See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/26794386

Toxicity of first-line drugs for treatment of

tuberculosis in children: Review
Article in Tropical Medicine & International Health October 2009
Impact Factor: 2.33 DOI: 10.1111/j.1365-3156.2009.02375.x Source: PubMed

CITATIONS

READS

22

52

2 authors, including:
Stephen M Graham
University of Melbourne
189 PUBLICATIONS 4,559 CITATIONS
SEE PROFILE

Available from: Stephen M Graham

Retrieved on: 11 April 2016

Tropical Medicine and International Health

doi:10.1111/j.1365-3156.2009.02375.x

volume 14 no 11 pp 13291337 november 2009

Review
Toxicity of first-line drugs for treatment of tuberculosis in
children: review
Alexis R. Frydenberg1 and Stephen M. Graham2
1 Department of General Medicine, Royal Childrens Hospital, Melbourne, Vict., Australia
2 Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute,
Royal Childrens Hospital, Melbourne, Vict., Australia

Summary

objective To determine the frequency and manifestations of adverse events associated with
recommended first-line anti-TB drugs in children.
method Literature review.
results Overall, children tolerate anti-TB drugs very well when using currently recommended dosages. Serious adverse events are rare and even mild symptoms such as nausea or vomiting are uncommon. There are occasional case reports of severe hepatotoxicity.
conclusions Surveillance and reporting of adverse events will need to be improved when
recommended dosages of the main first-line anti-TB therapy for children are increased. Co-morbidities
such as HIV infection and severe malnutrition may affect the incidence and complicate the management
of possible adverse events to anti-TB therapy.
keywords tuberculosis, co-morbidity, HIV, malnutrition, first-line drugs, literature review

Introduction
An estimated 1 million children develop tuberculosis (TB)
worldwide each year but difficulties with confirming
diagnosis and previous poor surveillance in high-burden
countries means that it is difficult to know the true burden.
Childhood TB has not been regarded as important within
the global TB control strategy, because most cases are not
infectious, but this view is changing. Childhood TB is
increasingly recognized as an important cause of morbidity
and mortality, and as an important sentinel event indicating ongoing transmission in the community. The World
Health Organization (WHO) has now published guidelines
for the management of childhood TB and directed
National TB Control Programmes to routinely report child
TB data and outcomes (World Health Organization
2006a,b).
There are some data from TB-endemic countries where
children represent 10% to more than 30% of the total
caseload being treated for TB (van et al. 1999; Harries
et al. 2002; Nelson & Wells 2004; Oeltmann et al. 2008).
The numbers of children receiving TB treatment has
increased markedly in HIV-endemic communities (Harries
et al. 1997). The majority of children being treated for TB

2009 Blackwell Publishing Ltd

in the world live in resource-limited TB endemic countries

where surveillance and reporting of adverse reactions to
anti-TB therapy are poor or non-existent, and co morbidities such as malnutrition and HIV infection are common.
This adds emphasis to the important issue that recommended dosages of anti-TB therapy for children must be
safe and well tolerated.
Data from resource-limited settings suggest that treatment adherence is poor in children (van et al. 1999;
Harries et al. 2002; Oeltmann et al. 2008). Adverse
reactions to anti-TB drugs could potentially cause
significant morbidity as well as adversely affect treatment
adherence and outcomes (Oeltmann et al. 2008;
Tostmann et al. 2008) and management of TB in
HIV-infected children is complicated by the addition of
other medications with potential toxicities. Finally,
recommended drug dosages for children are currently
under review and may be increased for isoniazid (INH),
rifampicin (RMP) and pyrazinamide (PZA), as they were
recently for ethambutol (EMB) (Donald et al. 2006; World
Health Organization 2006c; Hill et al. 2008). We aimed
to review the frequency and manifestations of toxicities
in children to currently recommended first-line anti-TB
therapy.

1329

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

2006c). WHO guidelines no longer recommend the use of

thiacetazone.

Methods
Articles were identified through Pub Med by use of
the Clinical Queries framework. The search strategy
employed was as follows: (antitubercul* agents OR
tuberculosis OR rifampicin OR isoniazid OR pyrazinamide
OR ethambutol OR streptomycin and (adverse drug
reaction OR adverse effect OR side effect OR poisoning
OR toxicity). The search was initially limited to English
language and humans and all child (018 years) and then
expanded to all ages. Search was limited initially to review
article OR randomized controlled trial. A similar strategy
was adopted to search EMBASE databases and the
Cochrane Library Reference. Reference lists were hand
searched and relevant articles that provided specific data
from children of tolerance or drug-related adverse
events were retrieved. Case reports or series describing
adverse reactions in children were not included if they
did not also provide background information that
allowed estimation of the prevalence of the event among a
larger study population of children receiving anti-TB
treatment.

