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Schaaf HS, Marais BJ.. Management of

multidrug-resistant tuberculosis in children: a
survival guide for paediatricians
ARTICLE in PAEDIATRIC RESPIRATORY REVIEWS MARCH 2011
Impact Factor: 2.2 DOI: 10.1016/j.prrv.2010.09.010 Source: PubMed

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Stellenbosch University

Children's Hospital at Westmead

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Paediatric Respiratory Reviews 12 (2011) 3138

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: Childhood TB in 2010

Management of multidrug-resistant tuberculosis in children: a survival guide for

paediatricians
H. Simon Schaaf *, Ben J Marais
Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, and Tygerberg Childrens Hospital, Cape Town, South Africa

EDUCATIONAL AIMS
 To discuss the epidemiology of and mechanisms responsible for the emergence of drug resistant TB in children
 To provide clear guidance on how best to diagnose and treat drug-resistant TB in children
 To discuss ancillary treatment options and the management of HIV-infected children with drug-resistant TB

A R T I C L E I N F O

S U M M A R Y

Keywords:
multidrug-resistant
tuberculosis
children
XDR-TB
MDR-TB
treatment

WHO estimated that of 9.4 million cases of tuberculosis (TB) worldwide in 2008, 440,000 (3.6%) had
multidrug-resistant (MDR)-TB. Childhood TB is estimated at 10-15% of the total burden, but little is
known about the burden of MDR-TB in children. Children in close contact with MDR-TB cases are likely to
become infected with the same resistant strains and are vulnerable to develop disease. Although MDRTB is a microbiological diagnosis, children should be treated empirically according to the drug
susceptibility result of the likely source case, as often cultures cannot be obtained from the child. MDRTB treatment in children is guided by the same principles, using the same second-line drugs as in adults,
with careful monitoring for adverse effects. Co-infection with HIV poses particular challenges and
requires early initiation of antiretroviral therapy. Preventive therapy for high-risk MDR-TB contacts is
necessary, but no consensus guidance exists on how best to manage these cases. Pragmatic and effective
Infection control measures are essential to limit the spread of MDR-TB.
2010 Elsevier Ltd. All rights reserved.

HOW COMMON IS TUBERCULOSIS AND MDR-TB IN CHILDREN?

The World Health Organization (WHO) estimated that in 2008,
440,000 (3.6%) of the 9.4 million tuberculosis (TB) cases worldwide
had multidrug-resistant (MDR)-TB (i.e. resistance to isoniazid and
rifampicin).1 Childhood TB comprise approximately 10-15% of the
global disease burden, with higher rates in developing countries.2
Little data is available on the occurrence of MDR-TB in children.3 A
prospective drug resistance surveillance study conducted from
1994-2007 in the Western Cape province, South Africa, demonstrated a clear upward trend with an increase in any resistance
(isoniazid and/or rifampicin) from 6.9% to 15.1% and in MDR-TB from
2.3% to 6.7%.4 Since the majority of children (>90%) who develop TB
do so within 12 months of infection, paediatric surveillance studies
provide unique epidemiologic insight into current Mycobacterium

* Corresponding author. Department of Paediatrics and Child Health, PO Box

19063, Tygerberg, 7505, South Africa. Tel.: +27 21 9389112; Fax: +27 21 9389138.
E-mail address: hss@sun.ac.za (H.S. Schaaf).
1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2010.09.010

tuberculosis transmission patterns within communities, indicating

which genotypes are successfully transmitted.5,6
The absence of data on drug-resistant TB among children reects
the fact that cultures for M. tuberculosis and drug susceptibility
testing (DST) are rarely done, since obtaining adequate specimens in
child TB suspects are difcult and mycobacterial culture yields are
low. In addition, careful identication of the likely adult source case
is poorly performed and if child contacts are identied, the
treatment response and/or DST of the adult source case is rarely
considered when treatment or chemoprophylaxis is initiated in
children.4,7 This overview describes what is known about the
epidemiology, diagnosis and management of children with MDR-TB.
HOW DOES DRUG RESISTANCE DEVELOP AND SPREAD?
There are two underlying concepts; 1) the acquisition of drug
resistance by individual patients, originally infected with drugsusceptible bacilli (acquired drug resistance), and 2) transmission
of drug-resistant bacilli (transmitted drug resistance).
M. tuberculosis acquires drug resistance through spontaneous
gene mutations; there is no horizontal gene transfer between

