Reviews

Fluoroquinolones in paediatrics: a risk for the

patient or for the community?
Dominique Gendrel, Martin Chalumeau, Florence Moulin, and Josette Raymond

Temperature (C)

Fluoroquinolones are an important group

40
of antibiotics widely used in adult patients
because of their excellent tissue
Ceftriaxone
penetration and their bactericidal activity.
They are not authorised for paediatric use
Ciprofloxacin
(except the limited indication of
39
pseudomonas infections in cystic
fibrosis), however, because of the
potential for joint toxicity reported from
experiments with young animals. Despite
S..., 8 y from India
the absence of official approval,
Blood culture: Salmonella typhi
38
fluoroquinolones are widely used in
paediatrics as second-line antibiotics
when all other treatments have failed.
Most of the information available about
paediatric use concerns ciprofloxacin,
37
which is used in children much more
often than the other members of this
0
1
2
3
4
5
6
7
8
9
10
Days
class. The published paediatric series
have shown that frequency of articular
side-effects varies according to age: all Typhoid fever in a young child from India, treated in Paris, infected with S typhi sensitive to all
the surveys have reported frequencies of antibiotics.
around 01% in adults and 23% in
children. Outside of cystic fibrosis and severe infections in indications to paediatrics because of the articular disorders
which no other treatment is possible, the only paediatric reported in growing animals during experimental toxicity
situations where fluoroquinolones are superior to standard trials. These articular problems have been seen in clinical
treatments for children, in speed of recovery and comfort as practice when these drugs have been used in children.15
well as in efficacy, are typhoid fever, severe shigella
Nalidixic acid, the only non-fluorinated quinolone in use,
dysenteries, and enterobacteria meningitis. Should the use was first marketed in 1962. Its side-effects, including articular,
of new fluoroquinolones active against pneumococci be are more numerous than those reported for fluoroquinolones,
authorised for upper respiratory infections (including but the regulatory requirements for approval then were less
recurrent otitis) in children, the potential emergence and strict than today.6,7 Nalidixic acid remains a treatment recomdissemination of pneumococci strains in which multidrug mended by WHO for shigellosis in children. Of the fluororesistance includes fluoroquinolones would create a real risk quinolones, only ciprofloxacin has been approved for use in
in the community. It is, therefore, important to continue the children, but only in some countries and in limited situations.
policy of second-line use in children, only after failure of an Ciprofloxacin is particularly effective on Pseudomonas
earlier treatment, and when other antibiotics approved for aeruginosa, and in France is authorised for use in P aeruginosa
paediatric use cannot be used.
respiratory infections in patients with cystic fibrosis.
Lancet Infect Dis 2003; 3: 53746

Soon after their introduction in the 1980s, fluoroquinolones

became one of the major classes of antibiotics among adults.
Their strong activity against Gram-negative bacteria, excellent
diffusion throughout tissue, and especially the ease of their
oral administration justify this widespread adoption. They
remain, however, contraindicated in children, except for
specific situations. The pharmaceutical companies that
market fluoroquinolones decided not to seek to extend their
THE LANCET Infectious Diseases Vol 3 September 2003

Despite the absence of official approval, fluoroquinolones

are widely used in paediatrics. In the USA the number of
annual ciprofloxacin prescriptions for patients younger than
18 years is estimated at 150 000, 20% of them for children
DG and MC are at the Department of Paediatrics; FM is at the
Department of Emergency Medicine; and JR is at the Department of
Bacteriology, Hpital Saint Vincent de Paul-Cochin, Paris, France.
Correspondence: Professeur Dominique Gendrel, Hopital Saint
Vincent de Paul, 82 Avenue Denfert-Rochereau, 75014 Paris,
France. Tel +33 (0)1 40488167; fax +33 (0)1 40488386;
email dominique.gendrel@svp.ap-hop-paris.fr

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537

Review

Fluoroquinolones in paediatrics

Table 1. Principal paediatric and adult studies on the side-effects of fluoroquinolones

Author

Year

Pediatric studies
Black9
1990

Location

Methodology

Belfast, UK

Compound

Age
Diseases
(years)

Number Side-effects*

Articular
side-effects*

Retrospective, Ciprofloxacin
Multicentre,
Uncontrolled
Retrospective, Ciprofloxacin
Multicentre,
Uncontrolled

117

Cystic fibrosis,
immunocompromised

202

27%

2%

017

Miscellaneous

634

13%

1%

Chysky10

1991

International
register, Bayer

Dab11

1992

Brussels
Belgium

Retrospective, Ciprofloxacin
Multicentre,
Uncontrolled

318

Cystic fibrosis

35

22%

9%

Hampel12

1997

International
register, Bayer

Retrospective, Ciprofloxacin
Multicentre,
Uncontrolled

017

Miscellaneous

2030

11%

2%

Leibovitz13

2000

Beer Sheva
Israel

Prospective,
One centre,
Controlled,
Randomised,
Double blind,
vs ceftriaxone

Ciprofloxacin

011

Invasive diarrhoea

95

14%

1%

Chalumeau14

2003

France

Prospective,
Multicentre,
Controlled,
Open-label

Ciprofloxacin,
ofloxacin,
pefloxacin

015

Miscellaneous

276

20%

4%

Adult studies
Ball15

1995

International,
phases I to IV,
Bayer

Prospective

Ciprofloxacin

Adults

Miscellaneous

>10 000 56%

00102%

Rahm16

1989

International,
Prospective
phases II and III,
Bayer

Ciprofloxacin

Adults

Miscellaneous

8861

01%

10%

*% of exposed patients. number of fluoroquinolone treatment/patient >1. versus 5% in ceftriaxone group, or 32 [10108], p=003. versus 5% in other antibiotics group, or
37 [1975], p <00001.

