Paediatric Respiratory Reviews 12 (2011) 22–26

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: Childhood TB in 2010

Treatment of paediatric TB: revised WHO guidelines

Stephen M. Graham 1,2,*
1
Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia
2
Child Lung Health Division, International Union Against Tuberculosis and Lung Disease, Paris, France

EDUCATIONAL AIMS

 To describe the current recommendations for dosages of first-line TB treatment in children following recent revision
 To outline the rationale for these revisions
 To highlight clinical and pharmacokinetic data that helped inform the revised recommendations

A R T I C L E I N F O S U M M A R Y

Keywords: The World Health Organization has recently revised the recommended dosages of the main first-line
isoniazid anti-tuberculosis drugs for use in children. The recommended dosages and range of isoniazid, rifampicin,
rifampicin pyrazinamide and ethambutol have been increased from the previous recommended dosages.
pyrazinamide
Ethambutol is now recommended for use in children of all ages including those of less than 5 years
ethambutol
of age. This review explains the rationale for these recent revisions. Children require higher dosages than
dosages
toxicity adults to achieve the same serum concentrations. Available data in HIV-uninfected children suggest that
children the revised dosages are within limits that have a very low risk of toxicity. An important challenge will be
to examine the impact of higher dosages on clinical response, drug-drug interactions and risk of toxicity
in HIV-infected children.
ß 2010 Published by Elsevier Ltd.

INTRODUCTION
The World Health Organization (WHO) has estimated that
around 10% of global tuberculosis (TB) caseload occurs in children
(0-14 years).1 Disease burden data in children is rarely reported
from TB endemic countries. However, there are reports that
children account for up to 40% of all cases being treated for TB.2–4
Marked variability is expected because the reported burden of
disease will depend on epidemiological and demographic differ-
ences between communities5 as well as differences in diagnostic
and notification practices. While there may be uncertainty of
actual disease burden, clinical and autopsy data from the sub-
Saharan African region show that TB is a major cause of morbidity
and mortality in children.6–9 Children are also susceptible to the
dual epidemic of TB/HIV. HIV-infected children are at 20-times
greater risk of TB disease than HIV-uninfected children and at
much higher risk of TB-related death.8–12
Paediatric TB has until recently not been a main priority of
global TB control efforts for various reasons. The control strategy
* Centre for International Child Health, University of Melbourne Department of
Paediatrics, Royal Children’s Hospital, Flemington Rd, Parkville, Victoria 3052,
Australia. Tel.: +61 3 9345 4788; Fax: +61 3 9345 6667.
E-mail address: steve.graham@rch.org.au.
has in the past primarily focused on the identification and effective
management of the most infectious cases of TB in order to reduce
the transmission of infection with Mycobacterium tuberculosis.
These cases are usually adults or adolescents with sputum smear-
positive pulmonary TB (PTB). Further, although there is evidence
that paediatric TB makes an important contribution to the global
burden of TB, it has been difficult to accurately determine (and
provide advocacy for) the burden of disease in children because
most cases are not confirmed. The burden of paediatric disease in
TB endemic settings is usually skewed towards the infants and
young children (< 5 years of age)2–5 from whom it is difficult to
obtain sputum, and the nature of disease in this age group is
usually paucibacillary meaning that culture is required to improve
yield of diagnostic confirmation. Therefore, most children with a
diagnosis of TB are categorised by National TB Programmes (NTPs)
as either ‘‘sputum smear-negative’’ PTB or extra-pulmonary TB
(EPTB) cases.3,4 These cases were not traditionally and are often
still not being routinely recorded and reported by NTPs.
RECENT ATTENTION BY WHO TO THE CHALLENGES OF
PAEDIATRIC TB
The direct observed treatment strategy [DOTS] has recently
been incorporated into WHO’s broader Stop TB Strategy13 which

1526-0542/$ – see front matter ß 2010 Published by Elsevier Ltd.

