Indian J Pediatr (April 2011) 78(4):456463

DOI 10.1007/s12098-010-0344-2

SYMPOSIUM ON PEDIATRIC TUBERCULOSIS

Multi-drug Resistant Childhood Tuberculosis

Varinder Singh & Satnam Kaur

Received: 29 November 2010 / Accepted: 30 November 2010 / Published online: 31 December 2010
# Dr. K C Chaudhuri Foundation 2010

Introduction

problems especially, in developing countries. Emergence of

drug resistant tuberculosismultidrug resistant tuberculosis
(MDR TB) followed by extensively drug resistant tuberculosis
(XDR TB) and most recently pan drug resistant tuberculosis
has further fuelled the situation. Drug resistance severely
threatens tuberculosis control since it raises the possibility of
return to an era where no effective drugs were available for its
treatment. Though progress is being made in global control of
drug susceptible tuberculosis viz. falling incidence of TB
since 2004, achievement of 87% success rate of anti
tuberculosis treatment in 2007, yet, the same is not true for
drug resistant tuberculosis [1].
Pediatric tuberculosis contributes to a significant
proportion of TB disease burden and children suffer
from severe tuberculosis related morbidity and mortality,
particularly in endemic areas. However, pediatric tuberculosis has been relatively neglected till now because of
difficulty in establishing an accurate diagnosis and lower
priority given to children by tuberculosis control programmes. Both research and surveillance data in the field
of childhood tuberculosis have been limited. Relatively
far lesser is known about the diagnosis and management
of childhood MDR TB. Clinical management as well as
outcome of treatment of MDR TB in children is not well
documented. The present review presents the issues related to
the management of drug resistant TB among children.

Despite all the advances made in treatment and management, tuberculosis remains one of the major global health

Drug ResistanceDefinitions

V. Singh (*) : S. Kaur

Department of Pediatrics, Lady Hardinge Medical College and
Associated Kalawati Saran Children Hospital,
Bangla Sahib Marg,
New Delhi 110001, India
e-mail: 4vsingh@gmail.com

Drug resistance in mycobacteria is defined as decrease in

sensitivity to a sufficient degree to be reasonably certain
that the strain concerned is different from a sample of wild
strains of human type that have never come in contact with
the drugs [2].

Abstract Emergence of drug resistant tuberculosis is one

of the major challenges faced by health community
globally. Tuberculosis is an important cause of morbidity
and mortality among children in endemic areas, yet little
is known regarding epidemiology of pediatric tuberculosis
and even far lesser information is available about
epidemiology, diagnosis, management and treatment outcome of drug resistant tuberculosis in children. Despite
limited data and difficulties in its management, drug
resistant tuberculosis can be successfully treated even in
resource poor settings with proper use of existing
technologies. A high index of suspicion and early drug
susceptibility testing is the key to early diagnosis and good
treatment outcome. Difficulties in establishing the diagnosis, drug toxicities and absence of pediatric formulations
add challenges to the management of Pediatric MDR TB
Cases. Active research is required to answer the unresolved issues of finding optimal diagnostic tools, treatment
regimens and duration and chemoprophylaxis in pediatric
drug resistant tuberculosis.
Keywords Multidrug resistant . Childhood tuberculosis .
Treatment . Chemoprophylaxis . Second line drugs

Indian J Pediatr (April 2011) 78(4):456463

Multidrug Resistant Tuberculosis (MDR TB) MDR TB is

caused by strains of Mycobacterium tuberculosis that are
resistant to at least isoniazid (INH) and rifampicin (RMP)
with or without resistance to other first line drugs.
Extensively Resistant Tuberculosis (XDR TB) XDR TB is
caused by strains of Mycobacterium tuberculosis that are
MDR with additional resistance to any fluoroquinolone and
one of the three second line injectable drugsamikacin,
kanamycin or capreomycin.
Polyresistance Strains of Mycobacterium tuberculosis that
are resistant to combination of drugs other than both INH
and RMP is called polyresistant.
Pan Drug Resistant Tuberculosis Pan drug resistant tuberculosis is caused by strains of mycobacteria resistant to all known
anti tuberculosis drugs and has been recently reported [35].
Monodrug resistant tuberculosis is also well documented
and monoresistance to INH and RMP is of particular
relevance as these are the two pivotal drugs in the treatment
of tuberculosis.