younger than 1 year.8 Few prospective series assessing

ciprofloxacins side-effects have been published,3,4 primarily
because it is most often used off-label (that is, for
indications neither tested by the manufacturer nor approved
by drug regulatory agencies) when all other treatments have
failed. Most of the information available about paediatric use
concerns ciprofloxacin, which is used in children much more
often than the other members of this class (table 1).
The rate of antibiotic use in community medicine is
clearly related to the increase in bacterial resistance, as shown
for resistance of pneumococci to penicillins and macrolides in
Europe.17,18 It is also true for the fluoroquinolones, as
Escherichia coli surveillance in Spain has shown.19
Pneumococci resistance to fluoroquinolones in adults
remains modest but is growing.20 Few adults, however, have
prolonged rhinopharyngeal pneumococci colonisation, but
young children do. For them, inter-individual transmission of
multidrug-resistant pneumococci in group settings is almost
inescapable.20,21 The appearance of a third generation of
fluoroquinolones more active against Gram-positive germs
and especially against pneumococci, is likely to increase their
use in paediatrics, in particular in young children with
recurrent otitis. There is thus a major risk that
fluoroquinolone-resistant pneumococci will spread further.21
Fluoroquinolone use in paediatrics thus presents two

538

risks, neither of which is adequately assessed: side-effects in

children, the precise frequency of which is not well known,
and the risk of generalising pathogens common in children to
the entire community so that they become resistant to
fluoroquinolones.

Antibacterial properties
The fluoroquinolones developed during the 1980s
pefloxacin, ciprofloxacin, and ofloxacinare especially
active against enterobacteria and meticillin-sensitive
Staphylococcus aureus; ciprofloxacin is also highly effective
against P aeruginosa.2224 The most recent fluoroquinolones,
developed at the end of the 1990slevofloxacin,
trovafloxacin, and now moxifloxacin and gatifloxacinare
more active than their predecessors against pneumococci
and, in general, against Gram-positive cocci.20,21
Fluoroquinolones exert their inhibitory effect by binding to
the topoisomerases of the bacteria, essential for replication
of DNA. These drugs target two of the four topoisomerases
that have been identified: topoisomerase 2 (also called DNA
gyrase) and topoisomerase 4. DNA gyrase contains four
subunits, two of which are coded by the gyrA and gyrB genes.
The structure of topoisomerase 4 is the same, with two
subunits coded by the parC and parE genes.
Fluoroquinolone resistance occurs after mutations of the

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Review

Fluoroquinolones in paediatrics

genes coding for these topoisomerases. In resistant Gramnegative bacteria, this stage usually involves a primary
mutation of the gyrA gene, and resistance to one
fluoroquinolone generally signifies resistance to all. It is thus
sufficient to test only one fluoroquinolone in vitro (for P
aeruginosa, only ciprofloxacin is effective). On the other
hand, for the Gram-positive cocci, fluoroquinolone
resistance results from the addition of mutations, first of the
parC gene and then the gyrA gene, sometimes with still other
mutations. The rate of resistance increases with the number
of mutations, and resistance to one fluoroquinolone does
not involve resistance to all others. For Gram-positive
bacteria, each of the various quinolones should be tested
separately in vitro. Gatifloxacin and moxifloxacin can
sometimes be more active in strains with a simple parC gene
mutation, especially in pneumococci. Fluoroquinolone
resistance of Gram-positive bacteria is thus evident after
successive mutations, and the resistant clones can spread
rapidly throughout a community or a wider geographic
region. An efflux mechanism can cause a low rate of
resistance in all bacterial species. No plasmid-mediated
resistance has been described.
Moxifloxacin and gatifloxacin act more effectively
against anaerobic bacteria than other fluoroquinolones.20,21
Haemophilus
influenzae,
Mycoplasma
pneumoniae,
Chlamydia pneumoniae, and Legionella pneumophila are
uniformly sensitive to all fluoroquinolones and do not
require routine sensitivity testing.
Their strong intracellular penetration makes this drug class
effective against bacteria that grow intracellularly, principally
salmonella and mycobacteria. Nonetheless the different
fluoroquinolones vary in their rate of cell permeation, which is
often measured by intracellular penetration in granulocytes:
their in-vivo activity against intracellular microbes is not
always identical to that measured in vitro.
The classic fluoroquinolones are active against 90% of
the strains of enterobacteria and Gram-negative germs
encountered in the community.2224 Resistance to them is
increasing progressively, however, and depends mainly on
whether the strain comes from the community or has a
nosocomial origin, but also on its geographic source. In
Spain, the number of E coli resistant to fluoroquinolones in
community-acquired urinary tract infections among adults
is growing substantially: 9% in 1992 and 17% in 1996.19 The
prevalence of ciprofloxacin-resistant E coli in France is
approximately 10%. For P aeruginosa, 6080% of strains
are sensitive to fluoroquinolones. In France, that frequency
is approximately 60%. In general, except for patients with
cystic fibrosis, 36% of the strains isolated are resistant to
ciprofloxacin; in those patients, 59% of the strains are
sensitive, 22% intermediate, and 19% resistant.2224 A
problem currently causing concern is the emergence of
fluoroquinolone-resistant salmonella strains worldwide.
Resistant strains of Salmonella typhi have been described, in
particular in Vietnam, as well as resistant non-typhoid
salmonella in other parts of the world.2528 The broad use of
fluoroquinolones for community-acquired diseases and
their addition to animal feed contribute substantially to the
emergence of resistance.5,29
THE LANCET Infectious Diseases Vol 3 September 2003

