INTRODUCTION

Tuberculosis is a widespread disease, and presents difficulties that transcend the conventional
medical approach. Tuberculosis is a very old scourge. Its mortality and morbidity increase
because it is a global health problem. It is the most ordinary opportunistic infection in AcquiredImmuno Deficiency Syndrome. Tuberculosis (TB) is a disease caused by a microorganism
(Mycobacterium tuberculosis) which invades the lungs and causes the beginning of disease.
Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the
presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative
agent of the disease. In recent years, even more serious forms of drug resistance have been
reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the
relevant molecular mechanisms involved will improve the available techniques for rapid drug
resistance detection and will help to explore new targets for drug activity and development. This
review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular
basis of drug resistance in M. tuberculosis.

CURRENT ISSUE
Global Scenario
According to WHO, TB is a worldwide pandemic. Among the 15 countries with the highest
estimated TB incidence rates, 13 are in Africa, while half of all new cases are in six Asian
countries, viz., Bangladesh, China, India, Indonesia, Pakistan and Philippines. A WHO fact sheet
dated March 2010 on tuberculosis stated that overall one third of the world's population (over 2
billion) is currently infected with the TB bacillus. According to it, every second, someone in the
world is newly infected with TB bacilli and 1 in every 10 of these newly infected people will
become sick or infectious later in life. Since concurrent infection with HIV weakens the immune
system, people with co-infection of HIV and TB are much more likely to develop TB; it is a
leading cause of death among HIV-positive people. In Africa, HIV is the single most important
factor contributing to the increase in the incidence of TB since 1990.

Local Scenario
Tuberculosis (TB) is a serious public health problem in Bangladesh. Bangladesh got rank of 6th
position globally in terms of the burden of TB on the population. According to the World Health
Organization, around 350,000 Bangladeshis developed TB in 2013 and around 80,000 die from
TB every year. Tuberculosis therefore accounts for just fewer than 9% of the deaths in
Bangladesh every year. Hence, every hour, nine people die of TB in Bangladesh, despite an
effective treatment being available.
The economic case for sustained investment in tuberculosis (TB) control in Bangladesh is
compelling. Put simply, TB treatment is low cost and effective, and this combination results in
substantial economic return. Moreover, the delivery of high quality TB services can also prevent
the spread of the disease to others and slow the emergence of multidrug- resistant TB (MDRTB), a dangerous and costly form of TB. Investment in TB is also important from a poverty
reduction perspective, where loss of earnings may force those with TB further into poverty in
Bangladesh.

The Etiological Agent

The Mycobacterium tuberculosis complex includes strains of five speciesM. tuberculosis, M.
canettii, M. africanum, M. microti, and M. bovis and two subspeciesM. caprae and M.
pinnipedii. These mycobacteria are characterized by 99.9% similarity at nucleotide level and
virtually identical 16S rRNA sequences but differ widely in terms of host tropisms, phenotypes
and pathogenicity. The most notable member of the complex is M. tuberculosis the causative
agent of human tuberculosis which has an exclusive tropism for this host. In contrast M. bovis,
the etiologic agent of bovine tuberculosis, causes only 5%10% of human tuberculosis cases
with a pathobiology indistinguishable from the one caused by M. tuberculosis and a wider host
spectrum. The impact of M. bovis in human health declined sharply after the advent of
pasteurization but there are records of new cases among immunocompromised individuals as
well as re-activation cases amongst elderly individuals. The third member of the complex with an
important, although geographically circumscribed, impact on human health is M. africanum
which is responsible for half of the TB cases in West Africa.

Mycobacterium Tuberculosi

Transmission of TB

TB infection is initiated when the mycobacterium comes into contact with the alveolar
macrophages. Mycobacterium tuberculosis (MTB) is free in its use of multiple cell surface
receptors to grow into macrophages. Te primary infection replicates within the endosome
macrophages, and then multiplies to the lymph nodes. Te primary infection has no symptom in
adults. Macrophages, B-lymphocytes, T-lymphocytes and fbroblasts are among the cells that
combine to form a granuloma adjoining the infected macrophages. Bacteria are not always
removed within the granuloma, but can become inactive, causing a latent infection Activation of
TB again mostly occurs in the lungs but involves other organs also. Secondary TB lesions can
grow in the lungs, peripheral lymph nodes, brain, kidneys and bone. All body parts can be
aected by the disease, although it rarely aects the heart, pancreas, skeletal muscles and
thyroid.

Transmission of tuberculosis

Pathogenesis

After inhalation of M. tuberculosis, innate immune responses involving alveolar macrophages

and granulocytes begin to combat the infection; in some persons, the bacilli are cleared, whereas
in others, infection is established. Replication of bacilli in macrophages and regional lymph
nodes leads to both lymphatic and hematogenous dissemination, with seeding of multiple organs,
which may eventually give rise to extrapulmonary disease. Containment of bacilli within
macrophages and extracellularly within granulomas limits further replication and controls tissue
destruction, resulting in a dynamic balance between pathogen and host. The classic interpretation
of this as a binary process with either truly latent M. tuberculosis infection or active tuberculosis
disease has recently been challenged as an oversimplification. Instead, a spectrum of
immunologic responses that are both protective and pathogenic and correlate with a range of
bacterial activation has been suggested.