32

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

bacilli. Therefore, the risk of acquiring drug resistance is directly

proportional to the number of bacilli present; a bacterial load of
>106 bacilli is likely to contain some drug-resistant mutants.8
Spontaneous resistance mutations occur with variable frequency;
mutations against second-line drugs occur with greater frequency
compared to rst-line drugs. The estimated number of bacilli
present in caseous foci (e.g. intrathoracic lymph node disease in
children), is low (104-105), while large numbers of bacilli (107-109)
are present within pulmonary cavities of adult-type lung disease.8
Drug-resistant TB is a man-made disease reecting sub-optimal
case management. Treatment with a single drug rapidly selects for
drug-resistant disease. Using a combination of 3-4 drugs kills
different mycobacterial subpopulations and protects against the
development of drug resistance. If single drugs are used in
succession, or a weak combination of drugs with insufcient
protection of companion drugs, then additional drug resistance
accumulates. Acquisition and amplication of drug resistance
result from poor drug regimens (e.g. adding a single drug to a
failing regimen, prescribing a weak combination of drugs,
interruption of drug supply or using drugs with poor bioavailability) and/or non-adherence to treatment. The risk is highest in
adults with lung cavities and relatively low in children with
paucibacillary disease.
Delayed diagnosis and/or poor management of infectious drugresistant TB cases allows drug-resistant M. tuberculosis strains to be
transmitted and cause disease, especially in vulnerable groups

[()TD$FIG]

such as young children and immunocompromised patients. Early

diagnosis of drug-resistant TB is essential to limit ongoing
transmission, and this is not achieved by sputum smear microscopy which is the only test available in most TB endemic areas.

HOW TRANSMISSIBLE (INFECTIOUS) AND VIRULENT (ABLE TO

CAUSE DISEASE) IS DRUG-RESISTANT TB?
Snider et al9 showed that isoniazid-resistant strains caused as
much infection as drug-susceptible strains in child contacts.
Successful transmission of MDR-TB strains from adult source cases
to child contacts with progression to disease was also conrmed by
DNA ngerprint studies.10 Infection control studies from Peru
showed that MDR-TB strains can be highly infectious and rapidly
transmitted within poorly ventilated hospital wards.11
The importance of close contact is reected by the concordance
observed between DST results in drug-resistant source cases and
their close contacts who developed disease; varying from 46% in
adults to 80% in children.7,12,13 Discordant results may result from
poor standardization of second-line DSTs, while contacts could
also have been infected by other, often unidentied, source cases
with drug-susceptible TB. In practice this means that special effort
has to be made to obtain specimens for culture and DST in any child
TB suspect who report recent close contact (within 12 months)
with someone diagnosed with drug-resistant TB. While awaiting

New child TB case

Conrmed DR-TB

DST known

Conrmed DS-TB

No

Contact with infecous TB case?

Yes
Yes or No

Drug-resistant source case

Source case DST not done &

- child failing 1st-line treatment or
- source retreatment or chronic TB case

Conrmed or Probable DR-TB

Suspected DR-TB

Treat as DR-TB according to

DST result of child or sources isolate
Do culture & DST
if DR not conrmed

Do culture/DST on child & sources

specimens. Treat as DS-TB
Close follow-up essenal

Check DST results

Check response to treatment
If DST shows DR or if failing
adherent therapy, treat as DR-TB

No source case known or

DST not done, no risk factor
Drug-suscepble source case

Probable or Conrmed DS-TB

Do culture/DST on childs
specimens if DS not conrmed
mainly if poor response to treatment

Check DST results

If DST shows DR treat as DR-TB

DST = drug suscepbility test; DR = drug-resistant; DS = drug-suscepble

Reference to culture and DST implies that facilies are available
[Adapted from ref 16]
Figure 1. Algorithm for the diagnosis of suspected or conrmed drug-resistant TB in children.