Many Gram-positive bacteria are sensitive to

fluoroquinolones, including meticillin-sensitive communityorigin staphylococcus. But a substantial proportion of
nosocomial S aureus infections are also resistant to
ciprofloxacin and to other fluoroquinolones: in France in
1984, 4% of the meticillin-resistant S aureus were resistant to
pefloxacin and in 1995, 99%.24 This fluoroquinolone
resistance concerns mainly coagulase-negative staphylococci,
often the cause of infection in premature babies
and immunocompromised individuals: the rate of
fluoroquinolone resistance can reach 20%.
Many penicillin-resistant pneumococci are sensitive
to the more recent fluoroquinoloneslevofloxacin,
sparfloxacin, moxifloxacin, gatifloxacin, and gemifloxacin
which are more active against them than are ciprofloxacin or
pefloxacin.20 The progressive emergence of fluoroquinoloneresistant pneumococci strains in adults is still a limited
event, but it may well grow worse.3032
The new fluoroquinolones will have only a minor role
in infection with S aureus, coagulase-negative staphylococci,
or enterococci. Moreover, ciprofloxacin remains the
compound most active against P aeruginosa.

Pharmacology
Very little pharmacological information is available about
fluoroquinolones in children, and what is known involves
mainly ciprofloxacin. Peltola et al33 showed that the half-life
of ciprofloxacin is longer in infants (younger than 1 year)
than in toddlers (15 years old) (273 vs 128 h).
Nonetheless, the maximum concentrations do not differ,
and one, or perhaps two, doses per 24 h are certainly
sufficient in babies. Most pharmacological studies in older
children involve cystic fibrosis. Clearance after intravenous
absorption is greater than in adults. Doses recommended in
cases of cystic fibrosis are therefore higher than the usual
doses. Rubio et al34 published the first important study in
1997: in cystic fibrosis they recommend ciprofloxacin doses
of 30 mg/kg per day intravenously and 40 mg/kg per day
orally. Another study recommends lower doses.35 These
doses are probably in the lower range necessary to obtain
concentrations above the minimal inhibitory concentrations
for Gram-negative strains such as P aeruginosa (table 2).36
In children who do not have cystic fibrosis, the
ciprofloxacin dose generally recommended is 20 g/kg per
day, administered in two doses. For Lipman et al,37 the
ciprofloxacin dose in children with severe sepsis must reach
30 mg/kg per day in three doses. Pharmacokinetics of
ofloxacin show that the adult regimen can be used in older
children.38 Several small trials have tested gatifloxacin. No
side-effects were recorded in the children, and a dose of
10 mg/kg, once a day, is recommended.39,40

Side-effects
The exact frequency of side-effects in children is difficult to
estimate because of the paucity of prospective studies. In
view of the severity of the clinical situations that lead to
quinolone prescription in children and the multiplicity of
clinical events possible, these studies should include control
groups with the same disease but receiving other antibiotics.

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539

Review

Fluoroquinolones in paediatrics

Here again, the studies seem limited to detailing and

retrospective analysis of incidents reported to the drugmonitoring agencies, and are thus inadequate.
Phase II and III and post-marketing studies in adults
show the most frequent risks for each compound, but there
are no equivalent studies of fluoroquinolones in paediatrics.
Furthermore, some risks cannot be predicted by premarketing trials, even the best designed, because of their very
low frequency. Very serious but very rare events led to the
withdrawal of two quinolones in 1999, trovafloxacin for liver
failure and grepafloxacin for arrhythmia (table 3).
Ciprofloxacin, by far the fluoroquinolone used most often
in paediatrics, is the only one for which adequate numbers of
children have been treated to allow any definitive conclusions
to be drawn. In a prospective multicentre study in France of
the possible side-effects of fluoroquinolones, 87% of the 276
patients received ciprofloxacin, 9% ofloxacin, and 4%
pefloxacin.14 In a large retrospective study in the USA,41
ciprofloxacin accounted for 75% of the prescriptions and
ofloxacin 24%. Finally, because cystic fibrosis involves
multiple clinical events, it is important to make a separate
comparison of patients who do and do not have this disease.
The principal difficulty in judging side-effects in children lies
in the retrospective nature of the series and, even more, in the
absence of publications reporting trials, series, or even cases.
Fluoroquinolone is often used for children in off-label
circumstances, and eventual adverse events are rarely
published. This is especially true for patients with complicated
urinary tract infections, for those who are severely
immunocompromised or have cancer, or for situations in
which fluoroquinolones are frequently prescribed.
Non-articular side-effects

