CHEST

Global Medicine

Multidrug-Resistant Tuberculosis*
A Menace That Threatens To Destabilize
Tuberculosis Control
Surendra K. Sharma, MD, PhD, FCCP; and Alladi Mohan, MD

Multidrug-resistant tuberculosis (MDR-TB), caused by Mycobacterium tuberculosis that is

resistant to both isoniazid and rifampicin with or without resistance to other drugs, is a
phenomenon that is threatening to destabilize global tuberculosis (TB) control. MDR-TB is a
worldwide problem, being present virtually in all countries that were surveyed. According to
current World Health Organization and the International Union Against Tuberculosis and Lung
Disease estimates, the median prevalence of MDR-TB has been 1.1% in newly diagnosed
patients. The proportion, however, is considerably higher (median prevalence, 7%) in patients
who have previously received anti-TB treatment. While host genetic factors may contribute to the
development of MDR-TB, incomplete and inadequate treatment is the most important factor
leading to its development, suggesting that it is often a man made tragedy. Efficiently run TB
control programs based on a policy of directly observed treatment, short course (DOTS), are
essential for preventing the emergence of MDR-TB. The management of MDR-TB is a challenge
that should be undertaken by experienced clinicians at centers equipped with reliable laboratory
services for mycobacterial cultures and in vitro sensitivity testing as it the requires prolonged use
of costly second-line drugs with a significant potential for toxicity. The judicious use of drugs;
supervised standardized treatment; focused clinical, radiologic, and bacteriologic follow-up; and
surgery at the appropriate juncture are key factors in the successful management of these
patients. With newer effective anti-TB drugs still a distant dream, innovative approaches such as
DOTS-Plus are showing promise for the management of patients with MDR-TB under program
conditions and appear to be a hope for future.
(CHEST 2006; 130:261272)
Key words: diagnosis; epidemiology; multidrug-resistant tuberculosis; predictors for development; prognostic factors;
treatment; tuberculosis
Abbreviations: ADR adverse drug reaction; CDC Centers for Disease Control and Prevention; DOTS directly
observed treatment, short-course; MDR-TB multidrug-resistant tuberculosis; PCR polymerase chain reaction;
RFLP restriction fragment length polymorphism; TB tuberculosis; WHO World Health Organization

(TB) is a medical, social, and ecoT uberculosis

nomic disaster of immense magnitude that is

occurring the world over.1 Strains of Mycobacterium

tuberculosis that are resistant to both isoniazid and
rifampicin with or without resistance to other drugs
have been termed multidrug-resistant strains. Isoniazid and rifampicin are keystone drugs in the man-

*From the Division of Pulmonary and Critical Care Medicine

(Dr. Sharma), Department of Medicine, All India Institute of
Medical Sciences, New Delhi, India; and the Division of Pulmonary and Critical Care Medicine (Dr. Mohan), Department of
Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India.
Drs. Sharma and Mohan have no financial interests in the subject
of this article and no conflicts of interest to report.
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agement of TB. While resistance to either isoniazid

or rifampicin may be managed with other first-line
drugs, multidrug-resistant TB (MDR-TB) demands
treatment with second-line drugs that have limited
Manuscript received January 31, 2006; revision accepted March
31, 2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Surendra K. Sharma, MD, PhD, FCCP,
Chief, Division of Pulmonary and Critical Care Medicine, Professor and Chairman, Department of Medicine, All India Institute
of Medical Sciences, New Delhi 110 029, India; e-mail:
sksharma@aiims.ac.in
DOI: 10.1378/chest.130.1.261
CHEST / 130 / 1 / JULY, 2006

261

sterilizing capacity, and are less effective and more

toxic. MDR-TB is one of the most worrisome elements of the pandemic of antibiotic resistance.2,3
Resistance to anti-TB drugs is usually described in
terms of resistance among new cases and resistance among previously treated patients.4 The term
susceptible strains refers to those strains that have
not been exposed to the first-line anti-TB drugs and
respond to these drugs in a uniform manner. The
term resistant strains refers to those strains that
differ from the sensitive strains in their capacity to
grow in the presence of a higher concentration of a
drug.3