Co-factors and toxicity

Studies of anti-TB drugs among large populations that
include mainly adults but also children consistently report
that advancing age is associated with higher rates of
toxicity (Kopanoff et al. 1978; Reed & Blumer 1983;
Ormerod & Horsfield 1996; Nolan et al. 1999; Tostmann
et al. 2008). This review focuses mainly on reports from
children, presenting some data from adults as examples to
illustrate this contrast. Other important factors that
potentially influence likelihood of toxicity to an anti-TB
drug are dosage, duration of therapy, daily or intermittent
regimen, concurrent use of other drugs including anti-TB
drugs, presence of TB disease, severity of TB disease, and
co-morbidities such as HIV infection or liver disease. This
information is included wherever possible in the presentation of the data.
Results
Isoniazid

Recommended drug dosages for children

Table 1 lists doses of first-line anti-TB drugs and Table 2
lists treatment regimens for children as currently recommended by WHO. Recommended dosages of INH, RIF and
PZA are currently being reviewed (Hill et al. 2008).
Recommendations for EMB are as per recent review and
revision (Donald et al. 2006; World Health Organization

There are two major adverse reactions to INH: neurologic

and hepatic. Both are rare in children. The level of INH at
any given dosage in children and adults depends on
whether the patient is a fast, intermediate or slow
acetylator. This is determined by the N-acetyltransferase 2
genotype which differs between ethnic groups (Schaaf et al.

Table 1 Recommended doses of first-line anti-TB drugs for children until 2008
Recommended dose
Daily

Three times weekly

Drug

Dose and range (mg kg body weight)

Maximum (mg)

Dose and range (mg kg body weight)

Daily maximum (mg)

Isoniazid
Rifampicin
Pyrazinamide
Ethambutol

5 (46)
10 (812)
25 (2030)
Children 20 (1525)
Adults 15 (1520)
15 (1218)

300
600

10
10
35
30

600

15 (1218)

Streptomycin

(812)
(812)
(3040)
(2535)

Source: Guidance for national tuberculosis programmes on the management of tuberculosis in children (World Health Organization
2006a).
N.B. Recommended dosages for isoniazid, rifampicin and pyrazinamide were increased in 2009.
The recommended daily dose of ethambutol is higher in children (20 mg kg) than in adults (15 mg kg), because the pharmacokinetics are
different. Although ethambutol was frequently omitted from treatment regimens for children in the past, due in part to concerns about the
difficulty of monitoring for toxicity (particularly for optic neuritis) in young children, a literature review indicates that it is safe in children
at a dose of 20 mg kg (range 1525 mg kg) daily (Donald et al. 2006).

1330

2009 Blackwell Publishing Ltd

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

Table 2 Recommended treatment regimens for children in each TB diagnostic category

TB diagnostic
category
III
I

I
II

Regimen
TB cases

Intensive phase

Continuation phase

New smear-negative pulmonary TB (other than in category I)

Less severe forms of extrapulmonary TB
New smear-positive Pulmonary TB
New smear-negative pulmonary TB with extensive parenchymal involvement
Severe forms of extrapulmonary TB (other than TB meningitis see below)
Severe concomitant HIV disease
TB meningitis
Previously treated smear-positive pulmonary TB
Release
Treatment after interruption
Treatment failure

2HRZ

4HR or 6HE

2HRZE

4HR or 6HE

2RHZS
2HRZES 1HRZE

4RH
5HRE

E, ethambutol; H, isoniazid; R, rifampicin; S, streptomycin; Z, pyrazinamide.

Direct observation of drug administration is recommended during the initial phase of treatment and whenever the continuation phase
contains rifampicin.
In comparison with the treatment regimen for patients in diagnostic category I, ethambutol may be omitted during the initial phase of
treatment for patients with non-cavitary, smear-negative pulmonary TB who are known to be HIV-negative, patients known to be infected
with fully drug-susceptible bacilli and young children with primary TB.
This regimen (2HRZE 6HE) may be associated with a higher rate of treatment failure and relapse compared with the 6-month regimen
with rifampicin in the continuation phase.
In comparison with the treatment regimen for patients in diagnostic category I, streptomycin replaces ethambutol in the treatment of TB
meningitis.

2005; Kubota et al. 2007; Possuelo et al. 2008). Slow

acetylator status has been associated with more adverse
reactions to INH (Parthasarathy et al. 1986; Possuelo et al.
2008; Tostmann et al. 2008).
Hepatitis is the most serious adverse reaction and there
are occasional case reports of severe INH-induced hepatitis and hepatic failure in children receiving doses of less
than 10 mg kg (Palusci et al. 1995; Lobato et al. 2008).
Subclinical, asymptomatic transient transaminase
elevation in the first few months of chemoprophylaxis is
observed in 510% of children receiving INH, the highest
rates being reported in adolescents (Beaudry et al. 1974;
Litt et al. 1976; Rapp et al. 1978; Spyridis et al. 1979;
Magdorf et al. 1994). One study reported transient
transaminase elevation as more common in those receiving
9 months (6%) than in those receiving 34 months of
prophylaxis (1.2%) (Spyridis et al. 1979). In contrast,
symptomatic hepatotoxicity resulting in discontinuation of
therapy is very uncommon in children. Jaundice was
reported in one child and discontinuation of therapy in
two of a total of 1 451 children from four studies using
INH prophylaxis at 10 mg kg (Beaudry et al. 1974;
Nakajo et al. 1989; Palusci et al. 1995; Spyridis et al.
2007). Similarly, large studies involving over 2 000
children receiving 1020 mg kg INH prophylaxis did not
report a single case of discontinuation due to hepatotoxicity (Rapp et al. 1978; Dash et al. 1980; Hsu 1984).