doi:10.1016/j.prrv.2010.09.005
 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26
Table 1
Treatment regimens for children recommended by WHO
TB cases and diagnostic category
New Patient Regimen
New smear-positive PTB
Smear-negative PTB with extensive parenchymal involvement
Severe forms of EPTB other than TB meningitis
New Patient Regimen
Smear-negative PTB without extensive parenchymal involvement
Less severe forms of EPTB (e.g TB cervical adenitis)
New Patient Regimen
TB meningitis
Retreatment regimen
Previously treated smear-positive PTB (relapse, treatment after interruption or treatment failure)
If low risk for MDR TB or risk unknown: continue with retreatment regimen
If high risk for MDR TB: use MDR TB regimen below
MDR Regimen
MDR-TB
The Table represents WHO recommendations up until August 2010 which have since been changed (and approved by Guidelines Review Committee) and this process is
mentioned in text below. The main changes are that all TB types (except TBM and OA TB) in HIV endemic setting should receive a fourth drug in intensive phase 2RHZE/4RH,
that TBM and osteoarticular TB should receive 2 RHZE/10RH and that streptomycin is no longer recommended as first-line in children.
H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin
a
: Other regimens are recommended for treatment of TB meningitits that include replacing streptomycin with ethionamide and treating for 9-12 months
gives due emphasis to all types of TB disease and vulnerable at-risk
groups, thereby including TB in children. As part of this new
strategy in response to the challenges of improving child TB
management, the child TB subgroup of the DOTS Expansion
Working Group of the Stop TB partnership was formed in 2003.
This has facilitated a number of important initiatives aimed at
greater engagement by NTPs to address child TB issues:
1. Published guidelines for NTPs on TB management in children14
2. Revision of recommended drug dosages of the four first-line
anti-TB drugs for children15,16
3. The development of guidelines for national TB and HIV
programmes on TB management in HIV-infected children17
4. Recommendations to include routine reporting by NTPs of
children receiving TB treatment in two age categories (0-4 years
and 5-14 years)18
5. A research agenda for child TB19
A major challenge that remains is to implement recent
guidelines and recommendations in resource-limited settings
through guidance and training of paediatric and NTP health
workers to increase effectiveness. This review aims to highlight the
rationale and evidence base behind these initiatives, focusing
particularly on revised WHO guidelines for the treatment of
paediatric TB which relate to the first three points above.
PRINCIPLES OF TB TREATMENT
The principles of TB treatment are the same for adults and
children. The combination regimens used to treat active disease
aim to eliminate actively replicating and dormant or near-dormant
mycobacteria using a combination of drugs with different actions
whilst preventing the emergence of drug-resistant organisms, and
all being achieved with a minimum of toxicity.20 Bactericidal drugs
that kill actively metabolizing and replicating organisms are
important to achieve a rapid reduction in microbial load which
leads to clinical improvement, contains disease progression and
terminates transmission.21 Isoniazid (H) and rifampicin (R) are
important first-line bactericidal drugs with isoniazid having the
most potent early bactericidal activity. Sterilizing drugs aim to
eradicate those organisms that are less active metabolically and
those that are in an acidic environment in order to prevent relapse.
23
Anti-TB drug regimens
Intensive phase Continuation phase
2HRZE 4HR
2HRZ 4HR
2HRZSa 4HR
2HRZES/1HRZE 5HRE
Individualized regimens
Rifampicin and pyrazinamide (Z) are important first-line steriliz-
ing drugs. Protection against emergence of drug-resistant organ-
isms is achieved by the combination of effective early bactericidal
activity to reduce microbial load combined with effective
sterilising activity of more slowly replicating organisms, and
strengthened by the addition of a fourth drug such as ethambutol
(E) or streptomycin (S).
The recommended treatment regimens for each TB diagnostic
category are also generally the same for children as for adults.