Epidemiology
Though published studies from the developing
world have suggested that drug resistance was a
potential problem,3 it was the emergence of
MDR-TB in the United States in the 1990s that
attracted the attention.5,6 The global extent of the
problem of drug-resistant TB is evident from the
three rounds of surveys coordinated by World
Health Organization (WHO) and the International
Union Against Tuberculosis and Lung Disease between 1996 and 2002. The third round of surveys7
included new data from 77 settings or countries that
were collected between 1999 and 2002. Among new
cases (Fig 1, top, A), the prevalence of MDR-TB
(median,1.1%) ranged from 0% in eight countries to
14.2% in Kazakhstan (51 of 359 patients) and Israel
(36 of 253 patients). Among previously treated cases
(Fig 1, bottom, B), the median prevalence of
MDR-TB was 7.0%. In the latest survey,7 as in the
two previous surveys, MDR-TB was found in all
regions of the world. The prevalence of MDR-TB
was exceptionally high in almost all countries from
the former Soviet Union that were surveyed, including Estonia, Kazakhstan, Latvia, Lithuania, the Russian Federation, and Uzbekistan. High prevalences
of MDR-TB were also found among new cases in
China (Henan and Liaoning provinces), Ecuador,
and Israel. Central Europe and Africa, in contrast,
reported the lowest median levels of drug resistance.
Recent estimates8 from 184 countries suggest that an
estimated 458,000 new cases of MDR-TB occurred
worldwide in 2003, with 276,000 of those cases
(60%) reported from high-burden countries China
and India constituting 3.2% of all new TB cases.
However, it should be remembered that increases in
the prevalence of resistance can be caused by poor or
worsening TB control, the immigration of patients
from areas of higher resistance, outbreaks of drugresistant disease, and variations in surveillance methodologies.3
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Molecular Basis of Drug Resistance

Spontaneous chromosomally borne mutations occurring in M tuberculosis at a predictable rate are
thought to confer resistance to anti-TB drugs.3,9 A
characteristic feature of these mutations is that they
are unlinked. A TB cavity usually contains 107 to 109
bacilli. If mutations causing resistance to isoniazid
occur in about 1 in 106 replications of bacteria, and
the mutations causing resistance to rifampicin occur
in about 1 in 108 replications, the probability of
spontaneous mutations causing resistance to both
isoniazid and rifampicin would be 106 108 1 in
1014 replications.3 Given that this number of bacilli
cannot be found even in patients with extensive
cavitary pulmonary TB, the chance of the development of spontaneous dual resistance to rifampicin
and isoniazid is practically remote.3,9
Table 1 lists the perturbations in the individual
drug target genes that are responsible for the genesis
of anti-TB drug resistance.3,9 Rifampicin resistance
has been shown to be caused by an alteration of the
-subunit of RNA polymerase, which is encoded by
the rpo gene. More than 95% of rifampicin-resistant strains are associated with mutations within an
81-base pair region of the rpo gene, which is
termed the rifampicin resistance determinant region.10 On the contrary, resistance to isoniazid is
more complicated, as mutations in several genes10,11
can lead to drug resistance (Table 1).
While certain mutations are widely present, pointing to the magnitude of the polymorphisms at these
loci, others are not common, suggesting diversity in
the multidrug-resistant M tuberculosis strains that
are prevalent in the given region. Furthermore,
rifampicin resistance has been considered to be a
surrogate marker for checking multidrug resistance
in clinical isolates of M tuberculosis since rifampicin
resistance is often accompanied by resistance to
isoniazid.12
Potential Causes of Drug Resistance
Following factors have been implicated in the
causation of MDR-TB.3,13
Factors Related to Previous Treatment
In most of the published studies, a history of TB
and anti-TB treatment have been implicated in the
causation of MDR-TB.3,14 17
Incomplete and Inadequate Treatment: A review
of the published literature strongly suggests that the
most powerful predictor of the presence of
MDR-TB is a history of treatment of TB (Table 2).
Global Medicine

Figure 1. Top, A: prevalence of MDR-TB in new cases from 1994 to 2002. Bottom, B: prevalence of
MDR-TB in previously treated cases from 1994 to 2002. Reproduced with permission from World
Health Organization, International Union Against Tuberculosis and Lung Disease.7

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CHEST / 130 / 1 / JULY, 2006

263

Table 1Antituberculosis Drugs and the Genes

Involved in Their Resistance
Drug

Genes Involved in Drug Resistance

Isoniazid

Enoyl acyl carrier protein (acp) reductase (inhA)

Catalase-peroxidase (katG)
Alkyl hydroperoxide reductase (ahpC)
Oxidative stress regulator (oxyR)
-Ketocyl acyl carrier protein synthase (kasA)
Rifampicin
RNA polymerase subunit B (rpoB)
Pyrazinamide
Pyrazinamidase (pncA)
Streptomycin
Ribosomal protein subunit 12 (rpsL)
16s ribosomal RNA (rrs)
Aminoglycoside phosphotransferase gene (strA)
Capreomycin
Haemolysin (tlyA)*
Ethambutol
Arabinosyl transferase (emb A, emb B, and
emb C)
Fluoroquinolones DNA gyrase (gyr A and gyr B)
*The tlyA gene in M tuberculosis encodes a 268-amino acid polypeptide, which shows striking similarity to a haemolysin/cytotoxin, tlyA,
from the spirochete Serpulina hyodysenteriae.