Minor gastrointestinal problems, diarrhoea, nausea, and

abdominal pain are common, at a frequency close to that
seen in adults, from 2 to 4%.1012 Very grave liver
impairment, with death or transplantation, has been
reported in adult patients with serious diseases. Despite its
extreme rarity, this side-effect led to the withdrawal of
trovafloxacin from the market.4
Table 2. Side-effects of fluoroquinolones and other
antibiotics in children in a prospective multicentre
controlled study in France (reference 28)
Fluoroquinolone group
(Cipro 87%, Oflo 9%)
Patients
276
Cystic fibrosis
90
Malignancy
74
UTI
33
< 2 years
64 (23%)
Potential adverse effects
(2 weeks follow-up)
Total
52 (20%)
Musculoskeletal
10
Neurological
3
Gastro-intestinal
15
Kidney
5
Cutaneous
7

Control group
(other antibiotics)
249
55
43
30
63 (12%)

13 (5%)*
1
0
2
2
7

UTI; urinary tract infection *OR=37 [1975] p <0001. OR=93 [12200] p=002

540

Table 3. Withdrawal of fluoroquinolones after marketing

licence
Side-effect
Haemolysis,
renal failure

Frequency
1/3500

1992

Temafloxacin

1995

Sparfloxacin
Phototoxicity
(restricted use)

2/100

1999

Trovafloxacin

0006/100

1999

Grepafloxacin

Severe hepatic
failure
Sudden deaths
(with increase of QT interval)

00016/100

Photosensitisation has been reported with all the

compounds, in children and adults. It is most frequent
with sparfloxacin, but this compound is not used in
paediatrics. Two cases of permanent green staining of the
teeth were attributed to fluoroquinolone prescribed for
babies.42
Transient kidney failure with increased creatinine is
possible in children and adults. Acute acidosis was
described in the 1960s in newborns and very young infants
treated with nalidixic acid. Although acute acidosis has
rarely been reported in children receiving fluoroquinolone,
it is possible.14
The principal cardiological risk associated with
fluoroquinolone toxicity is an increased QT interval. This
effect involves the entire class, although the risk is higher
for some compounds, such as grepafloxacin, which was
withdrawn from the market in 1999 because of (very rare)
sudden deaths attributed to severe arrhythmia. There is
also a risk for children and adults with a congenital long
QT or receiving another treatment that may alter the QT
interval, cisapride in particular.21,43
The effects on the central nervous system are a real
risk for children and are probably underestimated.
Intracranial hypertension, sometimes with convulsions,
is a well-known complication of nalidixic acid in young
children. In adults, vertigo or headaches are reported
by 4 to 5% of the patients receiving ciprofloxacin.
Apparently isolated convulsions or intracranial
hypertension, sometimes severe and accompanied by
convulsions, are possible in children receiving
fluoroquinolone. These complications must be sought
systematically, especially in neonatal meningitis, where
they are not rare.14,4446
Articular complications
Experimental data

All the quinolones and fluoroquinolones are potentially

arthrotoxic, but experimental data show that the risk of
arthropathies, particularly of the weight-bearing joints, is
greater in growing than in adult animals.1 The severity of
the articular complications in experimental protocols
varies according to the specific drug,43,47 and species: mice
are less sensitive to articular complications than rabbits or
guineapigs, and dogs are much more sensitive. Fissures and
cartilage erosion result from chondrocyte necrosis and
alterations of the extracellular matrix,48 and histological
damage may be noted even when no clinical damage is

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Review

Fluoroquinolones in paediatrics

evident. These injuries are reversible after the joint is rested

and the treatment stopped. The mechanism is so far
unknown and has not been related to the structure of the
different fluoroquinolones. One hypothesis is that
fluoroquinolone chelates the magnesium ion, thereby
blocking the transduction signal at the level of the cellsurface receptors of the chondrocytes integrins that have a
role in maintaining the cartilaginous matrix.49
It is this increased risk in growing animals that
caused pharmaceutical companies to exclude paediatric
indications from their marketing applications for
fluoroquinolones.
Articular complications in children

The incidence of articular complications is difficult to assess

because of the heterogeneity of the patient groups and the
variations in articular toxicity between drugs in this class.
All the fluoroquinolones are potentially arthrotoxic, but it is
thought that ciprofloxacin induces the fewest articular
complications.4,43,47 It is, by far, the fluoroquinolone used
most often in paediatrics, either for off-label use during
severe infection or in cystic fibrosis. It is the only
fluoroquinolone for which there are enough paediatric data
to warrant conclusions being drawn.15,16
Initial clinical alerts

Fluoroquinolones have been used off-label in children in

situations where no alternative treatments were available.
From the end of the 1980s there have been individual
reports of articular adverse effects in children treated with
pefloxacin and with ciprofloxacin. These involve mainly
adolescents, with or without cystic fibrosis, usually with
arthralgia and swelling of the knees during the first 2 weeks
of exposure. In all cases, complete recovery was seen within
3 months. Most patients had a work-up to test for an
underlying rheumatological disorder; it was negative in all
cases.
The question raised by these reports is thus whether
the articular complications are due to fluoroquinolone
toxicity or to the condition for which it was prescribed.
Ideally, the response would come from a large randomised
controlled double-blinded trial including patients of all
ages, only some of whom have cystic fibrosis, and including
short, intermediate, and long-term follow-up of articular
tolerance. Theoretically, a control group is necessary
to compare the rate of articular complications seen with
fluoroquinolones with another antibiotic treatment or
placebo. We know, for example, that children with cystic
fibrosis occasionally present with articular damage.50
Such a trial has never been done and probably never
will be. Off-label use of fluoroquinolones in paediatrics
is widespread for severe infections, and clinicians
would not be likely to include in randomised placebocontrolled studies children for whom they are strongly
convinced that fluoroquinolone offers a high benefitrisk ratio, as for example in cystic fibrosis. We must,
therefore, analyse the existing series and strongly
encourage the publication of further reports on off-label
series.
THE LANCET Infectious Diseases Vol 3 September 2003

