitis caused by susceptible pathogens. While outcome data for this
potential therapeutic indication are limited, there are case reports of effective treatment of
meningitis with intravenous fluoroquinolones in pediatric patients.1 It has also been shown
that a single dose of oral ciprofloxacin can successfully eradicate the nasopharyngeal carriage
of Neisseria meningitidis to prevent the development of meningococcal disease.1
Fluoroquinolones continue to be evaluated as a treatment option in the setting of
tuberculosis (TB) given the prevalence of the disease, its associated mortality and the fact that
resistance to first line anti-mycobacterial drugs is commonplace. 21 As well, given that the
9
development of new drugs for the treatment of TB is slow, established drugs such as the
fluoroquinolones are being revisited as possible therapeutic options.
Currently, the fluoroquinolones are registered as second-line agents for TB therapy.
Moxifloxacin and gatifloxacin have the lowest MICs and have shown the greatest bactericidal
activity against M. tuberculosis. The potential of moxifloxacin and gatifloxacin to shorten TB
treatment is currently being investigated in clinical trials.2
An evaluation of treatment of drug-resistant tuberculosis demonstrated that an
aggressive, comprehensive management program can cure more than 60% of patients with
extensively drug-resistant tuberculosis who are not HIV infected but who had received
previous unsuccessful anti-tuberculosis treatments. As recently reviewed by Mitnick, et al. 13
fluoroquinolones (and particularly, moxifloxacin and levofloxacin) have an important
therapeutic role in the treatment of multidrug-resistant tuberculosis.13 While there is limited
in vivo efficacy data which characterizes the utility of this class of antimicrobials as second
line tuberculosis treatment, a small prospective, randomized trial of moxifloxacin exhibited
bactericidal activity that was comparable to that of isoniazid as assessed by a reduction of
mycobacterium in the sputum following therapy.17
V. Potential Places in Pediatrics for Fluoroquinolones
In general, the fluoroquinolones remain an appealing class of antimicrobials due to
their wide availability, desirable pharmacokinetic characteristics (eg., availability of
formulations that enable flexible, accurate dosing over the entire pediatric age spectrum, good
and predictable oral absorption, extensive tissue penetration), their broad antimicrobial
spectrum (including effectiveness against multi-drug resistant organisms) and their generally
excellent safety profile. Large retrospective studies as mentioned above have demonstrated
efficacy and safety with documented adverse events being reversible with cessation of the
drug.
Although concerns remain about the potential of adverse cartilaginous effects on the
young child, recent studies have not shown a significant increase in risk for children who are
treated with fluoroquinolones. As denoted above, the complete evaluation of
fluoroquinolone-associated joint involvement has been difficult to address given that
spontaneous reports have been generally subjective with no biopsy or imaging data available
to confirm structural injury. Also, there have been no large, randomized control trials in
children which would be required to critically evaluate the safety of the fluoroquinolones in
pediatric patients.
In a commentary published in The Pediatric Infectious Disease Journal, Prof. Urs
Schaad stated that “the triad of feared arthrotoxicity, potential bacterial resistance explosion
and enormous requirements regarding adequate study and postmarketing control makes it
unlikely that fluoroquinolones will ever be recommended for common infections in
children.”20 Such an assertion could certainly be valid for developed counties where
alternative antimicrobial agents, many of them more well studied in children than the
fluoroquinolones, are widely available for consideration as first-line treatment for common
childhood infectious diseases. In contrast, for areas of the world with restricted medical
resources, the fluoroquinolones offer an attractive alternative for the treatment of serious
infections, especially when situations either preclude parenteral drug administration or make
it extremely difficult to provide. This is especially true for infections that have not responded
to standard care (eg, patients with HIV disease and associated immunocompromise) and for
those caused by pathogens where multiple drug resistance is a common problem (eg,
tuberculosis). Though more data from controlled trials to further define the efficacy and
10
safety profile for this class of drugs in pediatric patients are desirable, existing information is
sufficient to support their selection and to develop appropriate paradigms for their use in
infants and children. General wide availability of the fluoroquinolones for use in pediatric
patients guided by clear medical rationale and coupled with careful therapeutic monitoring is
recommended. This will result in an appropriately expanded therapeutic armementarium for
pediatric patients capable of significantly improving the outcome for those with life-treatening
infections.
11
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13