Types of Drug Resistance

Drug resistance may be broadly classified as Primary or
Acquired. When drug resistance is demonstrated in a patient
who has never received anti-TB treatment previously, it is
termed Primary drug resistance. The resistance that develops
in a patient who has received prior chemotherapy is Acquired
drug resistance. WHO has now replaced the term primary
resistance by the term drug resistance among new cases and
acquired resistance by the term drug resistance among
previously treated cases [6]. When one is not sure whether
the resistance is primary or acquired due to concealed history
of previous treatment or unawareness of treatment taken
before, it is known as initial drug resistance. Combined
resistance is sum of primary and acquired resistance. The
level of primary resistance in the community is considered to
reflect the efficiency of control measures in the past while
the level of acquired resistance is a measure of on-going TB
control measures.

Disease Burden
As per WHO, in 2008, there were an estimated 8.99.9
million incident cases (1.21.6 million HIV positive) and
9.613.3 million prevalent cases of tuberculosis with 1.1
1.7 million deaths among HIV negative persons and an

457

additional 0.450.62 million deaths among HIV positive

persons. However, number of notified cases of TB to WHO
during the same period were about 5.7 million (2.7 million
new smear positive cases, 2 million new smear negative
pulmonary cases and 0.8 million new extra-pulmonary
cases), equivalent to 5567% of all incident cases. India
and China alone account for an estimated 35% of TB cases
worldwide [1]. Despite TB being an important cause of
morbidity and mortality in children, the global burden of
childhood tuberculosis is unclear. WHO guidance (2006)
recommending reporting of all cases of childhood tuberculosis
(smear positive, smear negative and extra-pulmonary) in two
age bands (04 years and 514 years) is an important step to
throw light on true burden of pediatric disease [7]. According
to the estimates, in industrialized countries, childhood TB
constitutes about 7% of all TB cases and the disease is much
more prevalent in resource poor developing countries
(1540% of all TB) [8]. In India, 1.5% of about 2,45,000
new smear positive TB cases on DOTS were aged 0
14 years and pediatric cases made up 3% of the total load of
new cases registered [9]. However, it must be added that the
enrollment and reporting of pediatric cases under DOTS is
far from adequate and therefore these figures are likely to be
substantially lower than the true burden of the disease.
WHO estimates that 4,40,000 cases of MDR tuberculosis occurred in 2008 (3.6% of the estimated total incident
tuberculosis episodes) [10]. Of these 3,60,000 were new
and relapse cases and 94,000 were in individuals previously
treated for disease. However, only about 30,000 cases of
MDR TB were notified to WHO. India and China together
carry nearly 50% of the global burden followed by Russia
(7%). An estimated 1,50,000 deaths were caused due to
MDR TB in 2008 [10].
According to the Fourth WHO/ Union Global Project on
Anti-Tuberculosis Drug Resistance Surveillance report,
drug resistance was seen among 17% of new cases, 35%
of retreatment cases and 20% of all TB cases in the
specimens analysed till 2005. Corresponding figures for
INH resistance and multidrug resistance among the three
groups were 10.3%, 27.7%, 13.3% and 2.9%, 15.3%, 5.3%
respectively. As expected, drug resistance was higher in
retreatment than in untreated cases; moreover, rates of INH
resistance are high, and there is not much data on RMP
mono-resistance, but it appears to be rare, with rates as low
as 0.02% being reported [11].
High rates of MDR transmission (>3% of all new
tuberculosis) have been reported for at least one country
in all six WHO regions. Of particular note are several
countries of former Soviet Union, where not only more than
12% of new cases and 50% of previously treated cases are
MDR tuberculosis but nearly all cases of MDR are also
resistant to other first line drugs [10]. This high level of
drug resistance translates into a higher failure of the initial