Retrospective studies with no control group or derived from

databases

Retrospective studies are the principal source of information

(in terms of the number of exposed children) about childrens
tolerance for fluoroquinolones. The cohorts come either
directly from paediatric centres9,11,5154 or from the records of
Bayer Pharma.10,12 They do not concern only ciprofloxacin. The
patients exposed had cystic fibrosis9,11,53,54 or a range of other
infections.16,38,39 Only two studies include patients younger than
1 year old.10,12 The median rate of adverse events expressed as a
percentage of exposed patients was 13% and ranged from 5%52
to 27%.9 The median rate of articular adverse events was 25%
and ranged from 1%10 to 9%.11 Those described most often
involved adolescent girls with cystic fibrosis. The event was
typically arthralgia and knee effusion, and the problem
resolved in all cases.
Two studies of databases have assessed tolerance for
fluoroquinolones in paediatrics.41,55 The first55 used the General
Practice Research Database: of 1565 patients younger than
17 years (only 5% with cystic fibrosis) whose general
practitioners prescribed ciprofloxacin, not one was
hospitalised in the following 45 days for articular disorders.
The other study41 examined the database of a US health
maintenance organisation and found a 21% incidence rate of
possible articular adverse events among 7897 children who
received ciprofloxacin, ofloxacin, or levofloxacin. These rates
did not differ significantly from those seen with azithromycin.
Prospective uncontrolled studies

Schaad and colleagues56 prospectively followed-up 18 patients

with cystic fibrosis treated with ciprofloxacin according to a
very specific protocol that included magnetic-resonance
imaging (MRI) of the knee and measurement of the cartilage
growth. Only one of the 18 had arthralgia, and he had already
had knee pain before the treatment. The MRI measurements
showed that the size of articular cartilage increased after
ciprofloxacin was stopped, but it is unclear whether this was
due to drug toxicity or clinical improvement in the cystic
fibrosis with catch-up growth.56,57 Doherty and colleagues58
showed that ciprofloxacin did not affect the growth of children
treated for typhoid fever.
Prospective controlled non-randomised studies

Only one prospective controlled non-randomised study has

been publisheda French multicentre study.14 It compared
the adverse events seen during and in the 15 days following
fluoroquinolone treatment with those seen under a different
antibiotic therapy. Of the 276 patients exposed to fluoroquinolones, 20% had at least one possible adverse event. The
crude odds ratio relative to the control group was 37
(1975); it did not change significantly after adjustment for
potential confounding factors, in particular, the number of
other drugs administered simultaneously. Musculoskeletal
adverse events also took place significantly more often (38 vs
04%), but were all cured without sequelae.
Randomised trials

Leibovitz and colleagues13 did a randomised controlled

double-blinded trial that compared the efficacy and tolerance

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541

Review

Fluoroquinolones in paediatrics

of oral ciprofloxacin with intramuscular ceftriaxone in the

treatment of invasive diarrhoea in 201 children aged 6 months
to 10 years. Adverse events were more frequent in the
ciprofloxacin group: odds ratio 32 (111, p <003). A single
case of arthralgia was reported in the ciprofloxacin group
during this brief treatment, compared with none in the
ceftriaxone group. Petrilli and colleagues59 randomised study
of children with febrile aplasia observed no cases of arthralgia
in either the ceftriaxone or the ciprofloxacin group.
Tolerance data for adults

Tolerance data for adults is important as a reference

population for identifying the excess incidence of adverse
events in children. The information comes from the
compilation of data from phase II, III, and IV trials by Bayer
Pharma among several thousand patients.15,16,60 These trials
indicate an overall adverse event rate close to that reported
in children. Moreover, their distribution according to
category was very similar except for adverse musculoskeletal
events, essentially articular and tendinous (001 and 02%,
respectively, in adults). The articular complications induced
by fluoroquinolones are generally transient and reversible.
Severe forms, with tendinitis causing achilles tendon
rupture, have been described in adults mainly with
pefloxacin and ofloxacin.1,15,16,61,62
The frequency of articular side-effects varies according
to the drug but especially with age: all the surveys have
reported frequencies in the order of 01% in adults and
23% in children.