M. tuberculosis pathogenesis
This continuum encompasses a variety of hostmicrobe interactions, which are characterized by
clinical latency when host responses predominate and by disease when bacterial replication
exceeds the threshold required to cause symptoms. Recent evidence suggests that host

inflammatory responses, particularly with interleukin-1, may actually enhance mycobacterial

replication, which illustrates that the double-edged sword of immune responses seen in
tuberculosis disease may also be present in latent infection. In addition, persisting extra-cellular
bacilli may remain active in a biofilm-type of environment and thus evade host defenses; in such
cases, the term persistent (rather than latent) infection has been suggested to explain the
complexity of the phenomenon.

Diagnosis
There are no perfect methods for the diagnosis of latent tuberculosis infection. The tuberculin
skin test and the IGRAs indirectly measure tuberculosis infection by detecting memory T-cell
response, which reveals only the presence of host sensitization to M. tuberculosis antigens. The
tests are generally considered to be acceptable but imperfect. The tuberculin skin test is widely
used and inexpensive, but it has poor specificity in populations vaccinated with bacille Calmette
Gurin (BCG), is subject to cross-reactivity with environmental nontuberculosis mycobacteria,
and has poor sensitivity in immunocompromised persons. There are also logistic drawbacks,
including the need for a return visit in 2 to 5 days to read the amount of in duration, since selfreading is associated with a high error rate. Furthermore, there is a worldwide shortage of
tuberculin, attributed to market forces. IGRAs measure in vitro responses of T cells or
peripheral-blood mononuclear cells to M. tuberculosis antigens that are not found in BCG and
most nontuberculous mycobacteria, and thus specificity for M. tuberculosis is higher than with
the tuberculin skin test.

TB Signs and Symptoms

Patients with tuberculosis may present without symptoms or may present in an extremely
debilitated state. Symptom-free TB may be detected during routine screening. Symptoms of
tuberculosis may include malaise, weight loss, and night sweats. Most patients with TB have
pulmonary disease; extrapulmonary disease usually is seen in immunocompromised patients.
TB in patients infected with HIV may present atypically. These patients have a higher risk for
developing multidrug-resistant TB (MDR-TB) and miliary TB. Usually, a longer course of
therapy is needed and, because of interactions with other medications, the regimen may require
adjustment.

TB Signs and Symptoms

TB symptoms include:

cough that is worse in the morning (sometimes with hemoptysis, blood in the sputum),

chest pain,

breathlessness,

night sweats, and

signs of pneumonia.

TB treatment, the drugs

There are more than twenty drugs available for TB treatment. They are used in differing
combinations in different circumstances. So for example, some TB drugs are only used for the
treatment of new patients when there is no suggestion of any drug resistance. Others are only
used for the treatment of drug resistant TB. The new TB drugs bedaquiline and delamanid are
also now available to be used for the treatment of MDR-TB when there arent any other drugs
available. More than 90% of people with drug susceptible TB (that is TB which is not drug
resistant) can be cured in six months using a combination of first line TB drugs.

Drugs used for the treatment of TB

Killing the TB bacteria

The TB drugs that are taken for the treatment of TB, have the aim of killing all the TB bacteria in
the persons body. This means that the person is cured of TB. However, TB bacteria die very
slowly, and so the drugs have to be taken for quite a few months. Even when a patient starts to
feel better they can still have bacteria alive in their body. So the person needs to keep taking the
TB treatment until all the bacteria are dead.

Short course therapy

Short-Course Therapy to treat TB
Standard anti-TB therapy typically continues for six months. For the first 2 months, patients
receive three to four drugs, namely rifampin (R), isoniazid (H), pyrazinamide (Z), and, in some
cases, ethambutol (E). During the final 4 months, they continue with rifampin and isoniazid. This
six-month regimen paradoxicallyalso is called short-course anti-TB therapy. When
administered daily, a typical adult patient is required to consume more than one-third of a

kilogram of anti-TB drugs in a series of 182 daily dosesin contrast to 25 grams in 57 doses
for curing an uncomplicated, community-acquired bacterial pneumonia or similar infection.

General principles of drug treatment of pulmonary TB

Some general principles of pulmonary TB drug treatment (sometimes referred to as TB
chemotherapy) are:

Drug treatment is the only effective treatment for TB;

Single drug treatment for active TB is associated with a substantial relapse rate. A patient
is said to have a relapse if they improve whilst taking TB treatment but become ill again
after they have finished their treatment. Single drug treatment is also associated with the
development of bacteria that are resistant to the drug;

Patients with active TB disease should receive at least three drugs as their initial TB drug
treatment. Fewer than three drugs can result in the development of resistance;

Never add a single TB drug to a failing regimen, a regimen simply means the course of
treatment, in this instance the combination of TB drugs;

Compliance with TB treatment is the responsibility of the treating physician as well as

the patient.