458

drug therapy and emergence of further resistance due to

inadequate initial regimes. In India, drug resistance surveillance (DRS) surveys have been ongoing since 2005 in
Andhra Pradesh, Gujarat, Maharashtra, Orissa and Uttar
Pradesh. The reported prevalence of multidrug-resistant TB
(MDR-TB) in new smear-positive pulmonary TB cases
ranges from 1% to 3% in some districts. In the state of
Gujarat, the prevalence of MDR-TB in new TB cases was
2.4% (95% C.I.1.63.1) and in previously treated cases,
17.4% (15.019.7). It is estimated that 5.4% of all TB
patients in India have MDR-TB [12].
Comprehensive studies on resistance to anti TB drugs in
children are limited and the prevalence of drug resistant
tuberculosis in children is not well defined, given the
difficulties of culture confirmation in this age group. But
the pattern of drug resistance among children reflects the
one found among adults in the same population, as most
resistance in children is caused by primary transmission of
a resistant organism. A recent study from India, documented
INH resistance in 12.6% and MDR TB in 4% of culture
positive pediatric cases; similar to drug resistance rate in adult
population in the area [13]. Similar experience has been
reported from Western Cape province of South Africa as
well as Peru [1416].
XDR TB is far more difficult to evaluate, as drug
susceptibility testing against second line drugs is unavailable
in most resource limited settings. However, XDR TB is
widespread with 58 mainly low burden countries reporting at
least one case [10]. There appears to be high proportion of
XDR TB cases among MDR TB cases in countries such as,
Japan, Korea and countries of former Soviet Union. A
review of South Africas laboratory database found that 5.6%
of MDR TB cases were XDR TB. In Gujarat, India, 4% of
the MDR TB isolates from the adult retreatment cases were
found to be XDR [10].

Risk Factors for Drug Resistance

The clinician has few tools with which to gauge drug
resistance when evaluating a child presenting with
symptoms of TB and the only definite way of diagnosing
drug resistance is by isolating M. tuberculosis from
sputum or tissues and assessing its susceptibility pattern.
However, several studies have identified historical factors
that may increase the likelihood of drug resistance. These
include:
a. Residence in regions with known high MDR/ XDR TB
prevalence
b. Contact with a case of drug resistant TB or the contact
has been on irregular treatment and continues to be
sputum positive or died after irregular treatment.

Indian J Pediatr (April 2011) 78(4):456463

c. HIV/ AIDS/ other immunocompromised state

d. History of

previous TB therapy, especially within the past

year
Relapse/ recurrence after previous successful
treatment
Nonadherence/default
Malabsorption
Medications known to cause drug interaction with
concurrent TB therapy
Hospitalization within past 2 years

e. The child shows initial improvement on anti TB

treatment and then deteriorates.

Mechanism and Causes of Drug Resistance

Resistance to anti tuberculosis drugs arises as a result of
spontaneous mutations in the genome of M. tuberculosis
which occur at predictable rates for each antituberculosis
drug (e.g. isoniazid 106, rifamipicin 108) and not as a
result of horizontal gene transfer [17, 18]. Thus, in patients
with active tuberculosis, subpopulations of resistant mycobacteria arise spontaneously and can emerge as the
dominant strain in the presence of drug selection pressure.
For example, INH monotherapy selects INH resistant
mutants and allows them to multiply. Resistance to
additional tuberculosis drugs can be added in a step wise
manner to create polyresistant strains. This is the process of
acquired resistance and is the rationale behind not adding a
single drug to a failing regimen. However, for patients not
responding to first line tuberculosis treatment in high burden
settings, current practice is to replace standard first line
treatment with an extended regimen that adds streptomycin as
the only additional drug (Category 2 regimen) without doing
any drug susceptibility testing due to lack of resources. While
this practice has worked in most parts of our country, but has
led to acquisition of further drug resistance, especially in areas
with high level of drug resistance to first line drugs as in east
European region [19, 20].
Once created, drug resistant strains can be transmitted
giving rise to drug resistant tuberculosis in individuals
never previously exposed to anti tuberculosis drugs
(Primary Resistance). Thus, the global epidemic of drug
resistant tuberculosis is due to a combination of acquired
and primary resistance.
Identification of mechanisms leading to development of
drug resistance is important to control the factors that lead
to its development. Poor functioning national tuberculosis
programs, unnecessary administrative control on purchase
and distribution of drugs with no proper mechanism on
quality control; inappropriate drug combinations/ fixed

Indian J Pediatr (April 2011) 78(4):456463

dose combination, poor storage condition of drugs; lack of

knowledge of physicians regarding dosage, duration of
treatment, standard regimens and frequent change of brand
names; use of anti TB drugs (antibiotics) for indications
other than TB; non compliant patients due to monetary
problems, lack of information, side effect of drugs and
social myths and misconceptions; the epidemic of HIV
infection; lab delays in identification and susceptibility
testing of M. tuberculosis isolates; improper infection
control measures are all contributory [21].