Errors in TB management such as the use of single

drug to treat TB, the addition of a single drug to a
failing regimen, the failure to identify preexisting
resistance, the initiation of an inadequate primary
regimen, the failure to identify and address nonadherence to treatment, inappropriate isoniazid preventive therapy, and variations in the bioavailability

Table 2Causes of Inadequate Treatment*

Causes

Description

Lack of political commitment

Providers/programs:
Inappropriate guidelines
inadequate regimens
Noncompliance with available
guidelines
Absence of guidelines
Poor training
No monitoring of treatment
Poorly organized or funded TB control
programs
Drugs: inadequate
Poor quality
supply/quality
Unavailability of certain drugs (stockouts or delivery disruptions)
Poor storage conditions
Wrong dose or combination
Patients: inadequate
Poor adherence (or poor direct
drug intake
observation of treatment)
Lack of information
Lack of money (No free treatment
available)
Lack of transportation
Side effects
Social barriers
Malabsorption
Substance abuse disorders
*Adapted and reproduced with permission from Central TB Division,
Directorate General of Health Services, Ministry of Health &
Family Welfare, Government of India.17
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of anti-TB drugs predispose the patient to the

development of MDR-TB.18
Inadequate Treatment Adherence: Nonadherence
to prescribed treatment is often underestimated by
the physician and is difficult to predict. In the West,
demographic factors such as age, sex, marital status,
education level, and socioeconomic status have not
been found to correlate with the degree of treatment
adherence. On the other hand, certain factors such
as psychiatric illness, alcoholism, drug addiction, and
homelessness do predict nonadherence to treatment.3 The directly observed treatment, shortcourse (DOTS) strategy, which has been endorsed
by the WHO as the only effective way to control TB,
has to some extent addressed these problems.4,18 In
India, innovative measures such as public-private
mix and the use of Anganwadi workers have been
tried out under program conditions to improve
treatment adherence in patients with TB in general,
and these measures would help patients with
MDR-TB also. The reader can find more details on
this topic at the Web site http://www.tbcindia.org.
Logistic Issues
Good, reliable laboratory support is seldom available in developing nations. When facilities for growing cultures and sensitivity testing are not available,
therapeutic decisions are most often made by algorithms or inferences from previous treatment.19
While DOTS has been shown to reduce the transmission and incidence of both drug-susceptible and
drug-resistant TB even in settings with moderate
rates of MDR-TB,20 it has been observed that the
programmatic approach to the management of
patients who do not respond to treatment may fail in
certain settings.21,22 First-line therapy may not be
sufficient in settings with a high degree of resistance
to anti-TB drugs.21 Although the DOTS strategy is
the basis of good TB control, the strategy should be
modified in some settings to identify drug-resistant
cases sooner and to make use of second-line drugs in
appropriate treatment regimens.5,23
Virulence of the Organism
Substantial progress has been made in the understanding of the molecular epidemiology of tubercle
bacilli with the availability of genome sequence data in
the public domain (available at http:www.cdfd.org.in/
amplibase; http://www.cdc.gov/ncidod/EID/vol7no3/
sola_data.htm; and https://hypocrates.rivm.nl/bnwww/
IS6110-RFLP-bands.htm). Phylogenomic analysis
suggests that the ancient strains of M tuberculosis
may have undergone adaptive evolution as a result of
selection at many loci.23
Global Medicine

Extrapolating data on the virulence and survival

capability of isoniazid-resistant strains to multidrugresistant strains of M tuberculosis, it has been assumed that multidrug-resistant isolates have lower
virulence and survival capability.3 It has been observed that emergence of multidrug resistance may
result in the organism becoming unusually fit to
survive. This is exemplified by a genotype, which was
first described in 1995, known as the W-Beijing
family. Published reports24,25 have suggested that
W-Beijing genotype is highly prevalent in some
regions of Asia and Eastern Europe such as Estonia,
Azerbaijan, and Russia. The strains belonging to the
W-Beijing family have been shown to exhibit a
constant spoligotype and high degrees of similarity
among IS6110 restriction fragment length polymorphism (RFLP), polymorphic GC-rich sequence
RFLP, and variable numbers of tandem repeats
profiles. W-Beijing genotype is well-known for its
rapidity of spread and tenacity, and notably for its
strong association with multidrug resistance.24,25
Given that the Beijing strain has already made its
appearance in India where 20% of the TB patients in
the world are located, the consequences can be
disastrous.26 However, caution must be exercised
while interpreting these data as these observations
need to be validated in multiple settings before
definitely linking the clone to the given host population.23