2009 Blackwell Publishing Ltd

These reports on INH hepatotoxicity were all from low

TB-endemic, resource-rich settings.
INH competes with vitamin B6 (pyridoxine) in its
action as a cofactor in the synthesis of synaptic
neurotransmitters. Resulting dose-related neurologic side
effects include peripheral neuropathy, ataxia and
paresthesia. Children receiving INH are less susceptible
to developing pyridoxine deficiency or peripheral neuritis
than adults, even at doses up to 20 mg kg (Morales &
Lincoln 1957; Robson & Sullivan 1963). A study in
children in USA found 13% to be vitamin B6 deficient
on assay with a higher incidence in those receiving more
than 10 mg kg daily, but none had clinical features of
pyridoxine deficiency (Pellock et al. 1985). Similarly, no
cases of clinical pyridoxine deficiency were identified
in studies of children in Zaire and South Africa receiving
315 mg kg daily (Mbala et al. 1998; McIlleron et al.
2009). In contrast to these data in children, clinical
vitamin B6 deficiency was reported in 2% of adults
receiving low-dose (35 mg kg) INH therapy daily and
in 10% or more of those receiving around 20 mg kg
daily (Pellock et al. 1985). Pyridoxine supplementation
with INH therapy is not routinely recommended
for children but is recommended for those with
nutritional deficiencies such as severely malnourished or
HIV-infected children (World Health Organization
2006a).

1331

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

INH is used in combination with RMP as chemoprophylaxis and it may be difficult to know which drug is
responsible for an adverse event. Experience with the
combination is largely in low TB-endemic settings and
there are a number of reports from Western Europe.
A prospective, randomized, controlled study of treatment
of latent TB in children over an 11-year period detected no
serious drug related adverse effects (Spyridis et al. 2007).
Of 232 patients that received INH for 9 months, 6.5%
developed nausea epigastric pain and 6% had transient
transaminase elevation. Of 650 patients who received INH
(10 mg kg) and RMP (10 mg kg) for 34 months, 1.2%
had transient increase in liver enzymes, 0.7% experienced
nausea epigastric pain, 1.3% had transient macular papular rash and 0.7% had photosensitivity. The same
combination regimen was used for 39 months in two
studies including a total of 605 children and was well
tolerated (Ormerod 1987, 1998).Discontinuation or
modification of treatment was not required in any patient
enrolled in these studies.
Rifampicin
Rifampicin (RMP) given in currently recommended doses
is well tolerated. The most serious adverse events are
allergic or hepatotoxic. Allergic reactions include fever,
rash, flu-like syndrome, eosinophilia and much less often
haemolytic anaemia, haemoglobinuria and kidney damage
with acute renal insufficiency. They are largely described in
adults, and are more commonly observed with intermittent, high-dose administration and with increasing age
(Reed & Blumer 1983; Brasil et al. 1996).
There are limited data on rates of hepatotoxicity in
children using RMP alone. No adverse events were
reported in a study of 25 German children that
received RMP alone as chemoprophylaxis (Magdorf
et al. 1994). RMP (10 mg kg) was used alone as
chemoprophylaxis in 157 adolescents in USA who had
been in contact with a case of isoniazid-resistant TB
(Villarino et al. 1997). All remained asymptomatic
although RMP was discontinued in one adolescent
because of a rise in transaminase levels.
As chemoprophylaxis, RMP is mainly used in combination with INH as reported in the previous section on INH
(Ormerod 1987, 1998; Spyridis et al. 2007).
Most reports of RMP is when used with other drugs for
TB disease. A retrospective review of rates of hepatotoxicity in children in the USA reported that 14 (3.3%) of 430
children receiving INH and RMP as TB treatment had a
hepatotoxic reaction (OBrien et al. 1983). Large, prospective studies of children receiving INH, RMP and PZA
for at least 2 months in the intensive phase report a very
1332

low incidence of any adverse events including hepatotoxicity (Kopanoff et al. 1978; Biddulph 1990; Hussein 1990;
Tsakalidis et al. 1992; Padmini et al. 1993; Te Water
Naude et al. 2000; Al-Dossary et al. 2002; Swaminathan
et al. 2005). These studies represent a variety of settings
including high TB-endemic, resource-limited settings and
are reported in more detail in the following section on
treatment trials.
Pyrazinamide
Pyrazinamide (PZA) is most commonly used in combination with other agents in the first two months of therapy
for active TB disease. The most clinically significant
adverse events associated with PZA are hepatotoxicity,
gastrointestinal intolerance, non-gouty polyarthralgia and
gouty arthritis. However, these reflect findings from studies
in adults. The incidence of toxicity in British Medical
Research Council trials was low: 3 (0.2%) of 1 845
patients in East and Central Africa, 13 (0.6%) of 2 219
patients in Hong Kong and 11 (2.8%) of 397 patients in
Singapore (Girling 1984). Hepatotoxicity in adults is
related to dosage and duration of treatment (Tostmann
et al. 2008). There are few data on tolerance and adverse
effects of PZA alone in children.
Use of PZA in 86 children as part of combination
chemoprophylaxis with RMP for 2 months was well
tolerated with no hepatotoxicity reported (Magdorf et al.
1994; Tortajada et al. 2005). Hepatic enzyme
abnormalities were infrequent and transient in the first
month in children receiving PZA as part of TB treatment
(le Bourgeois et al. 1989; Sanchez-Albisua et al. 1997;
Corrigan & Paton 1999). A slight increase in serum
concentration of uric acid has been reported in a number of
studies (le Bourgeois et al. 1989; Tsakalidis et al. 1992;
Sanchez-Albisua et al. 1997). This may be accompanied by
clinical manifestations of gouty arthritis in adults but this
has not been reported in children.
Ethambutol
Usage of EMB in young children increased in TB
endemic countries when EMB was introduced to replace
thiacetazone, which commonly caused severe, often fatal
StevensJohnson reactions in HIV-infected adults and
children (Nunn et al. 1991; Chintu et al. 1993). At the
time, this caused concern about using EMB in children too
young to report early symptoms of optic neuritis and
resulted in a number of literature reviews of efficacy and
toxicity of EMB (Trebucq 1997; Graham et al. 1998).
WHO now supports the use of EMB in infants and young
children and recently revised the recommended dosages