Clinical Featurs
The spectrum of disease caused by multidrug resistant
bacilli is not any different from that caused by drug
sensitive bacilli. Children and adolescents with drug
resistant tuberculosis tend to have features of primary
tuberculosis as hilar and / or mediastinal lymphadenopathy,
segmental lesions or pleural involvement. The incidence of
extra-pulmonary tuberculosis appears to be similar among
drug sensitive and resistant infections. Thus, it may not be
possible to differentiate between the two on the basis of
clinical and radiological features [16, 2224]. Though in
three of these studies [16, 22, 24], around one-third to onehalf of patients had cavitary disease on chest radiograph
and a very high proportion were smear/ culture positive
(4494%), the authors had concluded that this was probably
due to delay in starting appropriate treatment and advanced
stage of disease. Also approximately one-third of adult
patients in one of the study, did not show the expected
radiographic pattern. The adult patients who developed
primary MDR TB during an outbreak showed non-cavitary
consolidations, pleural effusions, and a primary radiographic
pattern (70%) [25].
A high index of suspicion is therefore required to
diagnose drug resistant tuberculosis early. The presence of
risk factors should be sought in every case, especially the
history of contact with a known case of MDR tuberculosis.
In such cases the drug susceptibility tests (rapid tests if
possible) should be ordered and results obtained at the
earliest for starting appropriate treatment. Despite the time
consuming process and low mycobacterial isolation rates
among children (2550%, even in most well equipped
centers), the bacillary isolation should be pursued aggressively in such situations. All attempts should be made to
isolate the bacilli using early morning gastric aspirates or
induced sputum and/or bronchoalveolar lavage, and/or
tissue diagnosis (FNAC or open biopsy). Drug resistant
tuberculosis ultimately is a laboratory diagnosis.
However, sometimes it may be difficult to have access to
correct body specimen or the facilities for mycobacterial
isolation and sensitivity may not be there. In such

459

situations, the diagnosis needs to be suspected on the basis

of indirect clues. As per WHO guidelines, multidrug
resistance can be suspected in any tuberculosis patient
who is excreting bacilli after 5 months of retreatment
regimen (category II) given under direct observation. Some
later studies suggest that most of the patients who respond
to retreatment regime do so within first 3 months and therefore
persistent positivity after 3 month of treatment with a
supervised five drug regime, should alarm for a change in
treatment to second line drugs [26]. For the patients who have
received more than two courses of chemotherapy, WHO
suggests the termchronic patients. Chronic patients are
usually, but not always, excretors of resistant bacilli and
often excretors of multidrug resistant bacilli.
However, certain peculiarities of tuberculosis disease
tend to confound the diagnosis of drug resistance, if this is
inferred solely from clinical and / or radiological failure to
treatment as persistent symptoms are a poor proxy for
activity. Intercurrent pneumonia can cause a radiological as
well as clinical deterioration in patients with tuberculosis.
The persistence of clinical symptoms like cough and
sputum production can also be due to post tubercular
sequel like bronchiectasis and bronchial hyper-reactivity.
The resolution of radiological findings can be delayed for
months after a successful therapy and chest skiagrams can
sometimes show progression in the absence of a bacillary
failure [27]. Tuberculomas of brain are known to increase
in size and number despite successful therapy in a
proportion of cases. About 1520% of the patients with
susceptible organisms continue to have lymph nodes of
considerable size even after successful completion of
therapy. In some cases, these may fluctuate intermittently.
Thus, clinical definition of failure has limitation in
application. Demonstration or isolation of AFB is the only
sure way to differentiate such situations from a true failure.
Suffices to say that the diagnosis of drug resistant
tuberculosis in the absence of demonstration of AFB may
be more often untenable than correct.