Associations among HLA-DRB1*1, DRB1*14,29 and

HLA-DRB1*0803 haplotypes,30 and the susceptibility to MDR-TB suggests that these loci or the alleles
linked with them play a permissive role in conferring
increasing susceptibility to the development of
MDR-TB. These issues merit further study.
HIV Infection
A review of the published literature2,3 suggests
that, in the early 1990s, several institutional outbreaks of MDR-TB among HIV-infected patients
drew attention to the problem. Current evidence
suggests that HIV infection per se does not appear to
be a predisposing factor for the development of
MDR-TB. Some studies31,32 have found that
MDR-TB is not more common among people infected with HIV. However, increased susceptibility
to TB, increased opportunity to acquire TB due to
overcrowding, exposure to patients with MDR-TB
due to increased hospital visits, and malabsorption of
anti-TB drugs resulting in suboptimal therapeutic
blood levels despite strict adherence to the treatment regimen potentially increase the chances of
MDR-TB occurring in persons with HIV/AIDS, if
not adequately addressed.3
Diagnosis of MDR-TB
Conventional Methods

Multidrug Transporters
Multidrug transporters mediate both intrinsic and
acquired resistance to various drugs.27 P-glycoprotein is a human analog of these multidrug transporters and is expressed on immune effector cells. The
infection of experimental cell lines by M tuberculosis
results in the increased expression of P-glycoprotein
and the decreased accumulation of isoniazid inside
the cells. Apart from the up-regulation of host cell
P-glycoprotein, M tuberculosis per se expresses at
least three multidrug transporter proteins such as
Tap, Lfr A, and Mmr.3,27 Evidence is available
demonstrating a clear association between multidrug
resistance and transcription levels of a Tap-like
pump (Rv1258c) and the overexpression of an efflux
protein.28 The potential contribution of these multidrug transporter proteins in the causation of
MDR-TB merits further evaluation. They also appear to be novel targets for drug therapy in the
future.
Host Genetic Factors
Though there is some evidence to postulate host
genetic predisposition as the basis of the development of MDR-TB, it has not been conclusive.29,30
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Traditionally, Lowenstein-Jensen culture has been

used for drug sensitivity testing using (1) the absolute concentration method, (2) the resistance ratio
method, and (3) the proportion method.3 With the
conventional methods, a duration of 6 to 8 weeks is
required before sensitivity results are known.
Newer Methods
Several newer methods have been developed to
document anti-TB drug resistance faster. Most of
these methods are expensive and are not available in
the field setting. Radiometric methods (eg,
BACTEC-460; Becton-Dickinson; Franklin Lakes,
NJ) have been developed for rapid drug-susceptibility testing of M tuberculosis by which results are
available within 10 days.3,33 The mycobacteria
growth indicator tube system (Becton-Dickinson) is
a rapid, nonradioactive method for the detection and
susceptibility testing of M tuberculosis.3,33 Ligase
chain reaction facilitates the detection of a mismatch
of even one nucleotide.3,33 Luciferase reporter assay
is a reporter gene assay system for the rapid determination of drug resistance that can identify most
strains within 48 h.3,33 As rifampicin resistance is
considered to be a surrogate marker for MDR-TB,
CHEST / 130 / 1 / JULY, 2006

265

techniques such as a rapid bacteriophage-based test

(FASTPlaqueTB-RIF; Biotec Laboratories; Ipswich,
UK) that is used to identify rifampicin susceptibility
in clinical strains of M tuberculosis after growth in a
semi-automated liquid culture system (BACTEC460; Becton-Dickinson) have also shown potential to
diagnose MDR-TB.14,34
Polymerase chain reaction (PCR)-based sequencing has often been employed to understand the
genetic mechanisms of drug resistance in patients
with M tuberculosis.3,3335 RFLP patterns have been
used to categorize and compare isolates of M tuberculosis.35 As the DNA fingerprints of M tuberculosis
have been observed not to change during the development of drug resistance, RFLP analysis has also
been used to track the spread of drug-resistant
strains.35 Molecular markers for epidemiologic and
evolutionary studies such as mycobacterial interspersed repeat units-variable number tandem repeats, fluorescent amplified fragment length polymorphism have been used to study the molecular
epidemiology of M tuberculosis.14,36,37 Spoligotyping,