2009 Blackwell Publishing Ltd

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

following careful review (World Health Organization

2006c).
The most serious toxic effect of EMB is retrobulbar
neuritis, which is reversible if detected early. Because the
neuritis is retrobulbar, the fundus appears normal on
opthalmoloscopic examination. Signs of toxicity include
loss of visual acuity and colour vision or reduction in visual
fields. Detection of these symptoms may be delayed in
young children (Trebucq 1997). The occurrence of ocular
toxicity is related to dose and duration of therapy (Graham
et al. 1998; Donald et al. 2006; World Health Organization 2006c). More than 40% of adults developed toxicity
at doses of greater than 50 mg kg compared to 03% at a
dose of 15 mg kg daily. In only two of 3 811 children
(0.05%) receiving EMB doses of 1530 mg kg was EMB
stopped due to possible ocular toxicity (Graham et al.
1998; Donald et al. 2006). Reports of EMB toxicity
incidence in children represent a variety of TB endemic
settings including Europe, Asia and Latin America. The
current recommended daily dose is 20 mg kg and it is
mainly used only in the intensive phase for a limited
duration of 2 months (Table 2).
Streptomycin
The potential toxic effects of Streptomycin (SM) are doserelated and inherent to aminoglycoside antibiotics in
general: otovestibular toxicity, which can result in permanent deafness, and nephrotoxicity which has been rarely
reported in children (Reed & Blumer 1983). If SM is not
discontinued with onset of symptoms of toxicity, then
damage may be permanent. Difficulties associated with
prolonged parenteral therapy and potential toxicity means
its recommended use in children is now limited. SM
usage in pregnant women with TB has been associated
with deafness in their newborns (Robinson & Cambon
1964). SM should also be avoided in patients with renal
impairment.
Treatment trials and adverse events
The frequency of adverse events may be affected by the
presence of TB disease compared to reports of chemoprophylaxis where the patient presumably had TB infection
but not disease. Treatment trials report adverse events in
children with mainly pulmonary TB from a variety of
settings where patients have been carefully monitored
throughout the treatment regimen.
No significant side effects were noted in a prospective
randomized controlled trial of 206 South African children
comparing 6 months daily regimen (RMP 10 mg kg, INH
10 mg kg, PZA 25 mg kg) to a higher dose twice-weekly

2009 Blackwell Publishing Ltd

regimen (RMP 15 mg kg, 15 mg kg, PZA 55 mg kg)

(Te Water Naude et al. 2000). There have been a number
of similar studies from India. A study of 76 Indian children
compared intermittent (twice weekly INH 2030 mg kg,
RIF 1015 mg kg and PZA 5060 mg kg) to daily (INH
1015 mg kg, RMP 1015 mg kg, PZA 2030 mg kg) in
the intensive phase (Kumar et al. 1990). Monitoring
included monthly liver function tests and no adverse effects
requiring modification of treatment occurred. Six patients
complained of vomiting initially and two had mild joint
pains. Another compared daily regimen (INH 6 mg kg and
RMP 12 mg kg) of 9 months duration to an intermittent
regimen (INH 15 mg kg, RMP 12 mg kg and PZA
45 mg kg) of 6 months duration (Swaminathan et al.
2005). Patients were followed closely but liver function
tests were not monitored. Tolerance was reported as
excellent with no adverse events reported. A prospective
trial in 83 children using a variety of regimens, all including
INH at 15 mg kg and RMP at 1015 mg kg, reported
side-effects to be uncommon and mild: transient hepatitis
(four), vomiting (one) and skin rash (one) (Padmini et al.
1993).
A prospective study of 36 Greek children treated with
RMP (1012 mg kg), INH (1012 mg kg) and PZA (30
35 mg kg) resulted in no serious problems with drug
tolerance or toxicity. Temporary asymptomatic hyperuricaemia and transient elevation in serum transaminases
were observed in 11 patients but no drug modification was
required (Tsakalidis et al. 1992). An observational study of
175 children in USA reported experience with a 6-month
directly observed regimen including INH (2040 mg kg),
RMP (1020 mg kg) and PZA (5070 mg kg) twice
weekly from week 3. Only two (1%) had significant
adverse events of vomiting and skin rash, which interrupted drug treatment for 12 months (Al-Dossary et al.
2002). An additional nine patients had episodes of
gastrointestinal disturbance (vomiting or abdominal pain)
that did not require discontinuation of therapy or change in
drug doses. These occurred in young children during the
first month of therapy and were thought to be caused by
the large volume of medications. No patient developed
hepatitis, peripheral neuritis or joint pain.
In an uncontrolled prospective study, children in Papua
New Guinea were treated with RMP (1015 mg kg), INH
(1015 mg kg), PZA (2535 mg kg) and SM daily for
2 months and then twice weekly with RMP (1015 mg kg)
and INH (1520 mg kg) for 4 months (Biddulph 1990).
Of the 639 children, 15 (2%) developed side effects.
Twelve developed rash during the initial 2 months daily
treatment and it was attributed to SM in eight cases, PZA
in three cases and INH in one case and two developed
jaundice. One child who had received SM and INH for
1333