Table 1 lists the regimens by disease category as currently
recommended by WHO in 2010.15 The most common TB diagnostic
category in children is smear-negative PTB and so the commonest
regimen used in children is 2HRZ 4HR: denotes a two-month
intensive phase of daily isoniazid, rifampicin and pyrazinamide
followed by a four-month continuation phase of daily isoniazid and
rifampicin. A fourth drug is important for cure of disease with a
large microbial load such as sputum smear-positive PTB or PTB
with extensive parenchymal involvement, and to reduce the risk of
development of drug-resistance.21 These regimens are currently
being reviewed by an expert panel and are likely to change before
end of 2010. The use of a fourth drug in the intensive phase for the
common forms in children, PTB and TB adenitis, may in the future
be determined by epidemiological context i.e. population pre-
valence of HIV and isoniazid resistance, rather than by extensive-
ness of pulmonary disease. The recommended treatment of TB
meningitis and osteoarticular TB are also under review and
treatment for 12 months may be the preferred option.
The WHO guidelines of 2003 included 6HE as an alternative to
4HR for the continuation phase of new patient regimens.
Rifampicin is important in the continuation phase to kill slowly
metabolizing organisms whilst isoniazid is less potent for
bactericidal activity in that context and when combined with
rifampicin, is added to provide protection against drug resis-
tance.21 In the alternative combination of 6HE, isoniazid is used for
bactericidal activity but is less potent than rifampicin especially
against slowly metabolizing organisms, while ethambutol has less
potent bactericidal activity and is used for protection against
development of drug resistance. A multi-centre randomised trial
that compared HR to HE in continuation phase in adults with TB
found that relapse was more common in those in the 6HE arm than
for those in the 4HR.22 As a result, 4HR is now the only
recommended option for the continuation phase.
24 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26
Table 2
Recommended first-line drug dosages for children as currently recommended and as previously recommended by WHO
Drug Currently recommended (Ref 15, 16)
Daily dosage (dose range) in mg/kg
Isoniazid 10 (10-15)
Rifampicin 15 (10-20)
Pyrazinamide 35 (30-40)
Ethambutol 20 (15-25)
Streptomycin 15 (12-18)
Thioacetazone No longer recommended
*
Was not recommended for children of less than 5 years of age in 2003
USE OF ETHAMBUTOL IN CHILDREN
The rationale for the addition of ethambutol in certain forms of
TB has been mentioned. Ethambutol was not recommended (or
considered as contraindicated) for use in young children i.e.
children less than 5 years until recently. The need to reconsider the
usage of ethambutol in young children with TB was largely
prompted by toxicity problems with thiacetazone.23 Thiacetazone
commonly caused severe and usually fatal mucocutaneous
reactions in HIV-infected adults and children24,25 and had to be
withdrawn from anti-TB regimens given the risk associated with
its use in HIV-endemic settings where TB was also common.
Streptomycin was not considered an ideal alternative as a fourth
drug for most cases because it cannot be taken orally and therefore
its use often requires hospitalisation for at least two months.
The reasons for concern about the use of ethambutol in young
children relate to the fact that the commonest form of drug-related
toxicity is optic neuritis which can lead to irreversible blindness if
ethambutol is not discontinued when visual symptoms occur.
Thus, young children would be at particular risk because they are
not able to report the early visual symptoms associated with optic
neuritis. A number of extensive reviews report studies of
ethambutol use in children of all ages, including infants, using a
wide range of dosages and providing careful evaluation for visual
side-effects.16,26,27 These studies show that toxicity is dose-related
and related to the duration of therapy. Following review of the
data, it was concluded that ethambutol was safe and the risk of
toxicity negligible for children of all ages if the recommended
dosages were adhered to. Further, the abovementioned removal of
6HE as an alternative to 4HR for the continuation phase (as was
previously recommended23) also reduces the potential of toxicity
because duration of ethambutol usage is now usually limited to the
initiation phase of two months.