Potential indications
We must distinguish two types of paediatric situations in
which fluoroquinolones may be used. The first, and most
frequent, involves serious infections where no other
treatment is possible. In these severe infections,
fluoroquinolones must be used, because of the lifethreatening situation. They are then often administered by
injection, and all paediatricians practice this off-label use.
Several European63 and American2,8 expert committees
have examined the possibility of regulated use in the diseases
where the benefit for the child outweighs the risks. These
potential indications are principally P aeruginosa respiratory
infections in cystic fibrosis, multidrug-resistant Gramnegative infections, especially in immunocompromised
patients or those receiving chemotherapy, complicated
urinary tract infections, and multidrug-resistant shigella and
salmonella infections.
Other indications are chronic suppurative osteomyelitis
and multidrug-resistant mycobacterial infections, but they
concern very few patients. On the other hand, the principal
questions concern upper-respiratory infections, chronic
otitis in particular, and lower-respiratory infections.
Cystic fibrosis

There is now unanimous support for the treatment of

P aeruginosa pulmonary superinfections in children with
cystic fibrosis by ciprofloxacin. The deterioration of
respiratory functions that accompanies this infection,
especially if acquired early, has been clearly shown.55,6466 The

542

published studies show that oral ciprofloxacin is at least

as effective as the combination of -lactams and
aminoglycosides, and, in addition, the oral administration of
ciprofloxacin improves the childs quality of life. The
treatment protocols, alternated with intravenous -lactams or
combined with inhaled antibiotics, vary from one team to
another. 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, but the progressive increase in P aeruginosa resistance
suggests that the dose may still be inadequate. Systematic
screening for the disease should lead to better surveillance:
because colonisation with pathogenic bacteria is possible later,
the dose must be adjusted. In children with cystic fibrosis, the
number of articular side-effects may be close to that in adults,
and lower than that seen in other children without the disease.
But it is possible that this lower rate of articular side-effects is
linked to the low blood concentration of ciprofloxacin seen in
cystic fibrosis patients when the drug is used with a
conventional regimen.34,35
Immunocompromised patients, chemotherapy, and
febrile neutropenia

Severe infection in immunocompromised patients or those

in chemotherapy is one of the principal situations where
fluoroquinolones are administered for off-label indications.
The seriousness and diversity of clinical conditions makes
data analysis difficult, but it is unfortunate that so few
publications report the side-effects of fluoroquinolones, since
paediatricians are constrained to use them for many patients.
Several series of children alone or of children and adults have
assessed the use of fluoroquinolones in empirical treatment
of febrile neutropenia in paediatric medicine.59,6770 The
combination of ciprofloxacin plus amoxiclav was equivalent
but not superior to ceftriaxone or ciprofloxacin alone. Trials
in adults have shown that fluoroquinolones administered as
first-line treatment often have less efficacy than the standard
combinations. The possibility of oral administration would
be a step forward, in particular in apparently less severe
situations, where hospitalisation might be avoided, but there
have been no large, well-defined trials with prolonged
bacteriological surveillance. Attempted prophylaxis with
fluoroquinolone in neutropenic children provides protection
against Gram-negative infections, but Gram-positive
infections are more frequent. The Infectious Diseases Society
of America guidelines do not recommend fluoroquinolone
use for first-line treatment, and no evidence available today
supports such use in children.71
Delayed elimination of methotrexate with toxicity is
possible in children receiving ciprofloxacin.72
Complicated urinary tract infections

Complicated urinary tract infections are a frequent reason for

fluoroquinolone use in paediatrics, but the departments that
use it have not reported their experience with the induction of
resistance and especially with the occurrence of side-effects
in patients with impaired kidney function, for whom
fluoroquinolones offer the only possible cure. Few trials
involving fluoroquinolones in children in this domain have

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Review

Fluoroquinolones in paediatrics

been published73,74 and some others concern a limited number

of patients.75,76 Infection by fluoroquinolone-resistant germs is
possible after treatment is stopped. Nalidixic acid was
occasionally used in the 1980s as prophylaxis against urinary
tract infections, and prophylaxis with fluoroquinolones is
sometimes proposed. Resistant strains may thus emerge, but
the absence of publications makes it difficult to assess this risk.
In community medicine, the widespread use of
fluoroquinolones in urinary tract infections in adults has led
to increased resistance in urinary bacteria, as the Spanish
study about resistance in E coli has shown.19 In countries
where ciprofloxacin is sometimes used in children with
urinary tract infection, even if the number is low, the number
of ciprofloxacin-resistant E coli is growing.76
Infections and neonatal meningitis

Fluoroquinolones may be useful when severe infections

during the neonatal period are due to enterobacteria resistant
to standard treatments. This is particularly the case for Gramnegative neonatal meningitis, where cerebral abscess is a
major risk. Fluoroquinolones penetrate the brain tissue and
promote recovery from meningitis due to enterobacter,
salmonella, or E coli K1. In particular, they are thought to
have a preventive effect against cerebral abscess. There are
few series, but their results are interesting.7780 On the other
hand, intracranial hypertension is a risk for newborns during
treatment by fluoroquinolones.46
Infections of the central nervous system

Fluoroquinolones are remarkably effective against

enterobacterial meningitis because of the good intracellular
penetration. Fluoroquinolones seem to contribute to
reducing cerebral abscess in immunocompromised patients
and newborns. Although the series are too small to provide
definitive proof, most paediatric critical-care specialists use
them. They are essential in salmonella meningitis because of
their excellent intracellular penetration.
The most recent fluoroquinolones are active against
pneumococci, including penicillin-resistant strains, and are
thus a potential treatment for pneumococcal meningitis.
Partial results have been published from a large trial of
trovafloxacin, interrupted when it was withdrawn because of
cases of severe liver failure in adults.81 No liver complications
were reported, and the results were equivalent to those in the
group treated with ceftriaxone, with or without vancomycin.
Although the trial included few highly resistant pneumococci,
it was encouraging. Future trials with other fluoroquinolones
active against Gram-positive bacteria are essential, but they
will be difficult to organise in view of the risk of rare sideeffects and possible treatment delays, which are a more
important factor than resistance in the occurrence of sequelae.
Pneumococcal meningitis is a relatively rare but very
grave disease. Its mortality and the severity of the sequelae
require an analysis of the failures of the standard treatments,
but comparison with new treatments that carry a potential
risk cannot be left only to drug companies. Paediatricians and
medical societies must be the investigators in studies merited
by the potential quality of the drugs, for these studies will be
difficult to conduct otherwise.
THE LANCET Infectious Diseases Vol 3 September 2003