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

DST results, children should be treated according to the DST result

of the likely source cases isolate.
WHEN TO SUSPECT DRUG-RESISTANT TB IN A CHILD?
Potential drug resistance should be considered in any child
diagnosed with TB. The diagnosis of TB in children often relies on a
constellation of; a history of contact with an infectious TB source
case; symptoms and signs suggestive of TB (e.g. chronic cough,
weight loss/failure to thrive or signs of pulmonary or extrapulmonary TB); and special investigations (e.g. tuberculin skin test
(TST) and/or chest radiography). In most cases smear microscopy
for acid-fast bacilli (AFB), culture and DST are not done, as
adequate specimens are difcult to obtain and often negative.
Although drug-resistant TB is primarily a microbiological diagnosis, a history of previous TB treatment or contact with adult
drug-resistant TB cases is extremely important.
The following practice points should guide the diagnosis of
drug-resistant TB in children (see also Figure 1):1416
PRACTICE POINTS: MAKING THE DIAGNOSIS OF DRUGRESISTANT TB IN CHILDREN
 Isolating M. tuberculosis and demonstrating drug resistance on DST remains the only way to conrm drugresistant TB
 Probable drug-resistant TB can be diagnosed when a child
with TB reports recent close contact with an adult with
drug-resistant TB
 Drug resistance should be suspected in any child who fails
to improve while adherent to rst-line anti-TB therapy or
if the adult source case is a treatment failure, a retreatment
case or recently died from TB
 Although children usually develop transmitted drugresistant TB, some children develop lung cavities with
high bacillary loads and may acquire drug resistance if the
treatment regimen is inadequate, supply of drugs is
irregular or treatment adherence is poor.

WHAT SPECIMENS TO COLLECT?

When MDR-TB is suspected, every effort should be made to
conrm the diagnosis by obtaining specimens for culture and DST.
Respiratory specimens may be obtained by gastric aspirates,
induced sputum and/or nasopharyngeal aspirates. Bronchoalveolar lavage offers no advantage over less invasive methods. Older
children (>6-8 years) can often expectorate sputum.17 More
invasive methods for obtaining specimens may be justied in
children with extrapulmonary TB, for example ne needle
aspiration biopsy or formal biopsy from peripheral lymphadenitis,
or pus swab if a draining sinus has formed. Other specimens that
should be obtained are cerebrospinal uid in TB meningitis, pleural
or pericardial uid if effusions are present, ascitic uid, ear swabs
in chronic otorrhoea, bone marrow aspiration if disseminated TB is
suspected and biopsies/swabs from other areas such as abscesses
or osteoarticular TB.

33

from 6 weeks to 4 months. Automated liquid broth media, such as

the Mycobacterial Growth Indicator Tube (MGIT) 960 system
(Becton-Dickinson, Sparks, MD) improved culture yields and
reduced time to culture and DST results (10-14 days in specimens
with high organism loads). However, in children with paucibacillary TB, culture and DST results can still be delayed for 6-8 weeks.
These systems are expensive and need well equipped laboratories
and technical expertise.
The risk posed by ongoing transmission of drug-resistant
strains and the risk of amplication of resistance if patients are
treated with incorrect regimens call for rapid and reliable
diagnosis. More rapid culture and DST methods, such as the
microscopic observed drug-susceptibility (MODS) assay, in which
culture and DST is performed at the same time and results are
known within 7-14 days shows benet, but have not been
implemented widely.18 Since many of the genes encoding
resistance have been determined, nucleic acid amplication tests
(NAATs) offer great promise for rapid and accurate diagnosis.
NAATs that have shown promise include the GenoType MTBDRplus
(Hain Lifescience, Nehren, Germany) and INNO-LiPA.Rif.TB (Innogenetics, Zwijndrecht, Belgium).3 The GenoType MTBDRplus
identies the majority of rifampicin and isoniazid resistance while
the INNO-LiPA Rif.TB only identies rifampicin resistance.
Correlation with conventional culture and DST methods is high
(95% for rifampicin resistance).19 The INNO-LiPA.Rif.TB does not
identify isoniazid resistance, while the GenoType MTBDRplus assay
only identies isoniazid resistance associated with the inhA
promoter region or katG gene mutations, which may cause
over-diagnosis of rifampicin mono-resistance since a proportion
of isoniazid-resistant strains will not be detected. Rifampicinmonoresistant TB cases diagnosed by these assays only should be
managed as MDR-TB cases.
Between 5-10% of all MDR-TB patients have extensively drugresistant (XDR)-TB (i.e. MDR-TB plus resistance to the uoroquinolones and one of the second-line injectable agents). DST for rstline drugs other than isoniazid and rifampicin and second-line
drugs are still done by conventional culture and DST methods,
which remain time consuming and poorly standardized. New
genetic tests, such as the GenoType MTBDRsl (Hain Lifescience for
second-line drugs, Nehren, Germany) are being developed to
improve time-to-detection and reliability of DSTs for these drugs,
especially the uoroquinolones and injectable agents.20