REVISION OF DRUG DOSAGES IN CHILDREN
The focus on the safety and dosage issues for ethambutol usage
in children highlighted the general lack of pharmacokinetic (PK)
data in children. Dosage recommendations for anti-TB drugs in
children have been the same in milligrams per kilograms of body
weight as for adults, and the PK data that have informed these
dosages have been from studies in adults. Yet, rates of drug
metabolism, distribution and clearance are likely to be different
especially in young children.28 A number of PK studies in children
show that age is a determinant of serum levels for all the first-line
anti-TB drugs and that the infants and young children have lower
peak serum levels than older children or adults.29–35
A very extensive review conducted by Peter Donald on behalf of
WHO included a careful examination of the pharmacokinetic data
of ethambutol in children.36 It was recognised that using the
dosages recommended by WHO at the time23, the peak serum
concentrations of ethambutol were lower in children than in
adults, especially in young children of less than 5 years.16 Peak
Previously recommended (Ref 23)
Daily dosage (dose range) in mg/kg Thrice weekly dosage (dose range) in mg/kg
5 (4-6) 10 (8-12)
10 (8-12) 10 (8-12)
25 (20-30) 35 (30-40)
15 (15-20)* 30 (20-35)
15 (12-18) 15 (12-18)
2.5 Not applicable
serum concentrations were at such low levels that they might be
inadequate for effective treatment. As a result, the review advised
that the recommended dosages for ethambutol be increased for
children being careful to ensure that the upper limit of
recommended dosage range had an excellent safety profile.16,36
This initiative was followed by a review of the PK data in children
for other first-line anti-TB drugs coupled with a thorough review of
the data relating to the risk of major toxicity, i.e. hepatotoxicity, in
children at different dosages. Following review and consultation,
WHO has recently revised and increased recommended dosages
for rifampicin, isoniazid and pyrazinamide to add to the earlier
revision for ethambutol.16,17,28 The revised recommended dosages
are listed in Table 2 along with the previous dosage recommenda-
tions for comparison. The revised dosage is double that of the
previous recommendation for isoniazid with less of a relative
increase for rifampicin, pyrazinamide and ethambutol. There has
been no change to the recommended dosage of streptomycin but
streptomycin is no longer recommended as a first-line therapeutic
option. Dosage recommendations are no longer listed for inter-
mittent regimens. Daily regimens are preferred over thrice or twice
weekly regimens. A valid concern with intermittent regimens is
that each missed dose represents a larger fraction of the total
number of recommended treatment doses than it would for a daily
regimen.
The revised dosage recommendations are supported by recent
PK data from South African children with TB. Fifty-four South
African children with severe forms of TB received rifampicin (mean
dosage of 9.6 mg/kg body weight) at 1 and 4 months after
commencing anti-TB treatment.34 The mean area under the curve
and 2-hour post-dosing concentrations were lower in HIV-infected
children (n = 21) at 1 and 4 months compared to HIV-uninfected
children but the difference was not significant. However, the main
finding was that the values in all children were less than the
suggested lower limit for 2-hour rifampicin concentrations in
adults. Another study from the same group in South Africa found
that median peak concentrations of isoniazid in children receiving
4-6 mg/kg were 58% lower than in those in children receiving a
dose of 8-10 mg/kg.35 Each increase in the dose by 1 mg/kg and
each increase in age by one year were associated with increases in
peak concentrations of 21% (95% CI, 16%-25%) and 6% (95% CI, 3%-
10%), respectively. They concluded that a daily isoniazid dose of 8-
12 mg/kg should be recommended.
Clearly, the rationale for increasing drug dosages in children
should not simply be directed by an aim to increase serum
concentrations per se but also to improve treatment response. The
poorer outcomes noted in children with TB/HIV co-infection7–10
has increased attention on the need for dosages in children to
achieve optimal serum levels. Treatment trials in HIV-uninfected
children with TB including using the higher dosages currently
recommended have shown that treatment response is satisfactory
and that the drugs are well tolerated.37–43 However, survival is
poorer for HIV-infected children receiving anti-TB treatment and
deaths are particularly common during the initiation phase or first
 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26
two months of treatment.8,10,44 There is a need for PK data of anti-
TB drugs in children for comparison with clinical response. In HIV-
infected children, this comparison will inevitably be confounded
by other variables such as use of antiretroviral therapy (ART).