Diagnosis
Globally, smear microscopy has been the cornerstone of
tuberculosis diagnosis, but with growing threat of drug
resistant TB efforts are on to develop newer rapid
diagnostic tools for establishing drug resistance. Various
tests for diagnosis of drug resistance are listed below:
a) Microscopy (vital staining for viability of the excreted
bacteria)
b) Conventional indirect drug susceptibility testing (primary
culture of specimens and isolation of M. tuberculosis
(MTB), followed by drug susceptibility testing)

460

Indian J Pediatr (April 2011) 78(4):456463

c) Automated liquid culture platforms (radiometric and

nonradiometric)
d) Thin layer agar culture
e) Microscopic observation drug susceptibility (MODS)
assay
f) Colorimetric redox indicator assay
g) Nitrate reductase assay (NRA or Griess assay)
h) Genotypic testing(like GenExpert Assay)
i) Phage-based testing.

Management
Although management of MDR/ XDR TB is difficult, but
proper use of existing technologies and management
strategies can turn the tide against drug resistant tuberculosis.
Though no randomized control trials have been done to guide
optimum treatment strategies for MDR/ XDR TB, observational studies have shown effectiveness of treatment if

properly planned and tailored. In adults, treatment success

rates as high as 83% for MDR TB and 60% for XDR TB have
been reported in the absence of HIV infection [28, 29].
However, outcomes are substantially worsened with HIV coinfection. Treatment outcome for children with drug resistant
tuberculosis are based on case reports and cohort studies [22,
24, 30, 31]. In one study, cure rates of 95% were
documented in 38 children in Peru, showing that drug
resistant tuberculosis in children can be managed effectively
even in resource limited settings [16]. With regard to specific
treatment agents and regimens, there are no randomized
clinical trial data, and the choice of agents largely depends
on the results of DST or standardized regimens based on
knowledge of the profile of drug resistance in the geographic
region.
Despite scarcity of evidence, some guiding principles
have been developed for the treatment of MDR/XDR TB,
based on expert consensus and data from observational
studies [21].

Table 1 Groups of antituberculosis drugs

Group

Drugs

Remarks

Group 1 (First line oral

antitubercular agents)

Isoniazid, Rifampicin,Ethambutol,
Pyrazinamide

Group 2 (Injectable
antitubercular drugs)

Streptomycin, Kanamycin, Amikacin,

Capreomycin, Viomycin

Group 3
(Fluoroquinolones)

Ciprofloxacin, Ofloxacin Levofloxacin,

Gatifloxacin Moxifloxacin

Group 4 (Oral
bacteriostatic second
line drugs)

Ethionamide, Prothionamide, Cycloserine,

Terizidone, P-aminosalicylic acid,
Thioacetazone

Group 5 (Antitubercular
drugs with unclear
efficacy)

Clofazimine, Co-Amoxi-clav,
Clarithromycin, Linezolid

Most potent and best tolerated drugs.

Should be used only if there is lab evidence or clinical
history of efficacy.
Given to all patients in whom susceptibility is documented
or suspected.
Kanamycin/ amikacin (close to 100% cross resistance) is preferred
for MDR treatment due to low cost and good experience of use.
Streptomycin is a first line drug and not used for MDRTB unless
supported by sensitivity reports.
Capreomycin is used if the isolate is resistant to both streptomycin
and kanamycin/amikacin
Viomycin is very similar to capreomycin with high level
of cross-resistance to it.
Should be used if the strain is susceptible.
Descending order of potency (based on in vitro activity
and animal studies) [32]
Moxifloxacin = Gatifloxacin > Levofloxacin > Ofloxacin =
Ciprofloxacin
If only one agent is neededEthionamide/ Prothionamide is often
added due to proven efficacy and low cost. PAS is added first
(If cost is not a constraint) as enteric-coated formulas are relatively
well tolerated.
If two agents are neededCycloserine is added with Ethionamide/
Prothionamide or PAS.
Combination of Ethionamide/ Prothionamide and PAS can result in
high incidence of gastrointestinal adverse effects (They are used
together only when all three Group 4 agents needed).
TerizidoneSimilar efficacy to Cycloserine and can be used in its
place as it is better tolerated.
Thioacetazoneuse is limited as it can result in Stevens-Johnson
syndrome (more prevalent in HIV-positive individuals),
Not recommended by WHO for routine use because of unclear
efficacy.
However,it can be used if adequate regimens are impossible to form
with the medicines from Groups 14.