TB drug treatment is sometimes referred to as antitubercular treatment or ATT.

First line drugs for TB treatment

The first line drugs:

Isoniazid

Rifampicin

Pyrazinamide

Ethambutol

and Streptomycin

TB treatment, first line drugs are those TB drugs that generally have the greatest bactericidal
activity when used for TB treatment. The amount of drug that a TB patient needs to take depends
on the patients weight.

TB treatment for new patients

New patients are those who have not had TB treatment before, or they have received less than
one month of anti TB drugs. New patients are presumed to have drug susceptible TB (i.e. TB
which is not drug resistant) unless:
1. There is a high level of isoniazid resistance locally in new TB patients, or
2. the patient has developed active TB disease after known contact with a patient who is
documented as having drug resistant TB.

For new patients with presumed drug susceptible pulmonary TB, the World Health Organisation
(WHO) recommends that they should have six months of TB treatment. This consists of a two
month intensive TB treatment phase followed by a four month continuation phase.

For the two month intensive TB treatment phase they should receive:

Isoniazid

plus rifampicin

plus pyrazinamide

plus ethambutol

followed by

Isoniazid

plus rifampicin

for the continuation TB treatment phase.

Taking TB drug treatment

It is recommended that patients take the TB drugs every day for the six months. Although taking
the drugs three times a week is possible in some circumstances, it is essential that all the
recommended TB drugs are taken. If only one or two drugs are taken, then the TB treatment
probably wont work, because the TB bacteria that the patient has develops resistance to the

drugs. Not only is the patient then still ill, but to be cured they then have to take drugs for the
treatment of drug resistant TB. These drugs are more expensive and have more side effects.

TB treatment monitoring
All patients receiving TB treatment should be monitored during their treatment to assess their
response to the drug treatment. Regular monitoring also helps to ensure that patients complete
their treatment. It can also help to identify and manage adverse drug reactions. Patients need to
have their weight checked every month, and if the patients weight changes the drug dosages
may need to be adjusted.
When patients have pulmonary TB the patients response to TB treatment should be monitored
using sputum smear microscopy. The recommendation from the World Health Organisation
(WHO) is that for smear positive TB patients treated with first line drugs, the patients should
have smear microscopy performed at the end of the two month intensive phase of treatment.
Sputum should be collected when the patient is given the last dose of the intensive phase of
treatment.

The Future
The search for newer and more efficient biomarkers for predicating a durable (non-relapsing)
cure, indication of reactivation risk, prediction of eradication of LTBI; and prediction of vaccine
efficacy, discovery of newer anti-TB drugs and development of newer additional candidate
vaccines is required to achieve the WHO and UNMDG goal of halting the incidence, prevalence
and death rates associated with TB by 2015 and eliminating the disease altogether by 2050.
Translation of newer innovative diagnostics for TB, such as, use of a handheld nuclear
magnetic resonance (NMR) apparatus capable of offering a 30-minute diagnosis of TB,
applications of nanotechnology to point-of-care diagnostic tests needs to be pursued.
Presently, several newer or repurposed drugs are in pipeline in various stages of development as
anti-TB drugs. Among the newer drugs, delamanid (OPC67683), bedaquiline (TMC207) and the
nitroimidazole oxazine PA-824 have been found to be active against both drug-sensitive and
drugresistant strains. Bedaquiline (TMC207) has been approved for use by the United StatesFood and Drug Administration (US-FDA).

Conclusion
TB continues to be one of the greatest challenges in global health. Current therapeutic agents
against TB are life-saving for many patients, but cannot overcome increasing new challenges,
including the creation and dissemination of MDR-TB/XDR-TB and the need for simultaneous
treatment of TB and HIV. Recent advances in TB drug research and development are
encouraging, with nine compounds already in the clinical development pipeline, including five
new chemical entities specifically developed against TB. However, this slender pipeline is not
likely to be sufficient. New drugs are needed that have strong, synergistic and complementary
activities against various M. tuberculosis subpopulations in order to shorten TB treatment, be
effective against MDRTB/XDR-TB, and be easily administered in conjunction with ART.
Furthermore, from a programmatic standpoint, it is imperative to test new combinations of new
and old drugs in order to avoid misuse of the new compounds and prevent emergence of novel
resistance. This calls for the development of a broader drug pipeline and a new paradigm for the
identification of novel TB drug combinations. It requires the wide involvement of all relevant
parties (industry, academia, drug regulatory agencies, and international policy-making agencies)
who must collaborate effectively to deliver optimal future therapies for TB.

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