CHILD-FRIENDLY THERAPY
There are a number of ongoing challenges to the logistics of
providing anti-TB treatment for children.45 The production and
provision of anti-TB drug preparations has largely focused on
therapy for adults. In many settings, children of all ages with TB
receive therapy as tablets or portions of tablets. Tablet portions are
well taken and tolerated by children and have some advantages in
resource-poor setting as they are more readily transported and
stored than liquid preparations. However, the use of tablets means
that a fixed dosage amount is supplied within a certain weight
band and this can lead to a broad range of actual dose received in
mg/kg, especially in the younger children in the lower weight
bands.46 Further, weight gain in response to anti-TB therapy can be
such that the child moves to another weight band during therapy
requiring a higher dosage and this may not be noted. Neonates
deserve special attention. Neonates should be treated with
standard regimens but dosages need careful consideration and
review.
The recent increase in dosages for children has provided
another challenge regarding fixed-dose combinations.45 Tablets of
fixed-dose drug combinations have several advantages over
individual drugs including less likelihood of prescription errors
and lesser pill burden. A more ideal combination has been
proposed by WHO because currently available fixed-dose combi-
nations are not optimal for use in children.16 For example, available
fixed-dose combinations of RHZ for intensive phase have a dosage
ratio of rifampicin:isoniazid of 2:1 which means that extra single
isoniazid tablets are required as well to reach optimal dosage
levels.
TOXICITY OF TB TREATMENT IN CHILDREN
The increase in dosages raises the possibility of an increase in
adverse events due to drug-related toxicity. This is particularly
important to consider because the majority of children being
treated for TB live in settings where surveillance and reporting for
adverse events is poor or non-existent. It is well recognised that
children tolerate anti-TB drugs better than adults when using the
same dosages in mg/kg of body weight.47 Reasons for this include a
lower prevalence of underlying liver disease and alcohol usage but
the lower serum levels achieved in young children using these
dosages may be an additional important factor for fewer episodes
of toxicity.
Hepatotoxicity is the major drug-related adverse event of
concern. There are case reports in the literature of hepatic failure
when recommended dosages are used.47,48 However, serious
adverse events due to anti-TB drugs are rare in children and even
mild side effects are uncommon.47 The risk of hepatotoxicity using
a range of dosages of anti-TB drugs in children has been extensively
reviewed by Peter Donald on behalf of WHO. There is no evidence
that the increased dosages now recommended (Table 2) are
associated with an increased risk of hepatotoxicity. There are data
available for a range of dosages especially of isoniazid because of
its frequent use for preventive therapy.47 Previous studies in
children have used the dosages of anti-TB drugs that are now
currently recommended following recent revision (e.g. isoniazid
10-15 mg/kg/day) and report side-effects to be uncommon and
mild.37–42 Data from children using daily dosages of isoniazid
higher than currently recommended (i.e. greater than 15 mg/kg)
show a higher and significant risk of hepatotoxicity.49–51 However,
25
these studies have mainly been in the context of treatment of
severe disease such as TBM when there are other potential co-
factors for toxicity such as disseminated disease involving the liver,
the use of other anti-TB drugs and anticonvulsants.
Guidelines for the management of TB in HIV-infected children
has recently been published by WHO.17 HIV-infected children
with TB are recommended to receive the same dosages of anti-TB
therapy as HIV-uninfected children. Some studies in adults have
found that HIV infection is associated with an increased risk of
hepatotoxicity to anti-TB drugs.52 There are almost no published
data for children with HIV. A recent trial reported no increased risk
of hepatotoxicity associated with isoniazid (dosage around
10 mg/kg) use as preventive therapy in HIV-infected South
African children receiving ART.53 Peak serum levels of isoniazid,
rifampicin, pyrazinamide and ethambutol were lower, though not
significantly, in HIV-infected compared to HIV-uninfected chil-
dren.33–35 However, the potential for toxicity also relates to drug-
drug interactions and a greater likelihood of underlying liver
disease and co-infections in HIV-infected children. Anti-TB drugs,
mainly rifampicin, have important interactions with ART and have
many similar side effects.17 In addition, HIV-infected children
with TB will routinely receive cotrimoxazole preventive therapy.