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

several months in an earlier incomplete treatment course

complained of deafness. Four children were considered to
be allergic to either PZA or INH and were desensitized
with increasing dosages and had no further problems. This
study included children with various forms of TB including
43 with tuberculous meningitis (TBM) and 16 with miliary
TB.
The frequency of adverse events may be affected by the
severity of TB disease. A study of Indian children reported
hepatotoxicity in 2% of 323 children receiving daily INH,
RMP, PZA and EMB in intensive phase for more severe
forms of disease compared to 1% of 120 children who
received INH, RMP and PZA for less severe forms (Kabra
et al. 2004). Dosages of 1520 mg kg of INH in children
in TB-endemic countries are more commonly associated
with hepatotoxicity and clinical jaundice but these higher
dosages are used in children with TBM (Ramachandran
1980; Tsagaropoulou-Stinga et al. 1985; Parthasarathy
et al. 1986; Donald et al. 1987). In one study of TBM, the
risk of jaundice was higher (39% vs. 12%) in those
receiving 20 mg kg than in those receiving 12 mg kg INH
daily (Parthasarathy et al. 1986).
Discussion
Treatment trials in children using combination therapy in a
variety of regimens show that anti-TB drugs at currently
recommended dosages are well tolerated. Serious adverse
reactions are rare and even mild, reversible side effects are
uncommon. Poor treatment completion rates are reported
in children in resource-limited settings but it is unlikely that
adverse reactions are a major factor for this. INH is the
most extensively studied as a single agent because of its use
as prophylaxis. Hepatotoxicity is the major adverse event
of concern and there are case reports in the literature of
INH-induced hepatic failure when recommended dosages
are used.
Review of the literature shows that children tolerate
anti-TB drugs better than adults. This consistent observation has been related to alcohol use and a higher prevalence
of underlying disease such as chronic hepatitis with age
(Kopanoff et al. 1978; Reed & Blumer 1983). Another
important factor may be that young children eliminate
drugs faster than older children and adults, requiring a
higher dosage to achieve similar levels (McIlleron et al.
2009).Children have lower serum concentrations for antiTB drugs than adults when receiving equivalent milligram
per kilogram doses as recommended (Zhu et al. 2002;
Schaaf et al. 2005; Graham et al. 2006).
In the past, this has not been considered a problem as
clinical response and outcomes have generally been very
favourable in children with TB using these recommended
1334

dosages. The poorer outcomes noted in children with

TB HIV co-infection (Marais et al. 2007; Schaaf et al.
2007) have called attention to the need for appropriate
dosages in children to achieve optimal serum levels and the
need for more careful surveillance in such settings.
Recommended doses for first-line drugs such as RMP and
INH may be increased in the near future. It will be
important to monitor for the possibility of an increasing
incidence of side effects. There are some toxicity data from
children using higher daily dosages but this has mainly
been in the context of treatment of severe, disseminated
disease such as TBM when there are other potential
co-factors for toxicity such as disease involving the liver,
the use of other anti-TB drugs and anticonvulsants.
Some studies in adults have found that HIV infection is
associated with an increased risk of hepatotoxicity to antiTB drugs (Tostmann et al. 2008). There are no published
data for children. EMB and PZA levels were not significantly different between HIV-infected and HIV-uninfected
Malawian children (Graham et al. 2006). However, these
are the only published data that try to examine the impact
of age, HIV and malnutrition on TB drug levels in children.
The potential for toxicity also relates to drug-drug interactions and a greater likelihood of underlying liver disease
in HIV-infected children. Anti-TB drugs, mainly RMP,
have important interactions with antiretroviral therapy
(ART) and have many similar side effects. RMP reduces the
serum levels of almost all protease inhibitors except
ritonavir by more than 75% (Burman & Jones 2001) and
levels also fall for non-nucleoside reverse transcriptase
inhibitors such as efavirenz and nevirapine (Centers for
Disease Control and Prevention 2007).
It is also recommended that all HIV TB co-infected
children should receive cotrimoxazole preventive therapy
as well as pyridoxine while on anti-TB treatment (World
Health Organization 2006b). Hepatotoxicity, skin rash,
gastrointestinal upset, leucopaenia, anaemia and peripheral
neuropathy are all side effects that could be caused by
either anti-TB drugs or ART. It is therefore difficult to
distinguish which drug is responsible for these side effects
when treatment for both diseases is combined (Donald &
Schaaf 2007). As HIV and TB are frequent co-morbidities
in children in developing countries, and with the increasing
use of ART in HIV infected children, it will be important to
monitor for adverse effects in these populations.
In conclusion, anti-TB drugs at current recommended
doses are well tolerated in children. Although occasional
fatal hepatotoxic events are described in children, the
incidence of serious toxicity is very low. Monitoring for
adverse effects will need to be improved if increased
doses are to be used in children especially in regions where
co- morbidities are common. There is a need for more