which is based on the variability in the direct-repeat

locus of M tuberculosis, has been useful in detecting
new outbreaks as well as in tracking TB epidemics.23
Molecular assays,14,38,39 such as heteroduplex and
mismatch analyses, DNA sequencing, real-time
PCR, molecular beacons, and line probe assays have
all been used to screen for mutations that are
responsible for the development of anti-TB drug
resistance. Multiplex PCR, followed by hybridization
on an oligonucleotide microarray,40 or low-density
DNA oligonucleotide array (macroarray)10 have also
been used to detect the DNA of M tuberculosis
complex and to identify mutations associated with
isoniazid and rifampicin resistance.

Management
The treatment of MDR-TB is a challenge which
should be undertaken by experienced clinicians at
centers equipped with reliable laboratory service for
mycobacterial culture and in vitro sensitivity test-

Table 3Drugs Useful in the Treatment of MDR-TB*

Drug

Daily Dosage

Aminoglycosides
Streptomycin
Kanamycin
Amikacin
Capreomycin

15
15
15
15

Thioamides
Ethionamide
Prothionamide

1020 mg/kg (500750 mg)

1020 mg/kg (500750 mg)

mg/kg
mg/kg
mg/kg
mg/kg

(7501,000
(7501,000
(7501,000
(7501,000

mg)
mg)
mg)
mg)

Pyrazinamide
Fluroquinolones

2030 mg/kg (1,2001,600 mg)

Ofloxacin
Levofloxacin
Ethambutol
Cycloserine
Terizodone

7.515 mg/kg (600- 800 mg)

5001000 mg
1520 mg/kg (1,0001,200 mg)
1520 mg/kg (500750 mg)
1520 mg/kg (600 mg)

Para-aminosalicylic acid

150 mg/kg (1012 g)

Adverse Drug Reactions

Pain at injection site
Ototoxicity (vertigo and deafness), nephrotoxicity, hemolytic anemia, aplastic
anemia, agranulocytosis, thrombocytopenia, and lupoid reactions
Hypokalemia, hypocalcemia and hypomagnesemia, cutaneous reactions, and
occasionally hepatotoxicity; may potentiate the effect of neuromuscular
blocking agents administered during anesthesia.
Epigastric discomfort, anorexia, nausea, metallic taste and sulfurous belching,
vomiting and excessive salivation; psychotic reactions including hallucinations
and depression; hypoglycemia, hypothyroidism, and goiter; hepatotoxicity;
gynecomastia, menstrual disturbance, impotence, acne, headache, and
peripheral neuropathy; tolerance varies with ethnicity; usually well tolerated in
Africa and Asia
Hepatotoxicity, GI intolerance, hyperuricemia, and arthralgias
Uncommon GI disturbance (eg, anorexia, nausea, and vomiting), CNS symptoms
(eg, dizziness, headache, mood changes, and rarely convulsions)

Dose-dependent optic neuritis, and peripheral neuritis;

Dizziness, slurred speech, and convulsions;
Headache, tremor, insomnia, confusion, depression; and altered behavior; suicide
risk; generalized hypersensitivity reaction or hepatitis.
GI disturbance (eg, anorexia, nausea, vomiting, abdominal discomfort, and
diarrhea); general skin or other hypersensitivity, and hepatic dysfunction;
hypokalemia; hypothyroidism and goiter; best avoided in renal failure as it may
exacerbate acidosis; sodium salt should not be given when a restricted sodium
intake is indicated

*Adapted from Crofton et al19 and Blumberg et al.43

No cross-resistance with other aminoglycosides such as kanamycin and streptomycin.
With capreomycin administration.
Chemical structure resembles thioacetazone, with which there is frequent and partial cross-resistance. However, strains that are resistant to
thioacetazone are often sensitive to thioamides, but the reverse is seldom the case. Therapy is more acceptable if the drug is administered with
orange juice or milk, after milk ingestion, or at bedtime to avoid nausea.
Terizidone is a combination of two molecules of cycloserine.
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Global Medicine