It is therefore difficult to distinguish which drug is responsible for
toxicity in this context.21,47 HIV and TB are frequent co-
morbidities in children in developing countries and with the
increasing use of ART, it will be important to monitor and to report
adverse events.
SUMMARY
This review explains the rationale for the recent revision by
WHO of dosage recommendations for first-line anti-TB drugs in
children. Children require higher dosages than adults to achieve
the same serum concentrations. Available data in HIV-unin-
fected children suggest that the revised dosages are within
limits that have a very low risk of causing serious toxicity. An
important challenge will be to examine the impact of higher
dosages on clinical response and risk of toxicity in HIV-infected
children.
PRACTICE POINTS
 The recommended dosages and range for isoniazid,
rifampicin, pyrazinamide and ethambutol have recently
been increased for children
 Previous experience suggests that these drugs are well
tolerated with very low risk of toxicity when used in the
revised dosages, at least in HIV-uninfected children
 Ethambutol is no longer contraindicated for use in young
children of less than 5 years of age and is safe to use at
recommended dosages in all age groups
RESEARCH DIRECTIONS
 The impact of revised dosages on treatment response and
outcome, especially in HIV-infected children
 The risk of severe adverse events using revised dosages,
especially in HIV-infected children
 The impact of HIV infection and malnutrition on pharma-
cokinetic data
 The relationship between pharmacokinetic data, treat-
ment response and risk of toxicity
26 S.M. Graham / Paediatric Respiratory Reviews 12 (2011) 22–26
References
1. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc
Lung Dis 2004;8:636–47.
2. van Rie A, Beyers N, Gie RP, Kunneke M, Zietsman L, Donald PR. Childhood
tuberculosis in an urban population in South Africa: burden and risk factor. Arch
Dis Child 1999;80:433–7.
3. Harries AD, Hargreaves NJ, Graham SM, et al. Childhood tuberculosis in Malawi:
nationwide case-finding and treatment outcomes. Int J Tuberc Lung Dis
2002;6:424–31.
4. Law I, Poka H, Vince J, et al. The burden of childhood tuberculosis in Papua New
Guinea: 2005–2006. Int J Tuberc Lung Dis 2008;12(Suppl 2):S96.
5. Marais BJ, Obihara CC, Warren RM, Schaaf HS, Gie RP, Donald PR. The burden of
childhood tuberculosis: a public health perspective. Int J Tuberc Lung Dis
2005;9:1305–13.
6. Chintu C, Mudenda V, Lucas S, et al. Lung diseases at necropsy in African
children dying from respiratory illnesses: a descriptive necropsy study. Lancet
2002;360:985–90.
7. Schaaf HS, Marais BJ, Whitelaw A, et al. Culture-confirmed childhood tubercu-
losis in Cape Town, South Africa: a review of 596 cases. BMC Infect Dis
2007;7:140.
8. Palme IB, Gudetta B, Bruchfeld J, Muhe L, Giesecke J. Impact of human immu-
nodeficiency virus 1 infection on clinical presentation, treatment outcome and
survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J
2002;21:1053–61.
9. Jeena PM, Pillay P, Pillay T, Coovadia HM. Impact of HIV-1 coinfection on
presentation and hospital-related mortality in children with culture proven
pulmonary tuberculosis in Durban, South Africa. Int J Tuberc Lung Dis
2002;6:672–8.
10. Marais BJ, Graham SM, Cotton M, Beyers N. Diagnostic and management
challenges for childhood tuberculosis in the era of HIV. J Infect Dis
2007;26(Suppl 1):S76–85.