2009 Blackwell Publishing Ltd

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

clinical outcome and pharmacokinetic data from children

in resource-limited settings including those with HIV and
malnutrition.
Acknowledgements
We thank Dr Julian Kelly and Prof. Peter Donald for
suggestions and support. This review is part of the
International Child Health Review Collaboration: http://
www.ichrc.org.
References
Al-Dossary FS, Ong LT, Correa AG & Starke JR (2002) Treatment
of childhood tuberculosis with a six month directly observed
regimen of only two weeks of daily therapy. Pediatric Infectious
Disease Journal 21, 9197.
Beaudry PH, Brickman HF, Wise MB & MacDougall D (1974)
Liver enzyme disturbances during isoniazid chemoprophylaxis
in children. American Review of Respiratory Disease 110, 581
584.
Biddulph J (1990) Short course chemotherapy for childhood
tuberculosis. Pediatric Infectious Disease Journa 9, 794801.
le Bourgeois M, de Blic J, Paupe J & Scheinmann P (1989) Good
tolerance of pyrazinamide in children with pulmonary tuberculosis. Archives of Disease in Childhood 64, 177178.
Brasil MT, Opromolla DV, Marzliak ML & Nogueira W (1996)
Results of a surveillance system for adverse effects in leprosys
WHO MDT. International Journal of Leprosy and Other
Mycobacterial Diseases 64, 97104.
Burman WJ & Jones BE (2001) Treatment of HIV-related
tuberculosis in the era of effective antiretroviral therapy.
American Journal of Respiratory and Critical Care Medicine
164, 712.
Centers for Disease Control and Prevention (2007). Managing
drug interactions in the treatment of HIV-related tuberculosis
[online]. Available at: http://www.cdc.gov/tb/publications/
guidelines/TB_HIV_Drugs/default.htm (accessed on 28 August
2009)
Chintu C, Luo C, Bhat G et al. (1993) Cutaneous hypersensitivity
reactions due to thiacetazone in the treatment of tuberculosis in
Zambian children infected with HIV-I. Archives of Disease in
Childhood 68, 665668.
Corrigan D & Paton J (1999) Hepatic enzyme abnormalities in
children on triple therapy for tuberculosis. Pediatric Pulmonology 27, 3742.
Dash LA, Comstock GW & Flynn JP (1980) Isoniazid preventive
therapy: retrospect and prospect. American Review of Respiratory Diseases 121, 10391044.
Donald PR & Schaaf HS (2007) Old and new drugs for the
treatment of tuberculosis in children. Paediatric Respiratory
Reviews 8, 134141.
Donald PR, Schoeman JF & OKennedy A (1987) Hepatic toxicity
during chemotherapy for severe tuberculosis meningitis. American Journal of Disease in Children 141, 741743.

2009 Blackwell Publishing Ltd

Donald PR, Maher D, Maritz JS & Qazi S (2006) Ethambutol

dosage for the treatment of children: literature review and
recommendations. International Journal of Tuberculosis and
Lung Disease 10, 13181330.
Girling DJ (1984) The role of pyrazinamide in primary chemotherapy for pulmonary tuberculosis. Tubercle 65, 14.
Graham SM, Daley HM, Banerjee A, Salaniponi FM & Harries
AD (1998) Ethambutol in tuberculosis: time to reconsider?
Archives of Disease in Childhood 79, 274278.
Graham SM, Bell DJ, Nyirongo S et al. (2006) Low levels of
pyrazinamide and ethambutol in children with tuberculosis and
impact of age, nutritional status, and human immunodeficiency
virus infection. Antimicrobial Agents and Chemotherapy 50,
407413.
Harries AD, Parry C, Nyongonya Mbewe L et al. (1997) The
pattern of tuberculosis in Queen Elizabeth Central Hospital,
Blantyre, Malawi: 19861995. International Journal of Tuberculosis and Lung Disease 1, 346351.
Harries AD, Hargreaves NJ, Graham SM et al. (2002) Childhood
tuberculosis in Malawi: nationwide case-finding and treatment
outcomes. International Journal of Tuberculosis and Lung
Disease 6, 424431.
Hill S, Regondi I, Grzemska M & Matiru R (2008) Children and
tuberculosis medicines: bridging the research gap. Bulletin of the
World Health Organization 86, 658.
Hsu K (1984) Thirty years after isoniazid. Its impact on tuberculosis in children and adolescents. The Journal of the American
Medical Association 251, 12831285.
Hussein A (1990) Short-term chemotherapy of tuberculosis in
children. Pneumologie 44, 2431.
Kabra SK, Lodha R & Seth V (2004) Category based treatment of
tuberculosis in children. Indian Pediatrics 41, 927937.
Kopanoff DE, Snider DE Jr & Caras GJ (1978) Isoniazid-related
hepatitis: a U.S. Public Health Service cooperative surveillance
study. American Review of Respiratory Diseases 117, 991
1001.
Kubota R, Ohno M, Hasunuma T, Iijima H & Azuma J (2007)
Dose-escalation study of isoniazid in healthy volunteers with the
rapid acetylator genotype of arylamine N-acetyltransferase 2.
European Journal of Clinical Pharmacology 63, 927933.
Kumar L, Dhand R, Singhi PD, Rao KL & Katariya S (1990)
A randomized trial of fully intermittent vs. daily followed by
intermittent short course chemotherapy for childhood
tuberculosis. The Pediatric Infectious Disease Journal 9, 802
806.
Litt IF, Cohen MI & McNamara H (1976) Isoniazid hepatitis in
adolescents. Journal of Pediatrics 89, 133135.
Lobato MN, Jereb JA & Starke JR (2008) Unintended consequences: mandatory tuberculin skin testing and severe isoniazid
hepatotoxicity. Pediatrics 121, e17321733.
Magdorf K, Arizzi-Rusche AF, Geiter LJ, OBrien RJ & Wahn U
(1994) Compliance and tolerance of new antitubercular shortterm chemopreventive regimens in childhooda pilot project.
Pneumologie 48, 761764.
Marais BJ, Graham SM, Cotton MF & Beyers N (2007) Diagnostic and management challenges for childhood tuberculosis in