ing.3,41 In the early reports of outbreaks of MDR-TB

in HIV-coinfected patients in hospitals and prisons,
the mortality rate was very high (range, 72 to 89%).3
However, subsequent studies3 have documented decreased mortality and improvement in clinical outcome for both HIV-seropositive and HIV-seronegative patients with MDR-TB.
Principles of Management
When MDR-TB is suspected on the basis of
history or epidemiologic information, the patients
sputum must be subjected to culture and anti-TB
drug-sensitivity testing. These patients may be
started on WHO category II treatment42 (under
program conditions) or the regimens employing various drugs (Table 4), such as those suggested by the
American Thoracic Society, the Centers for Disease
Control and Prevention (CDC), and the Infectious
Diseases Society of America43 pending sputum culture report. Further therapy is guided by the culture
and sensitivity report. These guidelines clearly mention that a single drug should never be added to a
failing regimen. Furthermore, when initiating treatment, at least three previously unused drugs must be
employed to which there is in vitro susceptibility.19,43
These guidelines43 suggest that among the fluoroquinolone levofloxacin is best suited for the treatment of MDR-TB, given its good safety profile with
long-term use. The results of a study44 of communitybased outpatient treatment of MDR-TB reported from
Peru suggest that community-based outpatient treatment of patients with MDR-TB is possible with high
cure rates even in resource-poor settings.
Need for Standard Definitions
No randomized controlled trials exist addressing
the issue of the optimal management strategy for
MDR-TB. As in the case with the DOTS strategy,
the systematic study of the efficacy of DOTS-Plus
regimens requires the standardization of definitions
for MDR-TB case registration and treatment out-

comes. Such definitions would permit the accumulation of evidence and would facilitate cross-program
comparisons. The reader is referred to the study by
Laserson et al45 for these definitions.
DOTS-Plus Strategy
DOTS is a key ingredient in the TB control
strategy. In populations in which MDR-TB is endemic, the outcome of the standard short-course
regimen remains uncertain.13 As a consequence,
there have been calls for well-functioning DOTS
programs to provide additional services in areas with
high rates of MDR-TB. In order to promote the
programmatic treatment of MDR-TB in low-income
and middle-income countries that have adopted the
DOTS strategy, the WHO and its international
partners have been evolving the DOTS-Plus for
MDR-TB programs (Table 4) since 1998.13,41 The
WHO has also established a unique partnership
known as the Green Light Committee to lower the
prices of and to increase control over second-line
anti-TB drugs, and to date 35 DOTS-Plus projects
are underway across the globe.46 49 The DOTS-Plus
strategy of identifying and treating patients with
MDR-TB appears to have the potential to be effectively implemented on a nationwide scale even in a
setting with limited resources.17
The results from the retrospective study50 designed to assess treatment outcomes for the first full
cohort of MDR-TB patients (n 204), who were
treated under the Latvian DOTS-Plus strategy following WHO guidelines, have been encouraging;
66% patients were cured or completed therapy, 7%
died, 13% defaulted, and 14% did not respond to
treatment. Data on adverse drug reactions (ADRs)
collected from five DOTS-Plus sites in Estonia,
Latvia, Peru (Lima), the Philippines (Manila), and
the Russian Federation (Tomsk Oblast)51 showed
that, among 818 patients enrolled for MDR-TB
treatment, only 2% of patients stopped treatment
and 30% required removal of the suspected drugs
from the regimen and use of alternative drugs due to

Table 4 Comparison of the Principles Underlying DOTS and the DOTS-Plus Strategies*
DOTS Strategy
Political and administrative commitment
Good-quality diagnosis by sputum microscopy
Uninterrupted supply of good-quality first-line drugs for
standardized treatment through outpatient therapy
Directly observed treatment
Systematic monitoring and accountability

DOTS-Plus Strategy
Sustained political and administrative commitment
Accurate, timely diagnosis through quality-assured culture and drug susceptibility
testing
Uninterrupted supply of quality assured first and second-line drugs; appropriate
treatment strategies utilizing second-line drugs under strict supervision
Directly observed treatment
Standardized recording and reporting system that enable performance monitoring
and evaluation of treatment outcome

*DOTS-Plus is an integral component of the existing National Tuberculosis Control Program to be implemented through program infrastructure.
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CHEST / 130 / 1 / JULY, 2006