11. Hesseling AC, Cotton MF, Jennings T, et al. High incidence of tuberculosis among
HIV-infected infants: evidence from a South African population-based study
highlights the need for improved tuberculosis control strategies. Clin Infect Dis
2009;48:108–14.
12. Madhi SA, Petersen K, Madhi A, et al. Increased disease burden and antibiotic
resistance of bacteria causing severe community-acquired lower respiratory
tract infections in human immunodeficiency virus type 1-infected children. Clin
Infect Dis 2000;31:170–6.
13. World Health Organization. The Stop TB Strategy: building on and enhancing
DOTS to meet the TB-related Millenium Development Goals. World Health
Organization, Geneva 2006. WHO/HTM/STB/2006.37.
14. World Health Organization. Guidance for national tuberculosis programmes on
the management of tuberculosis in children. World Health Organization,
Geneva 2006. WHO/HTM/TB/2006.371.
15. World Health Organization. Ethambutol efficacy and toxicity: literature review
and recommendations for daily and intermittent dosage in children. World
Health Organization, Geneva 2006. WHO/HTM/TB/2006.365.
16. World Health Organization. Report of the meeting on TB medicines for children
- July 2008. World Health Organization, Geneva 2008 http://www.who.int/
selection_medicines/committees/subcommittee/2/en/index.html accessed
February 2010.
17. World Health Organization. Guidance for National Tuberculosis and HIV Pro-
grammes on the management of tuberculosis in HIV-infected children: recom-
mendations for a public health approach. Geneva: World Health Organization;
2010.
18. World Health Organization. Revised TB recording and reporting forms
and registers. World Health Organization, Geneva 2006. WHO/HTM/TB/
2006.373.
19. World Health Organization. A research agenda for childhood tuberculosis.
World Health Organization, Geneva 2007. WHO/HTM/TB/2007.381.
20. Mitchison DA. The action of antituberculosis drugs in short-course chemother-
apy. Tubercle 1985;66:219–25.
21. Donald PR, Schaaf HS. Old and new drugs for the treatment of tuberculosis in
children. Paediatr Respir Rev 2007;8:134–41.
22. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for
treatment of newly diagnosed pulmonary tuberculosis: international multi-
centre randomised trial. Lancet 2004;364:1244–51.
23. World Health Organization. Treatment of tuberculosis: guidelines for national
programmes. World Health Organization, Geneva 2003. WHO/CDS/TB/
2003.313.
24. Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensitivity reactions due to
thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet
1991;337:627–30.
25. Chintu C, Luo C, Bhat G, et al. Cutaneous hypersensitivity reactions due to
thiacetazone in the treatment of tuberculosis in Zambian children infected with
HIV-I. Arch Dis Child 1993;68:665–8.
26. Graham SM, Daley HM, Banerjee A, Salaniponi FM, Harries AD. Ethambutol in
tuberculosis: time to reconsider? Arch Dis Child 1998;79:274–8.
27. Trébucq A. Should ethambutol be recommended for routine treatment of
tuberculosis in children? A review of the literature. Int J Tuberc Lung Dis
1997;1:12–5.
28. Hill S, Regondi I, Grzemska M, Matiru R. Children and tuberculosis medicines:
bridging the research gap. Bull World Health Organ 2008;86:658.
29. Hussels H, Kroening U, Magdorf K. Ethambutol and rifampicin serum levels in
children: second report on the combined administration of ethambutol and
rifampicin. Pneumonologie 1973;149:31–8.
30. Zhu M, Starke JR, Burman WJ, et al. Population pharmacokinetic modeling of
pyrazinamide in children and adults with tuberculosis. Pharmacotherapy
2002;22:686–95.
31. Zhu M, Burman WJ, Starke JR, et al. Pharmacokinetics of ethambutol in children
and adults with tuberculosis. Int J Tuberc Lung Dis 2004;8:1360–7.
32. Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children
treated for respiratory tuberculosis. Arch Dis Child 2005;90:614–8.
33. Graham SM, Bell DJ, Nyirongo S, et al. Low levels of pyrazinamide and etham-
butol in children with tuberculosis and impact of age, nutritional status, and
human immunodeficiency virus infection. Antimicrob Agents Chemother
2006;50:407–13.
34. Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in children,
with and without human immunodeficiency virus infection, hospitalized for
the management of severe forms of tuberculosis. BMC Med 2009;7:19.
35. McIlleron H, Willemse M, Werely CJ, et al. Isoniazid plasma concentrations in a
cohort of South African children with tuberculosis: implications for paediatric
dosing guidelines. Clin Infect Dis 2009;48:1547–53.
36. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of
children: literature review and recommendations. Int J Tuberc Lung Dis
2006;10:1318–30.
37. Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tubercu-
losis with a six month directly observed regimen of only two weeks of daily
therapy. Pediatr Infect Dis J 2002;21:91–7.
38. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect
Dis J 1990;9:794–801.
39. Kumar L, Dhand R, Singhi PD, Rao KL, Katariya S. A randomized trial of fully
intermittent vs. daily followed by intermittent short course chemotherapy for
childhood tuberculosis. Pediatr Infect Dis J 1990;9:802–6.
40. Tsakalidis D, Pratsidou P, Hitoglou-Makedou A, Tzouvelekis G, Sofroniadis I.
Intensive short course chemotherapy for treatment of Greek children with
tuberculosis. Pediatr Infect Dis J 1992;11:1036–42.
41. Te Water Naude JM, Donald PR, Hussey GD, et al. Twice weekly vs. daily
chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000;19:405–10.
42. Kabra SK, Lodha R, Seth V. Category based treatment of tuberculosis in children.
Indian Pediatr 2004;41:927–37.
43. Swaminathan S, Raghavan A, Duraipandian M, Kripasankar AS, Ramachandran
P. Short-course chemotherapy for paediatric respiratory tuberculosis: 5-year
report. Int J Tuberc Lung Dis 2005;9:693–6.
44. Hesseling AC, Westra AE, Werschkull H, et al. Outcome of HIV-infected children
with culture-confirmed tuberculosis. Arch Dis Child 2005;90:1171–4.
45. Gie RP, Matiru RH. Supplying quality-assured child-friendly anti-tuberculosis
drugs to children. Int J Tuberc Lung Dis 2009;13:277–8.
46. Lodha R, Menon PR, Kabra SK. Concerns on the dosing of antitubercular drugs
for children in RNTCP. Indian Pediatr 2008;45:852–4.
47. Frydenberg AR, Graham SM. Toxicity of first-line drugs for treatment of
tuberculosis in children: review. Trop Med Int Health 2009;14:1329–37.
48. Wu SS, Chao CS, Vargas JH, et al. Isoniazid-related hepatic failure in children: a
survey of liver transplantation centers. Transplantation 2007;84:173–9.
49. Tsagaropoulou-Stinga H, Mataki-Emmanouilidou T, Karida-Kavalioti S, Manios
S. Hepatotoxic reactions in children with severe tuberculosis treated with
isoniazid-rifampin. Pediatr Infect Dis J 1985;4:270–3.
50. Parthasarathy R, Sarma GR, Janardhanam B, et al. Hepatic toxicity in South
Indian patients during treatment of tuberculosis with short-course regimens
containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986;67:99–108.
51. Donald PR, Schoeman JF, O’Kennedy A. Hepatic toxicity during chemotherapy
for severe tuberculosis meningitis. Am J Dis Child 1987;141:741–3.
52. Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced
hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol 2008;23:
192–202.
53. Gray D, Nuttall J, Lombard C, et al. Low rates of hepatotoxicity in HIV-infected
children on anti-retroviral therapy with and without isoniazid prophylaxis. J
Trop Pediatr 2009 Aug 26 [Epub ahead of print].