Indian J Pediatr (April 2011) 78(4):456463

a) Regimens should be based on the history of drugs

taken by the patient and the prevalence of resistance to
first-line and second-line drugs in the area.
b) Regimens should consist of at least four drugs with
either certain, or almost certain, effectiveness. If the
evidence about the effectiveness of a drug is unclear, the
drug can be included in the regimen but it should not be
depended upon for success. Often, more than four drugs
may be started if the susceptibility pattern is unknown, if
effectiveness is questionable for an agent or if extensive,
bilateral pulmonary disease is present.
c) Drugs are administered at least 6 days a week. When
possible, pyrazinamide, ethambutol and fluoroquinolones should be given once per day because the high
serum levels attained in once-a-day dosing may be
more efficacious. Once-a-day dosing is permitted for
other second-line drugs, depending on patients
tolerance. However, ethionamide/prothionamide, cycloserine and PAS have traditionally been given in split
doses during the day. Intermittent therapy with the
injectable agent (three times weekly after an initial
period of 23 months of daily therapy) can be
considered for patients in whom the injectable agent
has been used for a prolonged period and when the risk
of toxicity increases.
d) The drug dosage should be determined by body weight.
e) An injectable agent (an aminoglycoside or capreomycin)
is used for a minimum of 6 months and at least 4 months
after the patient first becomes and remains sputum smear
or culture negative.
f) Treatment is for a minimum duration of 18 months beyond
conversion. If a patient fails to get bacillary quiescence
(culture negative) by 6 months of therapy, then the
probability of success of the current regime is very poor.
Because XDR TB is still quite a new phenomenon, data on
treatment duration required for cure are limited.
g) Each dose should preferably be given under observation
throughout the treatment.
h) DST, when available and from a reliable laboratory,
should be used to guide the therapy.
i) Pyrazinamide can be used for the entire treatment if it is
judged to be effective. Many MDR-TB patients have
chronically inflamed lungs, which theoretically produce
the acidic environment in which pyrazinamide is active.
j) If pulmonary disease is sufficiently localized and
residual lung function is adequate, resective surgery
should be considered as an adjunct to chemotherapy.

461

pyrazinamide, ethambutol and streptomycin being the

primary first-line drugs. A group system based on efficacy,
experience of use and drug class is also being used for ease
of design of treatment regimens and is detailed in Table 1.
Monitoring Therapy
Patients should be monitored (clinical monitoring supplemented with objective laboratory evaluation) closely for
signs of treatment failure and adverse effect of the drugs. A
pediatrician should examine the child monthly till bacillary
conversion and 23 monthly thereafter. A normal growth
rate should resume after few months of successful treatment.
DOT worker should screen the patient regularly for adverse
eventsrashes, gastrointestinal symptoms, psychiatric symptoms (psychosis, depression, anxiety, suicidal tendencies),
jaundice, ototoxicity, peripheral neuropathy and symptoms of
electrolyte wasting (muscle cramps, palpitations). Table 2
details various laboratory tests needed to be done during
treatment.

Chemoprophylaxis
Though the role of chemoprophylaxis in children exposed
to drug susceptible TB is well established, little information
is available regarding optimal chemoprophylaxis for children
with MDR TB contacts. Current WHO guidelines recommend
close follow up of contacts of patients with MDR TB for a
period of 2 years and prompt initiation of treatment with a
Table 2 Lab monitoring during treatment
Tests*

Follow up

Smear and culture from

appropriate specimen

Monthly till smear and culture

conversion**
Thereafter smear monthly and
culture quarterly
Repeated if patient remains sputum
positive (but not earlier than
3 months)

DST

Chest Radiograph
Complete blood count
Renal function test
S. Electrolytes
Liver function test
HIV ELISA

Classes of Antituberculosis Drugs

Antituberculosis drugs have traditionally been divided into
first and second-line drugs, with isoniazid, rifampicin,

Six monthly (earlier if clinical

worsening or surgery is planned)
612 monthly
Monthly till patient is on injectable
drugs
Monthly till patient is on injectable
drugs
36 monthly

* All these tests should be first done at Baseline and repeated during
follow up as stated
** conversion is defined as 2 consecutive negative smear and culture
taken 30 days apart