WHAT ARE THE PRINCIPLES OF CASE MANAGEMENT?

Children with MDR-TB are managed in much the same way as
adults, but there are some differences. Conrmation of MDR-TB
may not be possible and child TB cases in recent close contact with
an adult MDR-TB case or failing to respond to adherent rst-line
treatment should be empirically treated as MDR-TB cases. Because
of the paucibacillary nature of early primary disease (contained
primary lung lesion or uncomplicated hilar/mediastinal lymph
node enlargement), these children may need fewer drugs and
shorter duration of treatment,7,21 although there are no randomized control studies to conrm this. Important principles in the
management of MDR-TB are summarized as follows:14,15

WHAT DIAGNOSTIC METHODS ARE AVAILABLE?

PRACTICE POINTS: PRINCIPLES OF MDR/XDR-TB CASE

MANAGEMENT

Many developing countries either have no culture and DST

facilities (although there is a strong drive to improve laboratory
capacity) or use solid culture media (Lowenstein-Jensen or agar
plates) and the indirect proportion method for DST. Culture yields
are poor with solid media, and culture and DST results could take

 Never add a single drug to a failing regimen; this may lead

to amplication of resistance
 All treatment should be given daily and under direct
observation

34

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

 Treat the child according to the DST results from the likely
source case, unless M. tuberculosis culture and DST is
available from the child
 Do second-line DST in all MDR-TB cases to exclude
resistance to the uoroquinolones and/or second-line
injectables, as this may call for additional drugs early in
therapy
 Give at least 3 (only in early primary disease) or preferably
4 drugs to which the patient or adult source case is nave or
their isolates susceptible
 A regimen should be build from different drug groups (see
table 1) taking into account drug resistance, possible
cross-resistance, adverse effects and previous use of drugs
 Caregivers need counseling and support regarding adverse
effects, treatment duration and importance of adherence
at every follow-up visit.
 Clinical, radiological and culture response to treatment
should be monitored. Monthly smear microscopy and/or
cultures should be done until conrmed negative on 3
consecutive occasions, thereafter 2-3 monthly follow-up
cultures can be done
 Clinical monitoring for adverse effects should be done at
every visit. Special investigations should be guided by the
adverse effect prole of the drugs used

WHICH DRUGS TO USE IN THE TREATMENT OF CHILDREN WITH

MDR-TB AND XDR-TB?
WHO identies standardized, empirical and individualized
treatment regimens.15 The choice of treatment regimen will differ
according to the availability of DST and drug resistance surveillance data in a particular setting. With standardized treatment all
patients in certain categories (e.g. treatment failure) are started on
the same xed regimen. This may be the most pragmatic option,
but is accompanied by a risk of amplifying drug resistance if not

