US Pharm. 2012;37(8):56-59.
In the use of medications—particularly antibiotics—in pediatric
patients, it is imperative to remember that pharmacokinetic and
pharmacodynamic processes may be different in children compared with
adults. These physiological changes can result in unfavorable outcomes
for the pediatric patient. This article aims to outline those changes,
focusing on the use of two antibiotic classes historically
contraindicated in children: fluoroquinolones and tetracyclines.
Physiological Changes in Pediatric Patients
Throughout childhood, significant changes in the absorption,
distribution, metabolism, and excretion of medications take place,
thereby necessitating age-dependent dosage adjustments.1 Drug
absorption is largely affected by developmental transformations, such
as changes in gastrointestinal pH, or by lung development, in the case
of inhaled antibiotics.1 Reduced protein binding can result
in an increased half-life for certain antibiotics. Changes in the
expression of individual CYP450 enzymes, phase II metabolism, and renal
function significantly alter the metabolism and plasma clearance of
numerous antibiotics.1-3 Specific examples of pharmacokinetic changes and their effects on various medications are given in TABLE 1.
Although numerous pharmacokinetic differences in pediatric patients are
known, little information has been published concerning pharmacodynamic
Because of their excellent tissue penetration and broad spectrum of
activity, fluoroquinolones have become a staple of antimicrobial
pharmacotherapy for adult patients. The first fluoroquinolone, nalidixic
acid, was introduced in 1964 and for the last two decades has been
approved for the treatment of urinary tract infections (UTIs) in
children aged 3 months and older; however, it is rarely used.4,5
The more commonly used fluoroquinolones ciprofloxacin and levofloxacin
were approved for use in children solely for the postexposure treatment
of inhalation anthrax prior to 2004.4,5 In 2004, ciprofloxacin gained approval for treatment of complicated UTIs and pyelonephritis in children aged 1 to 17 years.5 Currently, moxifloxacin is not approved for pediatric use.5
Although the last decade has seen increasing use of fluoroquinolones in
the pediatric population, significant controversy exists.
Controversy: Fluoroquinolones have demonstrated
adverse effects on cartilage development in juvenile animals through the
inflammation and destruction of weight-bearing joints.4,5
These arthropathies were often irreversible, and their potential
occurrence in children limited the use of fluoroquinolones in this
population.4 In one pediatric study, ciprofloxacin had a 3.3%
(9.3% vs. 6.0%) absolute risk increase in musculoskeletal events within
6 weeks of treatment compared with control agents used to treat
complicated UTIs or pyelonephritis.4 Adefurin and colleagues
found a 57% increased relative risk of arthropathy in children given
ciprofloxacin (21% overall) versus those in a nonfluoroquinolone
comparator arm.6 In contrast to animal models, neither dose nor duration had an effect on the rate or severity of arthropathy.6
A 2007 study by Noel and colleagues determined the incidence of
musculoskeletal events (primarily arthralgias) to be greater in children
treated with levofloxacin compared with nonfluoroquinolone-treated
children at 2 months (2.1% vs. 0.9%; P = .04) and 12 months (3.4% vs. 1.8%; P = .03).7
These results and the severity of the effects should be weighed heavily
when initiation of fluoroquinolones is being contemplated in pediatric
Another significant concern with fluoroquinolone use is increased
bacterial resistance. Resistance patterns to fluoroquinolones, which
have consistently worsened in adults over the last 20 years, can occur
via multiple mechanisms, such as changes in target enzymes (DNA gyrase
and DNA topoisomerase) or the expression of efflux pumps.4,5,8,9
The synthesis of newer fluoroquinolones, such as moxifloxacin, created
expectations that resistance to gram-positive bacteria would be limited.
However, resistance is often considered a class effect and may become a
significant concern in the pediatric population with continued use.
Potential Benefits: Fluoroquinolones have been
used successfully in a variety of pediatric infections, including cystic
fibrosis exacerbations, complicated UTIs, and otitis media.4 Use in children with neutropenic fever or multidrug-resistant gram-negative infections has also increased.4
However, most of the literature supporting the use of fluoroquinolones
in children comes from retrospective or small, uncontrolled studies.