462

regimen to treat MDR TB if active disease develops [21]. Use

of second line drugs for routine chemoprophylaxis of MDR
TB contacts is not recommended despite ineffectiveness of
INH and rifampicin in this setting. In 2005, the CDC
published guidelines proposing 2 years of clinical follow-up
and individual decision-making about appropriate LTBI
treatment [33]. A Cochrane review in 2006, found no
randomized control studies assessing the efficacy of treating
latent tuberculosis infection in people exposed to MDR-TB
[34]. A prospective cohort study of childhood contacts of
MDR-TB cases in the Western Cape included 105 contacts
without active disease at study entry who were followed up
for 30 months. Forty-one received chemoprophylaxis tailored
to the susceptibility profile of the index case. Of the 41
children who received chemoprophylaxis, 68% were infected
(defined as Mantoux test 15 mm induration) at baseline, as
were 52% of the untreated contacts. Active disease resulted in
only 5% of contacts who received chemoprophylaxis and in
20% of contacts who did not. This suggests that a chemoprophylactic regimen customized to the susceptibility pattern of
the adult contacts isolate may be effective in preventing
disease [35]. Kritski et al conducted a retrospective cohort
study of household contacts of drug resistant TB cases.
Among infected contacts (defined as Mantoux test 10 mm
induration), active disease developed in 4% of treated
contacts compared with 9% who did not receive INH.
Although the study results were not statistically significant, the
trend was toward a lower incidence of TB disease with INH
chemoprophylaxis [36]. More studies are needed to identify
the right agent and to support use of chemoprophylaxis in
MDR contacts.

References
1. Global tuberculosis control: a short update to the 2009 report.
Geneva, World Health Organization, 2009 (WHO/HTM/TB/
2009.426).
2. Mitchison DA. Drug resistance in mycobacteria. Br Med Bull.
1984;40:8490.
3. Migliori GB, Iaco GD, Besozzi G, Centis R, Cirillo DM. First
tuberculosis cases in Italy resistant to all tested drugs. Euro
Surveill. 2007;12:pii=319.
4. Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new
forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in
Iran. Chest. 2009;136:4205.
5. Shah N, Richardson J, Moodley P, et al. Increasing second-line
drug resistance among extensively drug-resistant tuberculosis
patients in rural South Africa. 40th Union World Conference on
Lung Health; Cancun, Mexico; Dec 37, 2009.
6. Anti-tuberculosis drug resistance in the world. Fourth global
report. Geneva, World Health Organization 2008 (WHO/HTM/
TB/2008.394).
7. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva, World Health
Organization, 2006 (WHO/HTM/TB/2006.371).