tailored according to ongoing drug resistance surveillance data.22

Children are best managed with empirical or individualized
treatment regimens, which utilize the same rationale. Empirical
treatment is designed on the basis of previous treatment history
and DST results of the child (or likely source case), while
individualized treatment is based on the patients own current
DST result and previous treatment history.
With extensive pulmonary or disseminated extrapulmonary
disease, a minimum of 4 active drugs should be included in the
regimen.3 When building a regimen, start with rst-line (Group 1
Table 1) drugs to which DST results show susceptibility. Previous
treatment (i.e. treatment for >1 month) with any specic drug in a
failing regimen should indicate possible resistance to that drug. DST
results for pyrazinamide are difcult to obtain and for ethambutol
notoriously unreliable.23,24,25 Therefore, if either the child or the
source case had previously been treated with pyrazinamide and/or
ethambutol, then these drugs could still be used empirically or if DST
shows susceptibility, but only as additional drugs.25,26
Add one drug from group 2 (injectable agents). There is much
debate about which injectable agent should be used in MDR-TB,
because of cross-resistance between these drugs. We currently use
amikacin in children because of fewer adverse effects and
convenience of smaller ampoules appropriate for dosaging in
children. The majority of MDR-TB patients are resistant to
streptomycin, therefore this drug is not considered in MDR-TB
therapy. However, in XDR-TB DST for streptomycin is worthwhile
doing, since cross-resistance with second-line injectable agents
may not be complete and if susceptible streptomycin could be
added to an XDR-TB regimen.
Thereafter add a uoroquinolone (Group 3 Table 1).
Levooxacin and moxioxacin are superior to ooxacin and if
resistance to ooxacin is found, resistance to the newer generation
uoroquinolones such as moxioxacin, may not be complete
(important for management of XDR-TB).27,28 Use of ciprooxacin
in anti-TB treatment is no longer recommended.26
More than one drug from group 4 (Table 1), taking into account
similar drugs and adverse effects, should be included in the

Table 1
Drug groups for MDR and XDR-TB treatment regimens [Adapted from reference 26]
Drug Group

Drug name

Daily dosage in mg/kg

Maximum dose (mg)

Ethambutol
Pyrazinamide
Streptomycin (1st-line)
Amikacin
Kanamycin
Capreomycin
Ooxacin
Levooxacin
Moxioxacin
Ethionamide (or prothionamide)
Cycloserine (or terizidone)
e
Para-aminosalisylic acid (PAS; 4gr sachets)
High-dose INH
f
Linezolid
Amoxicillin/clavulanate
Clarithromycin
g
Thioacetazone
Imipenem/cilastatin
Clofazimine

20-25
30-40
15-20
15-20
15-20
15-20
15-20
7.5-10
7.5-10
15-20
10-20
150
15-20
10-12 twice daily
15 amoxicillin 3 x daily
7.5-15 twice daily
3-4
(only IV)
3-5

2000
2000
1000
1000
1000
1000
800
750
400
1000
1000
12g
400
300 once/twice daily

Group 1: Oral rst-line drugs

Group 2: Injectable agents.

Aminoglycosides
Cyclic polypeptide
Group 3: Fluoroquinolones

Group 4: Second-line oral drugs

Group 5: Drugs of uncertain value

500 twice daily

150
300

a. DST could be unreliable use as additional drug if DST result susceptible or not done25
b. Choose one drug in each of these groups; amikacin preferred to kanamycin in children
c. Choose one or more of these drugs to make up total of 4 new drugs
d. Consider use of these drugs if insufcient drugs to build an acceptable regimen with previous groups. Each drug only considered as half a drug, therefore 2 drugs in this
group counts as one additional drug.
e. PAS is administered in acidic base (e.g. yoghurt or orange juice) for improved absorption
f. Linezolid dosage for TB is uncertain, but lower doses (300 mg twice daily or even 300 mg daily in adults) cause less adverse effects and still seem effective.33
g. Thioacetazone should NOT be used in HIV-infected patients

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

regimen according to DST or non-exposure to these drugs to a total

of 4 active drugs.
If these groups are not sufcient to build an acceptable regimen
of 4 active drugs (excluding drugs with doubtful activity), drugs
from group 5 could be added. WHO recommends that two drugs in
group 5 should be added to make up one active drug.26 Isoniazid at
high-dose (15-20 mg/kg daily) may be benecial especially when
given with ethionamide where minimal inhibitory concentrations
(MIC) for isoniazid and ethionamide DST are not available.
Depending on which mutation causes resistance, either ethionamide or high-dose isoniazid is likely to retain some activity.29 A
randomized control trial in India showed that the addition of
high-dose isoniazid to a standard MDR-TB treatment regimen,
compared with normal dose (5 mg/kg) or no isoniazid, resulted in
earlier sputum conversion and improvement in chest radiographs.30 Linezolid, another group 5 drug, has been used with good
clinical effect in MDR/XDR-TB cases, but cost and severe adverse
effects are restricting its use.31,32 Some reports have shown lower
dosages (300 mg/day in adults) to be effective and to have fewer
adverse effects.33
Treatment of tuberculous meningitis requires drugs that
effectively penetrate the blood-brain barrier such as isoniazid,
pyrazinamide, the thioamides, cycloserine/terizidone and the
uoroquinolones. The second-line injectable drugs only penetrate
the blood-brain barrier during acute inammation.
WHAT IS THE OPTIMAL TREATMENT DURATION?
The optimal duration of MDR-TB treatment in children and
adults remains unknown; current recommendations are based on
personal experience and expected efcacy of the various secondline drugs. WHO guidelines15,26 recommend treatment until 18
months after the rst negative culture (24 months in XDR-TB).
Because children often have paucibacillary disease shorter
duration of treatment (12 months) may be sufcient for early,
non-extensive disease.7,21 In case of children with extensive lung