Evidence of fluoroquinolone-induced arthropathies in pediatric
patients is well documented, but no cases of clinician-diagnosed
cartilage destruction in children have been noted in either controlled
clinical trials or unsolicited FDA reports.5 Additionally,
one retrospective study involving more than 20,000 children demonstrated
no significant difference in joint or tendon disorders with
fluoroquinolones versus azithromycin.10 Although
fluoroquinolones carry a black box warning regarding tendon rupture,
there are no published reports of this adverse event in children.5,11
Regarding fluoroquinolone resistance, the overall resistance pattern
in pediatric gram-negative isolates (excluding cystic fibrosis patients)
has been documented at less than 5%.12 However, it is likely that resistance rates will rise with increased pediatric fluoroquinolone use.8
Tetracyclines: Tetracyclines are a class of
broad-spectrum antibiotics with activity against gram-positive,
gram-negative, anaerobic, acid-fast (atypical), and Rickettsia bacteria.13
Useful for numerous infections, tetracyclines were first introduced in
1948, with initial concerns of tooth discoloration in children being
reported in 1956.14 This adverse event is most likely during the tooth-calcification process, which is completed by age 8 years.15 Other adverse events include light hypersensitivity, gastrointestinal effects, and rare hepatotoxicity.13
Despite these adverse events, tetracyclines have been successfully used
for respiratory infections, community-acquired methicillin-resistant Staphylococcus aureus,
malaria, and acne in patients aged 8 years and older. However,
tetracyclines are relatively contraindicated in children aged less than 8
years, and their use in this age group is examined in the following
Controversy: The routine use of tetracyclines in
children aged less than 8 years is not recommended because of a
long-standing association of these agents with permanent tooth
discoloration. Tetracyclines, which bind to cations, can result in the
formation of tetracycline–calcium complexes that irreversibly deposit in
developing bones and teeth.16 Once calcification is
complete, no further calcium exchange occurs, which limits
tetracycline’s ability to deposit in the teeth.15 The degree
of tetracycline exposure, number of courses, total dosage, and exact
timing of tooth development may affect the risk of occurrence.15-17
Staining may vary by agent, with doxycycline potentially having the
lowest incidence owing to its decreased affinity for calcium binding
compared with other tetracyclines.16,18 Volovitz and
colleagues reported no cases of tooth discoloration in a study of 31
children (mean age 4 years) treated with doxycycline for atypical
Tetracycline-induced photosensitivity, another adverse event in the
pediatric population, usually manifests as a light-sensitive rash
similar to an exaggerated sunburn. This occurs because of the extensive
absorption of ultraviolet light by the tetracyclines.20 In a
study of 106 adults and children treated for acne, Layton and colleagues
reported a 36% incidence of light-sensitive rash from doxycycline, with
increased risk at higher doses (>150 mg/day) and in subjects with
While phototoxicity can be a significant concern, the permanent
nature of tooth discoloration underscores the importance of avoiding the
use of these agents in young children whenever possible. However, when
tetracycline use is imperative, limited evidence suggests that
minimizing the total dose and length of exposure and using a
tetracycline with decreased calcium binding may reduce the risk of tooth
Potential Benefits: In certain
difficult-to-treat infections with limited alternative therapies,
tetracycline may be efficacious and relatively safe in children aged
less than 8 years. Tetracyclines are useful for the treatment of both
Rocky Mountain spotted fever (RMSF) and ehrlichiosis, a separate
rickettsial disease that can mimic RMSF and should be empirically
covered whenever RMSF is suspected.22 Additionally, a
retrospective study suggested that chloramphenicol, the only other
antibiotic with activity against RMSF, may be less effective than
doxycycline, with a fatality rate of 8.9% versus 1.6% in the doxycycline
group.23 Given the adverse effects of chloramphenicol,
including peripheral neuropathy and aplastic anemia, tetracyclines may
be considered a more desirable option for RMSF even in children aged
younger than 8 years.
Another indication for the use of tetracyclines and fluoroquinolones in children is the treatment of Bacillus anthracis infection or exposure.24
While penicillin can be efficacious, it should be used only in cases
where the susceptibility of the isolates is known, leaving the choice of
empiric therapy to ciprofloxacin or doxycycline.24 In
deciding which agent to use, the potential risk factors of the foregoing
medications should be weighed against patient-specific concerns.
Current Recommendations on Pediatric Fluoroquinolone and Tetracycline Use
The 2006 American Academy of Pediatrics (AAP) recommendations on
fluoroquinolones limit their use to three major circumstances: 1)
FDA-approved indications; 2) multidrug-resistant pathogens with no safe
or effective alternative; and 3) oral fluoroquinolone sensitivity when
all other options are IV only (see dosing recommendations, TABLE 2).4
Fluoroquinolones may be considered in pediatric patients with acute
otitis media, sinusitis, lower respiratory tract infections, pneumonia,
gastrointestinal infections, or Mycobacterium infections.5
Additionally, topical fluoroquinolones are approved and recommended for
acute conjunctivitis in children aged older than 12 months and for
The AAP recommends the use of tetracyclines in infections where the
benefits outweigh the risks of adverse events. These include rickettsial
infections such as RMSF or ehrlichiosis, and other infections such as
cholera and anthrax.25 The AAP suggests the use of
doxycycline specifically in these patients, as it has a lower risk of
dental staining with less frequent dosing intervals (see dosing
recommendations, TABLE 3).25 Additionally, the CDC recommends doxycycline or ciprofloxacin for any patient with B anthracis infection or exposure.24
In children, the pharmacokinetic and pharmacodynamic processes of
many drugs, especially antibiotics, may be different compared with those
in adults. These physiological changes can result in unfavorable
outcomes for the pediatric patient. Because of the ongoing safety
concerns surrounding the use of fluoroquinolones and tetracyclines in
children, these agents should continue to be limited to treatment of
FDA-approved indications or for infections for which no safe and
effective alternative exists.
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