1335

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

the era of HIV. Journal of Infectious Disease 196(Suppl. 1),

S76S85.
Mbala L, Matendo R & Nkailu R (1998) Is vitamin B6 supplementation of isoniazid therapy useful in childhood tuberculosis.
Tropical Doctor 28, 103104.
McIlleron H, Willemse M, Werely CJ et al. (2009) Isoniazid
plasma concentrations in a cohort of South African children
with tuberculosis: implications for international pediatric dosing
guidelines. Clinical Infectious Diseases 48, 15471553.
Morales SM & Lincoln EM (1957) The effect of isoniazid therapy
on pyridoxine metabolism in children. American Review of
Tuberculosis 75, 594600.
Nakajo MM, Rao M & Steiner P (1989) Incidence of hepatotoxicity in children receiving isoniazid chemoprophylaxis.
Pediatric Infectious Disease Journal 8, 649650.
Nelson LJ & Wells CD (2004) Global epidemiology of childhood
tuberculosis. International Journal of Tuberculosis and Lung
Disease 8, 636647.
Nolan CM, Goldberg SV & Buskin SE (1999) Hepatotoxicity
associated with isoniazid preventive therapy. The Journal of the
American Medical Association 281, 10141018.
Nunn P, Kibuga D, Gathua S et al. (1991) Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive
patients treated for tuberculosis. Lancet 337, 627630.
OBrien RJ, Long MW, Cross FS, Lyle MA & Snider DE Jr (1983)
Hepatotoxicity from isoniazid and rifampin among children
treated for tuberculosis. Pediatrics 72, 491499.
Oeltmann JE, Chengeta B, Mboya JJ et al. (2008) Reported
childhood tuberculosis treatment outcomes, Gaborone and
Francistown, Botswana, 19982002. International Journal of
Tuberculosis and Lung Disease 12, 186192.
Ormerod LP (1987) Reduced incidence of tuberculosis by prophylactic chemotherapy in subjects showing strong reactions to
tuberculin testing. Archives of Disease in Childhood 82, 1005
1008.
Ormerod LP (1998) Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis. Archives of Disease in Childhood
78, 169171.
Ormerod LP & Horsfield N (1996) Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. Tubercle and Lung Disease 77, 3742.
Padmini R, Srinivasan S, Nalini P & Mahadevan S (1993) Short
course chemotherapy for tuberculosis in children. Journal of
Tropical Pediatrics 39, 361364.
Palusci VJ, OHare D & Lawrence RM (1995) Hepatotoxicity and
transaminase measurement during isoniazid chemoprophylaxis
in children. The Pediatric Infectious Disease Journal 14, 144
148.
Parthasarathy R, Sarma GR, Janardhanam B et al. (1986) Hepatic
toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin
and pyrazinamide. Tubercle 67, 99108.
Pellock JM, Howell J, Kendig EL Jr & Baker H (1985) Pyridoxine
deficiency in children treated with isoniazid. Chest 87, 658661.
Possuelo LG, Castelan JA, de Brito TC et al. (2008) Association of
slow N-acetyltransferase 2 profile and anti-TB drug-induced