267

ADRs. These findings indicate that ADRs are manageable in the treatment of MDR-TB even in resource-limited settings provided that standardized
management strategies are followed.
Monitoring Response to Treatment
Patients receiving treatment for MDR-TB should
be closely followed up. Clinical, radiologic, laboratory, and microbiological parameters should be frequently reviewed to assess the response to treatment. Additionally, considerable attention must be
focused on monitoring the ADRs.3
Prognostic Markers
Table 5 summarizes markers of poor prognosis in
patients with MDR-TB. Recognition of these factors
may help clinicians to monitor the patients more
closely and to correct remediable factors such as
malnutrition.3,44,50,5255
Newer Anti-TB Drugs
Patients are 4 to 10 times more likely to not
respond to the currently available drugs used to treat
MDR-TB (Table 3) than to the standard therapy for
drug-susceptible TB.3 After the introduction of rifampicin, no worthwhile anti-TB drug with new
mechanisms of action has been developed in 30
years. Some of the older drugs that are being tested
and the newer drugs with potential as anti-TB agents
that are at various stages of development are listed in
Table 6.
A series of compounds containing a nitroimidazopyran nucleus that have shown anti-TB activity have
been described.56 After activation by a mechanism
that is dependent on M tuberculosis F420 cofactor,
nitroimidazopyrans inhibited the synthesis of protein
and cell wall lipid, and exhibited bactericidal activity
against both replicating and static M tuberculosis.

Table 6 Some of the Older Drugs and Newer Drugs

With Potential as Anti-TB Agents at Various Stages of
Development*
Drugs
Older drugs
Rifmaycin derivatives
Rifapentine
Rifabutin
Fluoroquinolones
Ofloxacin
Sparfloxacin
Levofloxacin
Moxifloxacin
Gatifloxacin
Newer drugs
Diarylquinoline
R207910
Nitroimidazopyran
PA-824
Nitro-dihydroimidazo-oxazole
OPC 67683
Pyrrole
LL3858, LL3522
Macrolides
Clarithromycin
Telithromycin
Oxazolidinones
Linezolid
PNU-100480
Diamine
SQ109
Ring-substituted imidazoles
*Based on the studies of Sharma and Mohan,3 and OBrien and
Spigelman.56

Compound PA-824 showed potent bactericidal activity against MDR-TB and promising oral activity in
animal infection models.57,58 Further, compounds
belonging to the class pyrroles, such as LL3858 and
LL3522, are also evoking interest.56 Recently, Andries et al59 reported a new class of inhibitors
(diarylquinolines) that blocks the function of an

Table 5Markers of Poor Prognosis in Patients With MDR-TB

Study
52

Park et al
Drobniewski et al53
Flament-Saillour et al54
Tahaoglu et al55
Mitnick et al44
Leimane et al50

Subjects, No.
(% HIV-Positive)
173 (52)
90 (29)*
51 (16)
158
75 (1.5%)
204 (0.5)

Markers of Poor Prognosis

Extrapulmonary involvement
Immunocompromised status, failure to culture the bacterium in 30 d or to apply
appropriate treatment with three drugs to which the organism is susceptible, and age
HIV coinfection, treatment with less than two active drugs, and knowledge regarding
the multidrug-resistant status at the time of diagnosis
Older age and history of previous treatment with a larger number of drugs
Low hematocrit and a low body mass index
Previous treatment for MDR-TB, the use of five or fewer drugs for 3 mo, resistance
to ofloxacin, and body mass index of 18.5 at the start of treatment

*Twenty-three of the 79 patients tested had HIV infection.

One of the 65 patients tested had HIV infection.
One of the 197 patients tested had HIV infection.
268

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Global Medicine

essential membrane-bound enzyme that makes

adenosine triphosphate. Of the 20 interesting drug
candidates, R207910 showed the best activity profile,
is bactericidal, and is exceptionally specific against
mycobacteria, with little or no activity against the
other
microorganisms
tested.
Furthermore,
R207910 is active against both the drug-sensitive and
drug-resistant forms of M tuberculosis. There have
also been reports60 of novel ring-substituted-1Himidazole-4-carboxylic acid ethyl esters as a new class of
anti-TB agents. Whether the initial enthusiasm with
these newer compounds will eventually become
established as practically useful newer first-line
anti-TB drugs remains to be seen.
Surgery
Surgery is currently recommended for MDR-TB
patients whose prognosis with medical treatment is
poor and can be performed with a low mortality rate
( 3%).3 The operative risks are acceptable, and the
long-term survival is much improved over that with
continued medical treatment alone. However, for
this to be achieved, the chemotherapeutic regimen
needs to continue for prolonged periods after surgery, probably for well 1 year, otherwise recrudescence of the disease with poor survival is a real
possibility.3
Nutritional Enhancement
TB is a wasting disease. The degree of cachexia is
most profound when MDR-TB occurs in patients
with HIV infection/AIDS. Furthermore, several second-line drugs used to treat MDR-TB, such as
para-aminosalicylic acid and fluoroquinolones, cause
significant anorexia, nausea, vomiting, and diarrhea,
which interfere with food intake, further compromising the cachectic state. Therefore, nutritional assessment and regular monitoring of the nutritional state
by a dietician are essential for the successful management of MDR-TB patients and should be an
essential part of such programs.3
Immunotherapy
Since the early efforts by Robert Koch, several
attempts have been made to modify the immune
system of patients with TB to facilitate a cure. Some
of the methods currently being tried are discussed
below.
Mycobacterium vaccae Vaccination
Transiently favorable results were observed61
when immunoenhancement using M vaccae vaccination was used to treat drug-resistant TB patients who
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did not respond to chemotherapy. However, definite