35

involvement, severe forms of extrapulmonary disease or disseminated (meningitis or miliary TB) disease, the same duration as in
adults apply.
HOW TO ENSURE TREATMENT ADHERENCE?
It is essential to ensure adequate adherence to treatment, since
treatment options are limited. Treatment of MDR/XDR-TB should
only be given as directly observed therapy by health care workers
or treatment supporters. Hospitalization for the rst 4-6 months of
treatment is often required to administer second-line injectable
agents, monitor for adverse effects and ensure adequate treatment
response.
Comprehensive and continuous counseling of the child and/or
parent/caregiver is essential to ensure that they understand the
seriousness of the situation and the justication of prolonged and
complicated treatment regimens. Socioeconomic evaluation and
support of the family is important. Teenagers need special
attention and in our own experience, adherence should be checked
with the person responsible for direct observation of treatment.
Adverse effects of second-line drugs are more frequent than in
rst-line drug treatment; fortunately, these adverse effects can
usually be managed without stopping drugs (see Table 2).34 Nonavailability of child-friendly drugs and dosages complicates
administration of drugs to children.
Hospital/clinic-based and community-based treatment models
provide comparable outcomes.7,35 Some children require initial
admission because of their clinical condition or social circumstances. In our experience hospitalization in a specialized unit
during the intensive phase allows for daily injections by experienced
nursing staff and better monitoring of adverse effects and repeat
cultures. The remainder of the treatment is usually given at primary
health care level. Community home-based directly observed
treatment of HIV-uninfected MDR-TB patients in Peru was shown
to be very effective.35 In both models expert health care teams
should be involved in the continued care of the children.

Table 2
Adverse effects of rst and second-line drugs used in the treatment of children with multidrug-and extensively drug-resistant tuberculosis
Drug

Adverse effects

How to monitor

Isoniazid

Hepatotoxicity
Rash
Peripheral neuropathy (rare)
Psychosis
Hepatotoxicity
Arthralgia
Rash
Optic neuritis (rare)

Jaundice, liver enzymes

Clinical observation for
other adverse effects

Pyrazinamide

Ethambutol
Second-line injectable drugs
Amikacin
Kanamycin
Capreomycin
Fluoroquinolones
Ooxacin
Levooxacin
Moxioxacin
Thioamides
Ethionamide
Prothionamide
Cycloserine
Terizidone
Para-aminosalisylic acid (PAS)
Linezolid

Ototoxicity (starts with high frequency hearing

loss and may continue after stopping culprit drug)
Nephrotoxicity (Renal failure and severe hypokalaemia)

Gastro-intestinal disturbance
Insomnia
Arthralgia

Jaundice, liver enzymes

Clinical observation for
other adverse effects
Vision screening if possible
Hearing test (audiology)

Serum creatinine and potassium levels

Clinical observation and caregivers report
Serum uric acid if used with pyrazinamide

Gastro-intestinal disturbance (nausea, vomiting,

abdominal pain and anorexia)
Hepatotoxicity
Hypothyroidism
Psychosis, convulsions, parasthesia, depression

Clinical observation
Jaundice serum alanine transferase and billirubin
Thyroid stimulating hormone and free T4 levels
Clinical observation

Gastro-intestinal disturbance (mainly diarrhoea)

Hypothyroidism
Myelosuppression
Lactic acidosis
Peripheral neuropathy
Pancreatitis

Clinical observation
Thyroid stimulating hormone levels and free T4
Full blood counts
Serum lactate level
Clinical observation
Clinical observation

36

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

HOW SHOULD ADVERSE EFFECTS BE MANAGED?