Indian J Pediatr (April 2011) 78(4):456463

8. Nelson LJ, Wells CD. Global epidemiology of childhood
tuberculosis. Int J Tuberc Lung Dis. 2004;8:63647.
9. Consensus Statement. Formulation of guidelines for diagnosis and
treatment of pediatric TB cases under RNTCP. Indian J Tuberc.
2004;51:1025.
10. Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010
global report on surveillance and response. Geneva, World Health
Organization, 2010 (WHO/HTM/TB/2010.30).
11. Guidelines for surveillance of drug resistance in tuberculosis.
Fourth WHO/ Union Global Project on Anti-Tuberculosis Drug
Resistance Surveillance report. Geneva, World Health Organization, 2009 (WHO/HTM/TB/2009.422).
12. WHO. A brief history of tuberculosis control in India. Geneva,
World Health Organization, 2010 (WHO/HTM/TB/2010.4).
13. Swaminathan S, Datta M, Radhamani MP, et al. A profile of
bacteriologically confirmed pulmonary tuberculosis in children.
Indian Pediatr. 2008;45:7437.
14. Schaaf HS, Marais BJ, Hesseling AC, Gie RP, Beyers N, Donald
P. Childhood drug-resistant tuberculosis in the Western Cape
Province of South Africa. Acta Paediatr. 2006;95:5238.
15. Salazar GE, Schmitz TL, Cama R, et al. Pulmonary tuberculosis in
children in a developing country. Pediatrics. 2001;108:44853.
16. Mukherjee JS, Joseph JK, Rich ML, et al. Clinical and programmatic
considerations in the treatment of MDR-TB in children: a series of 16
patients from Lima, Peru. Int J Tuberc Lung Dis. 2003;7:63744.
17. David HL. Probability distribution of drug-resistant mutants in
unselected populations of Mycobacterium tuberculosis. Appl
Microbiol. 1970;20:8104.
18. Supply P, Warren RM, Banuls AL, et al. Linkage disequilibrium
between minisatellite loci supports clonal evolution of mycobacterium tuberculosis in a high tuberculosis incidence area. Mol
Microbiol. 2003;47:52938.
19. Cox HS, Niemann S, Ismailov G, et al. Risk of acquired drug
resistance during short-course directly observed treatment of
tuberculosis in an area with high levels of drug resistance. Clin
Infect Dis. 2007;44:14217.
20. Espinal MA, Kim SJ, Suarez PG, et al. Standard short-course
chemotherapy for drug-resistant tuberculosis: treatment outcomes
in 6 countries. JAMA. 2000;283:253745.
21. Guidelines for the programmatic management of drug-resistant
tuberculosis. Geneva, World Health Organization, 2006 (WHO/
HTM/TB/2006.361).
22. Schaaf HS, Shean K, Donald PR. Culture confirmed multidrugresistant tuberculosis: diagnostic delay, clinical features and
outcome. Arch Dis Child. 2003;88:110611.
23. Schaaf HS, Gie RP, Beyers N, Sirgel FA, de Klerk PJ, Donald PR.
Primary drug resistant tuberculosis in children. Int J Tuberc Lung
Dis. 2004;4:114955.
24. Drobac PC, Mukherjee JS, Joseph JK, et al. Community based
therapy for children with multidrug resistant tuberculosis. Pediatr.
2006;117:20229.
25. Fishman JE, Sais GJ, Schwartz DS, Otten J. Radiographic
findings and patterns in multidrug-resistant tuberculosis. J Thorac
Imaging. 1998;13:6571.
26. Feng-zeng Z, Levy MH, Sumin W. Sputum microscopy results at
two and three months predict outcome of tuberculosis treatment.
Int J Tuberc Lung Dis. 1997;1:5702.
27. Akira M, Sakatani M, Ishikawa H. Transient radiographic
progression during initial treatment of pulmonary tuberculosis:
CT findings. J Comput Assist Tomogr. 2000;24:42631.
28. Mitnick C, Bayona J, Palacios E, et al. Community-based therapy
for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med.
2003;348:11928.
29. Mitnick C, Shin S, Seung K, et al. Comprehensive treatment of
extensively drug-resistant tuberculosis. N Engl J Med. 2008;359:563
74.

Indian J Pediatr (April 2011) 78(4):456463

30. Feja K, McNelley E, Tran C, Burzynski J, Saiman L. Management
of pediatric multidrug-resistant tuberculosis and latent tuberculosis
infections in New York City from 1995 to 2003. Pediatr Infect Dis
J. 2008;27:90712.
31. Schluger N, Lawrence R, McGuiness G, Park M, Rom W.
Multidrug-resistant tuberculosis in children: two cases and a
review of the literature. Pediatr Pulmonol. 1996;21:13842.
32. Rastogi N, Labrousse V, Goh KS. In vitro activities of fourteen
antimicrobial agents against drug susceptible and resistant clinical
isolates of Mycobacterium tuberculosis and comparative intracellular
activities against the virulent H37Rv strain in human macrophages.
Curr Microbiol. 1996;33:16775.
33. Centre For Disease Control and Prevention. Guidelines for the
investigation of contacts of persons with infectious tuberculosis.

463
Recommendations from the National Tuberculosis Controller
Association and CDC. MMWR. 2005;54:147.
34. Fraser A, Paul M, Attamno A, Leibovici L. Drugs for
preventing tuberculosis in people at risk of multiple drug
resistant tuberculosis. Cochrane Database Syst Rev. 2006;2:
CD005435.
35. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald
PR. Evaluation of young children in contact with adult multidrug
resistant pulmonary tuberculosis: a 30 month follow up. Pediatr.
2002;109:76571.
36. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of
tuberculosis to close contacts of patients with multidrug
resistant tuberculosis. Am J Respir Crit Care Med.
1996;153:3313.