evidence confirming these observations is expected
from randomized controlled trials.62
Mycobacterium w
Results from controlled studies63,64 suggest that
adjuvant therapy with Mycobacterium w vaccination
along with anti-TB drugs is well-tolerated and facilitates early sputum conversion. A large-scale multicenter trial that is already underway is expected to
provide definitive evidence regarding this treatment
modality in category II TB patients (see http://
www.clinicaltrials.gov/ct/show/NCT00265226?order
1).
Cytokine Therapy
Aerosolized IFN-, granulocyte-macrophage colony-stimulating factor-aerosolized IFN-, and lowdose recombinant human interleukin-2 may have all
been used as adjunctive treatment for patients with
MDR-TB.3 Evidence establishing their efficacy, optimal dosage, and schedule, however, needs to be
generated in further studies.
Other Agents
Other agents used in the treatment of MDR-TB
are listed in Table 7.3 Although there have been
anecdotal reports of their usefulness, further studies
are required to clarify their role.
Prevention of Transmission of MDR-TB
As TB poses a significant risk to health-care
workers, doctors, and other patients, recommendations such as those issued by the WHO65 and the
CDC in Atlanta, GA,66 regarding the prevention of
the transmission of TB in hospitals, workplaces, and
institutional settings should be implemented wherever it is feasible.

Table 7Other Agents Used in the Treatment of

MDR-TB*
Thalidomide
Pentoxifylline
Levamisole
Transfer factor
Inhibitors of transforming growth factor-
Interleukin-12
Interferon-
Imiquimod (an oral agent that stimulates the production of
interferon- )
*Based on the studies of Sharma and Mohan,3 and OBrien and
Spigelman.56
CHEST / 130 / 1 / JULY, 2006

269

Treatment of Latent MDR-TB Infection

Newer IFN--based assays show potential for the
diagnosis of latent MDR-TB infection. For contacts
thought to be infected with M tuberculosis that is
resistant to both isoniazid and rifampicin, no satisfactory chemoprophylaxis is available.67 There is no
consensus regarding the choice of the drugs and the
duration of treatment. The CDC has put forth
guidelines66 for the management of persons exposed
to MDR-TB. The two suggested regimens for
MDR-TB preventive therapy are as follows68: (1)
pyrazinamide (25 to 30 mg/kg daily) plus ethambutol
(15 to 25 mg/kg daily); or (2) pyrazinamide (25 to 30
mg/kg daily) plus a quinolone with anti-TB activity
(eg, levofloxacin or ofloxacin). The recommended
duration of therapy is 12 months for those patients
with underlying immunosuppression and at least 6
months for all other patients. All patients should be
closely observed for at least 2 years, and a low
threshold for referral to a center with experience in
managing MDR-TB should be maintained. Initial
results indicate that the pyrazinamide and levofloxacin regimen was found to be poorly tolerated as
severe ADRs developed in several patients. These
issues merit further study in randomized controlled
studies.

3
4
5

8
9
10
11

Future Directions
The efficacy of strategies such as DOTS-Plus in
the management of MDR-TB patients under program conditions should be tested in well-designed
operational field clinical trials strictly following standardized definitions and nomenclature. Ethnic variations in the pharmacokinetics of anti-TB drugs and
the utility of therapeutic drug monitoring in the
management of patients with MDR-TB need further
study. The field testing of newer anti-TB drugs that
is on the horizon and generating evidence regarding
their efficacy deserves special mention as there is
renewed hope of shortening the duration of treatment.
ACKNOWLEDGMENTS: We sincerely thank Dr. L.S. Chauhan, Deputy Director General (TB), Central TB Division, Directorate General of Health Services, Ministry of Health and Family
Welfare, Government of India; and Dr. Fraser Wares, STP (TB),
Office of the WHO Representative to India, New Delhi, for
critically reading the manuscript and providing valuable suggestions.

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