Corticosteroids

Children should continue on effective MDR-TB treatment

regimens, therefore, adverse effects should be managed rather
than drugs stopped. Isoniazid, pyrazinamide and the thioamides
should be stopped immediately if jaundice develops. Once liver
enzymes return to normal these drugs could be reintroduced one
by one, with careful monitoring for an increase in alanine
transferase. The gastrointestinal disturbances caused by the
thioamides and para-aminosalisylic acid (PAS) can be mostly
overcome by splitting the dose or starting with a lower dose
increasing to full dose in 1-2 weeks. Hypothyroidism (thioamides
and PAS) may need addition of low-dose thyroxine supplementation until completion of MDR-TB treatment.
Ethambutol may cause optic neuritis, which is difcult to
monitor in children less than 5 years of age. Although the risk
seems low at recommended dosages (15-25 mg/kg/day),36 older
children should be screened by testing visual acuity and colour
vision. Vision disturbance is reversible if stopped early.
All children on injectable agents should be evaluated at 1-2
monthly intervals for hearing loss. If hearing loss develops in a child
responding well to treatment it may be considered to stop the
injectable agent earlier (at four rather than six months). However, if
the child has extensive disease and few effective drugs are available
the risk versus benet of continuing the injectable agent should be
considered. Nephrotoxicity, renal failure and hypokalaemia in
children is rare, although it has been described in adults.27,37
Joint or musculoskeletal adverse effects from the uoroquinolones in children seems mild and are rare.7,35 Psychosis is rarely
seen in children, but could be caused by isoniazid or cycloserine/
terizidone. Discontinuing isoniazid and/or lowering the dose of
cycloserine/terizidone may be sufcient.

Corticosteroids are often used in TB meningitis, large airway

obstruction by mediastinal lymph nodes or pericardial TB. Most
commonly oral prednisone at 2 mg/kg daily (maximum 60 mg) for
4 weeks (reduced over 1-2 weeks) is used.42 The use of
corticosteroids in children with undiagnosed MDR-TB may cause
further progression of disease.16

ADJUNCTIVE THERAPIES

MANAGEMENT OF HIV-INFECTED CHILDREN WITH MDR-TB

All child TB suspects should be screened for HIV infection if
either living in a high prevalence HIV area (prevalence >1%) or
considered to be at risk for HIV infection.17 HIV-infected children
with TB, especially MDR-TB, are at increased risk of severe disease
and death, which emphasizes the need for early diagnosis and
optimal treatment. Concomitant antiretroviral therapy (ART)
markedly improves TB outcome in children and adults.43,44 A
prospective trial showed clear benet for starting ART early in TB
treatment despite the stage of HIV disease with no increase in
adverse effects.44 XDR-TB patients co-infected with HIV also had
improved outcome if started early on ART.3 WHO recommends
starting ART within 2-8 weeks after starting anti-TB treatment in
HIV-infected children with MDR-TB.41
Drug interactions are usually not a problem with regimens not
containing rifampicin. Reasons for postponing ART initiation
include possible confusion of overlapping drug adverse effects
and the risk for immune reconstitution inammatory syndrome
(IRIS), a paradoxical worsening of symptoms and signs with
improvement in the bodys immune response.41 IRIS, if severe,
could be managed by corticosteroids. In addition to early ART
initiation, all co-infected child TB cases should receive cotrimoxazole prophylaxis and pyridoxine supplementation.41

Surgery

MANAGING CHILD CONTACTS OF INFECTIOUS MDR-TB CASES

Some conditions, such as severe airway obstruction by

mediastinal lymph nodes, pericardial or pleural effusion, or noncommunicating hydrocephalus may require surgery. In adults,
resectional lung surgery has been reported as an adjunct in the
treatment of MDR/XDR-TB, especially those patients resistant to
most drugs.38,39 Patients for lung surgery need careful selection
and experienced surgeons as these procedures are not without
complications.38,39