Efficacy of fluoroquinolone chemoprophylaxis against

meningococci in children was studied with ofloxacin82 and
ciprofloxacin.83 Eradication rate of meningococcal carriage
was some percent lower than that obtained with rifampicin.
Digestive infections
Salmonella

Fluoroquinolones rapidly became the treatment of choice for

typhoid fever. A short (57 days) oral treatment is possible,
and the rate of clinical and bacteriological failure is less than
1%, much better than the results with ceftriaxone, which has
a clinical relapse rate that can reach 10%.38,8485 The -lactams
often have good in-vitro activity but their poor intracellular
penetration prevents them from reaching the sites where
salmonella multiply and in which fluoroquinolones arrive
easily. Usual paediatric practice in Europe and North
America is to await clinical failure by -lactams before
trying fluoroquinolones. This, however, prolongs the
hospitalisation. It is simpler to treat children with
fluoroquinolone as soon as typhoid fever is confirmed
bacteriologically. The treatment is short and, because
adolescents are more frequently affected than young children,
the articular risks are limited. For these reasons, typhoid fever
is one of the rare indications in which fluoroquinolones
should be used as a first-line treatment in children, as a recent
review pointed out.84 This is especially true for the multidrugresistant forms of Salmonella enterica serotype typhi: Duttas
paediatric study85 showed an absence of side-effects and
resolution of the fever within 3 days.
Cases of quinolone resistance have been reported in
southeast Asia and India.8689 Strains resistant to nalidixic
acid but still sensitive to high doses of quinolone are more
frequent, and in those cases, the increased dose can cause
problems in children.84 Azithromycin may be an alternative
for uncomplicated forms of typhoid fever, but it acts more
slowly.90
Non-intestinal salmonella infections, in particular
osteomyelitis and meningitis, require fluoroquinolone
treatment.52,91 Patients with sickle-cell anaemia are
particularly susceptible to salmonella: 50% of bacteraemias
in such patients are due to non-typhoid samonella.92 They
are at high risk of osteitis of the vertebrae, the long bones,
and the bones of the hand: fluoroquinolones are thus very
useful, but emergence of resistance was reported.93
For intestinal, non-typhoid salmonella infections,
antibiotic treatment is indicated only in severe cases,
with invasive diarrhoea and risk of septicaemia. Here again,
the -lactams, although active in vitro, may fail clinically,
and the patients condition, in particular among the
youngest, may require use of second-line fluoroquinolone
treatment.94
There is no consensus about symptomless salmonella
carriage. This is primarily a problem in paediatrics: 8 weeks
after the acute episode, more than 40% of the children
younger than 5 years still excreted salmonella in their
stool, compared with 510% of adults.95 The -lactams
are inactive here. A short fluoroquinolone treatment
would probably help eradicate them, but few studies are
available.96

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543

Review

Fluoroquinolones in paediatrics

Shigella

Pneumococci

According to the WHO as well as consensus among

paediatricians, shigellosis is the only bacterial diarrhoea that
requires systematic antibiotic treatment. The clinical picture is
extremely variable, ranging from apparently banal simple
gastroenteritis to dramatic collapse. Mortality is much higher
in children than in adults. Epidemics in endemic areas strike
80% of children and are always serious, even for Shigella
sonnei or Shigella boydii, although they are considered less
severe than Shigella flexneri and Shigella dysenteriae. Because
of widespread resistance, amoxicillin and co-trimoxazole can
be used only rarely. Nalidixic acid is usually suggested, but it
requires three doses daily for 5 days. The fluoroquinolones
reduce the duration of the fever and the diarrhoea, as well as
bacterial excretion in stool: they have become the reference
treatment. Several studies have shown the efficacy of
fluoroquinolones and their superiority to standard antibiotic
treatments in children.97101 The emergence of multidrugresistant strains, even of nalidixic acid,99 requires the use of
fluoroquinolones in children but strains with intermediate
resistance to fluoroquinolones have also been described.
Leibovitzs study13 showed the efficacy of three doses of
ciprofloxacin in children. A precise bacteriological study is
therefore essential before treating the child, including in
Europe where indigenous shigelloses have mortality rates that
can reach 12% in children.
Shigella dysentery occurs in closed communities and in
the large population centres of the developing world. To stop
an epidemic and treat the maximum number of patients, a
single-dose drug would be ideal. Bennish et al100 showed in
Bangladesh that a single dose of ciprofloxacin was effective in
more than 90% of infected adults. We conducted two small
paediatric studies in Madagascar and Burundi and found that
a single dose of pefloxacin was as effective as a 3-day
treatment, even after clinical failure of a previous
treatment.99,101 Serious shigellosis is one of the only diseases
where the use of fluoroquinolones as a first-line treatment
might be justified in children;84 typhoid fever is another. In
both cases, the benefits far exceed the risks.