1336

hepatotoxicity in patients from Southern Brazil. European Jouranl of Clinical Pharmacology 64, 673681.
Ramachandran P (1980) Chemotherapy of tuberculous meningitis
with isoniazid plus rifampicin: interim findings in a trial in
children. Indian Journal of Tuberculosis 27, 5457.
Rapp RS, Campbell RW, Howell JC & Kendig EL Jr (1978) Isoniazid hepatotoxicity in children. American Review of Respiratory Disease 118, 794796.
Reed MD & Blumer JL (1983) Clinical pharmacology of antitubercular drugs. Pediatric Clinics of North America 30, 177193.
Robinson GC & Cambon KG (1964) Hearing loss in infants of
tuberculous mothers treated with streptomycin during pregnancy. New England Journal of Medicine 271, 949951.
Robson JM & Sullivan FM (1963) Antituberculosis drugs. Pharmacological Reviews 15, 169223.
Sanchez-Albisua I, Vidal ML, Joya-Verde G et al. (1997) Tolerance of pyrazinamide in short course chemotherapy for pulmonary tuberculosis in children. The Pediatric Infectious
Disease Journal 16, 760763.
Schaaf HS, Parkin DP, Seifart HI et al. (2005) Isoniazid pharmacokinetics in children treated for respiratory tuberculosis.
Archives of Disease in Childhood 90, 614618.
Schaaf HS, Marais BJ, Whitelaw A et al. (2007) Culture-confirmed
childhood tuberculosis in Cape Town, South Africa: a review of
596 cases. BMC Infectious Diseases 7, 140.
Spyridis P, Sinaniotis C, Papadea I, Oreopoulos L, Hadjiyiannis S
& Papadatos C (1979) Isoniazid liver injury during chemoprophylaxis in children. Archives of Disease in Childhood 54, 65
67.
Spyridis NP, Spyridis PG, Gelesme A et al. (2007) The
effectiveness of a 9-month regimen of isoniazid alone versus
3- and 4-month regimens of isoniazid plus rifampin for
treatment of latent tuberculosis infection in children: results of
an 11-year randomized study. Clinical Infectious Disease 45,
715722.
Swaminathan S, Raghavan A, Duraipandian M, Kripasankar AS
& Ramachandran P (2005) Short-course chemotherapy for
paediatric respiratory tuberculosis: 5-year report. International
Journal of Tuberculosis and Lung Disease 9, 693696.
Te Water Naude JM, Donald PR, Hussey GD et al. (2000) Twice
weekly vs. daily chemotherapy for childhood tuberculosis. The
Pediatric Infectious Disease Journal 19, 405410.
Tortajada C, Martinez-Lacasa J, Sanchez F et al. (2005) Is the
combination of pyrazinamide plus rifampicin safe for treating
latent tuberculosis infection in persons not infected by the
human immunodeficiency virus? International Journal of
Tuberculosis and Lung Disease 9, 276281.
Tostmann A, Boeree MJ, Aarnoutse RE et al. (2008) Antituberculosis drug-induced hepatotoxicity: concise up-to-date review.
Journal of Gastroenterology and Hepatology 23, 192202.
Trebucq A (1997) Should ethambutol be recommended for routine
treatment of tuberculosis in children? A review of the literature.
International Journal of Tuberculosis and Lung Disease 1,
1215.
Tsagaropoulou-Stinga H, Mataki-Emmanouilidou T, KaridaKavalioti S & Manios S (1985) Hepatotoxic reactions in chil-

2009 Blackwell Publishing Ltd

Tropical Medicine and International Health

volume 14 no 11 pp 13291337 november 2009

A. R. Frydenberg & S. M. Graham Toxicity of first-line drugs for treatment of TB in children

dren with severe tuberculosis treated with isoniazid-rifampin.

Pediatric Infectious Disease Journal 4, 270273.
Tsakalidis D, Pratsidou P, Hitoglou-Makedou A, Tzouvelekis G &
Sofroniadis I (1992) Intensive short course chemotherapy for
treatment of Greek children with tuberculosis. The Pediatric
Infectious Disease Journal 11, 10361042.
van Rie A, Beyers N, Gie RP et al. (1999) Childhood tuberculosis
in an urban population in South Africa: burden and risk factor.
Archives of Disease in Childhood 80, 433437.
Villarino ME, Ridzon R, Weismuller PC et al. (1997) Rifampin
preventive therapy for tuberculosis infection: experience with
157 adolescents. American Journal of Respiratory and Critical
Care Medicine 155, 17351738.
World Health Organization (2006a) Guidance for national
tuberculosis programmes on the management of tuberculosis in
children. Document WHO_HTM_TB_2006.371. World Health
Organization, Geneva, http://www.who.int/tb/publications/
2006/en/index.html.

World Health Organization (2006b) Revised TB recording and

reporting forms and registers. Document
WHO HTM TB 2006.373. World Health Organization,
Geneva, http://www.who.int/tb/publications/2006/en/
index.html.
World Health Organization (2006c) Ethambutol efficacy and
toxicity: literature review and recommendations for daily
and intermittent dosage in children. Document
WHO_HTM_TB_2006.365. World Health Organization,
Geneva, http://www.who.int/tb/publications/2006/en/
index.html.
Wu SS, Chao CS, Vargas JH et al. (2007) Isoniazid-related hepatic
failure in children: a survey of liver transplantation centers.
Transplantation 84, 173179.
Zhu M, Starke JR, Burman WJ et al. (2002) Population pharmacokinetic modeling of pyrazinamide in children and adults with
tuberculosis. Pharmacotherapy 22, 686695.

Corresponding Author Alexis R. Frydenberg, Department of General Medicine, Royal Childrens Hospital, Flemington Rd, Parkville,
Melbourne, Vict. 3052, Australia. Tel.: +61 3 9345 5522; Fax: +61 3 9345 4751; E-mail: lexi.frydenberg@rch.org.au

2009 Blackwell Publishing Ltd

1337