Preventive therapy for MDR-TB remains controversial. Current

WHO guidelines do not recommend preventive therapy for
contacts of MDR-TB patients.15 Failure of isoniazid or isoniazid/
rifampicin preventive therapy in MDR-TB contacts has been
documented.12,45 No randomized controlled trials have been done
on preventive therapy in MDR-exposed or infected individuals.
There is general agreement that preventive therapy is warranted,
especially for high-risk contacts such as immune compromised
individuals or very young children, but there is no consensus on
what regimen(s) should be used.46
TB guidelines from the United States recommend a two-drug
regimen for people with latent TB infection exposed to MDRTB.47,48 In a prospective observational study where child contacts
of adult MDR-TB cases were offered individually tailored
preventive therapy, with two drugs to which the source cases
isolates were susceptible or nave for a period of six months, was
found to be effective.21 Immune immature children (<3 years) and
immunocompromised children, irrespective of their age are highly
vulnerable.
In TB endemic areas, exposure to multiple source cases, both
drug-susceptible and drug-resistant TB, is not uncommon. We
currently use a 3-drug combination of high-dose (15-20 mg/kg)
isoniazid and two drugs to which the source cases isolate is
susceptible or nave, usually a uoroquinolone (ooxacin) and
ethambutol (or ethionamide). Single-drug preventive therapy with
the new generation uoroquinolones (levooxacin) is currently
explored. Further studies are urgently needed to evaluate regimens
and duration of preventive therapy in high-risk children in close
contact with infectious MDR-TB cases.

Nutritional support
Malnutrition increases the risk of developing disease after M.
tuberculosis infection, and optimal nutrition is an important part of
treatment. Because the diagnosis and treatment of MDR-TB is often
delayed,7 nutritional status in these children may have deteriorated. Additionally TB is known to be a disease associated with
poor socioeconomical circumstances, and second-line drugs such
as ethionamide and PAS may have gastrointestinal adverse effects
including nausea and anorexia. For these reasons children with
MDR-TB usually require nutritional support.
Several anti-TB and antiretroviral drugs may cause adverse
neurological effects which could be associated with low levels of
pyridoxine (vitamin B6). Low levels of pyridoxine was found in a
large proportion of children hospitalized for TB and levels
remained low in many HIV-infected children despite receiving
daily recommended doses of pyridoxine.40 Therefore pyridoxine is
recommended in TB/HIV-co-infected children but also for MDR-TB
patients receiving high-dose isoniazid and/or cycloserine/terizidone.15,40 Recommended dosage is 1-2 mg/kg daily.41

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138

Preventive therapy for XDR-TB contacts is not recommended,

but in the light of possible low-level isoniazid resistance, which
could be conrmed by isoniazid MIC or presence of inhA promoter
region mutation on line probe assay, high-dose isoniazid (1520 mg/kg) may provide some protection to high-risk child
contacts.
Most important is that child contacts of infectious MDR/XDR-TB
source cases, especially those less than 5 years of age or those HIVinfected irrespective of age, should be closely followed up for a
minimum of two years and appropriate treatment started as soon
as TB is diagnosed.15
INFECTION CONTROL

14.
15.
16.

17.

18.

19.

Although childhood TB is generally not infectious, children with

progressive lung disease or cavitary TB (often smear-positive) are
infectious and should be isolated.49,50 Isolation in hospital should
last until they are sputum smear-negative on at least two occasions
2-4 weeks apart and preferably culture-negative as well. Also,
accompanying or visiting adults may have infectious pulmonary
TB and pose a transmission risk.51

22.

CONCLUSION

23.

Despite the lack of epidemiologic data on drug-resistant TB in

children, it is evident that they are as much affected by the growing
MDR/XDR-TB epidemic as adults, especially in settings where
ongoing transmission is poorly controlled. Most children with
MDR-TB have been infected by an infectious adult MDR/XDR-TB
source case. Failing to identify such contact may delay diagnosis of
MDR/XDR-TB, with unnecessary progression of disease and/or
death. Since microbiological conrmation of drug-resistant TB in
children is difcult, empiric treatment is reasonable and should be
guided by the DST pattern of the likely source case. Children
tolerate second-line anti-TB drugs well and, if diagnosed timeously
their outcome is generally good.

20.

21.

24.
25.

26.

27.

28.

29.

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