Pneumococci raise the principal problem of excessive

fluoroquinolone use in childrenthat is, that pneumococci
strains resistant to quinolone may become widespread.12,13 In
Canada, there were no ciprofloxacin-resistant pneumococci
strains in 1990, but in 1997 they accounted for 17% of the
total and the resistance rate could grow rapidly.22 In adults
treated with levofloxacin, strains that were initially sensitive
become resistant after clinical treatment failure.104 The increase
in pneumococcal fluoroquinolone resistance is not isolated:
even though these drugs are in principle prescribed only in
adults, rates have reached 152% in Northern Ireland105 and
53% in Spain.106 In Hong Kong, the reported rate is 121%,
principally through community dissemination of a multidrugresistant clone.107
Dagan108 and Arguedas109 have shown in a limited number
of patients with otitis media non-responsive to repeated
-lactam treatment that recovery was obtained with
gatifloxacin. These patients were at risk of severe chronic otitis
and gatifloxacin was a second or third line treatment. If
fluoroquinolones are licensed in this indication, precautions
should be taken to limit treatment only to those in real need of
the drug; this use presents a major risk for the community.
Many children younger than 3 years have rhinopharyngeal
colonies of several, often multidrug-resistant, pneumococci,
while few adults have pneumococci in their nasopharynx, and
then only in limited numbers. In surveillance of a Parisian
orphanage, we found that 80% of the youngest children
carried the same pneumococcus clone, which was replaced
after 2 or 3 months by a new clone, regardless of the strain they
carried when they arrived. More than 85% of pneumococci
were resistant to penicillin and to macrolides.110 The exchange
of multidrug-resistant strains in groups of young children is
extremely common, either directly or by gene exchanges from
different streptococci or pneumococci.23
These resistant pneumococci do not only cause otitis. In
national surveillance in France, Geslin111 showed that 40% of
the pneumococci from blood cultures in pneumonia in
children younger than 3 years had diminished sensitivity to
penicillin and belonged to serotypes carried in the
nasopharynx. By contrast, in children older than 7 years, only
20% of the samples had diminished sensitivity to penicillin
(18% in adults) and they belonged primarily to the invasive
serotypes, as among adults. The distribution was similar,
although less clear cut, for the pneumococci that cause
meningitis. In adults, multidrug-resistant clones may spread
throughout groups, but among young children it happens
nearly always and much more rapidly. Widespread
prescription of fluoroquinolones in young children thus
creates a major risk for the community. The only justification
would be the demonstration of the superiority of
fluoroquinolones over the standard treatments for a given
disease, but this is far from the case. Moreover, children with
recurrent otitis usually receive several successive antibiotics.
Studies in Hong Kong have shown that previous and repeated
treatments by fluoroquinolones lead by successive mutations
to resistance to several quinolones.112 The risk of paediatric use
is the emergence of pneumococci strains resistant not to one
but to all the new fluoroquinolones.

Otitis and respiratory infections

Chronic otitis with Pseudomonas spp

Several trials have assessed treatment for chronic suppurative

otitis due to Pseudomonas spp. Local ciprofloxacin treatment
was effective in 79% of the cases, compared with 72% for local
tobramycin.102 Lang et al103 used oral ciprofloxacin to treat 21
patients with chronic suppurative otitis and previous
treatment failure: 86% were cured at the end of the treatment,
but one-third relapsed. Moreover, during treatment, three
patients developed ciprofloxacin-resistant strains. Oral
ciprofloxacin was more comfortable for the children than the
usual intravenous treatments against pseudomonas but this
disease is rare and comparative trials thus difficult. A
risk related to this treatment is that P aeruginosa is a
saprophyte of the external auditory canal and may be seen
in ear samples if the procedure does not totally prevent
possible contamination. In these conditions, if the clinician
automatically accepts the results, fluoroquinolones may be
prescribed abusively.

544

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Review

Fluoroquinolones in paediatrics

Conclusion
Overall, paediatric use of fluoroquinolones has dangers for the
child, since the rate of side-effects is greater than in adults.
This fact alone justifies a policy of using fluoroquinolones in
children only as a second-line treatment, in the case of major
risk for the patient, when no other treatment, or at least no
other oral treatment, is possible. In severe, life-threatening
infections, fluoroquinolones must be used in children without
second thoughts if the data from antibiotic susceptibility
testing require it. In these cases a comparison of benefits and
risks argues clearly for their use. It is regrettable, however, that
paediatricians do not publish results about their off-label use:
information about the efficacy and possible side-effects of
off-label fluoroquinolones is urgently needed.
Outside of cystic fibrosis, the only paediatric situations
where fluoroquinolones are superior in children to standard
treatments in speed of recovery and comfort as well as in
efficacy, are typhoid fever, severe shigella dysenteries, and very
probably enterobacteria meningitis, despite the paucity of
reported cases. In these infections with increased mortality
rates, fluoroquinolones provide a real advantage and their use
as a first-line treatment may be appropriate. Even in the
absence of approval for paediatric indications, they are
prescribed for children. In adult medicine, where they are very
widely used, the rates of fluoroquinolone resistance are
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None declared.

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