The treatment of multi drug resistant tuberculosis (mdr-tb) with sirturo (bedaquiline)(1)

THE TREATMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB)
WITH SIRTURO(BEDAQUILINE)
I.INTRODUCTION
Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal,
infectious disease caused by various strains of mycobacterium, usually Mycobacterium
tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body.
It is spread through the air when people who have an active TB infection cough, sneeze, or
otherwise transmit their saliva through the air. Most infections are asymptomatic and latent, but
about one in ten latent infections eventually progresses to active disease which, if left untreated,
kills more than 50% of those so infected (Centers for Disease Control and Prevention ,2012).
Tuberculosis (TB) is an infection caused by slow-growing bacteria that grow best in areas of the body
that have lots of blood and oxygen. That’s why it is most often found in the lungs. This is called
pulmonary TB. But TB can also spread to other parts of the body, which is called extrapulmonary TB.
Treatment is often a success, but it is a long process. It usually takes about 6 to 9 months to treat TB. But
some TB infections need up to 2 years to treat (http://www.cdc.gov/tb/).

Tuberculosis is either latent or active:
Latent TB means that you have the TB bacteria in your body, but your body’s defenses
(immune system) are keeping it from turning into active TB. This means that you don't
have any symptoms of TB right now and can't spread the disease to others. If you have
latent TB, it can become active TB.
Active TB means that the TB bacteria are growing and causing symptoms. If your lungs
are infected with active TB, it is easy to spread the disease to others.
II. EPIDEMIOLOGY
One third of the world's population is thought to have been infected with M. tuberculosis, with
new infections occurring at a rate of about one per second. In 2007, there were an estimated 13.7
million chronic active cases globally, while in 2012, there were an estimated 8.8 million new
cases and 1.5 million associated deaths, mostly occurring in developing countries. The absolute
number of tuberculosis cases has been decreasing since 2006, and new cases have decreased
since 2002. The distribution of tuberculosis is not uniform across the globe; about 80% of the

CMR College of Pharmacy, (Pharmacology), Page 1

population in many Asian and African countries test positive in tuberculin tests, while only 5–
10% of the United States population tests positive. More people in the developing world contract
tuberculosis because of compromised immunity, largely due to high rates of HIV infection and
the corresponding development of AIDS (World Health Organization).
III. TB DEFINITIONS
3.1 Tuberculosis (TB):
Tuberculosis, commonly known as TB, is a contagious and an often severe airborne disease
caused by a bacterial infection. TB typically affects the lungs, but it also may affect any other
organ of the body. It is usually treated with a regimen of drugs taken for 6 months to 2 years,
depending on the type of infection.(World Health Organization 2012, http://www.cdc.gov/tb).
3.2 Multidrug-Resistant Tuberculosis (MDR TB):
MDR TB is a form of drug-resistant TB in which TB bacteria can no longer be killed by at least
the two best antibiotics, isoniazid (INH) and rifampin (RIF), commonly used to cure TB. As a
result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2
years of multidrug treatment ( World Health Organization 2012, http://www.cdc.gov/tb).
3.3 Extensively Drug-Resistant Tuberculosis (XDR TB):
XDR TB is a less common form of multidrug-resistant TB in which TB bacteria have changed
enough to circumvent the two best antibiotics, INH and RIF, as well as most of the alternative
drugs used against MDR TB. These second-line drugs include any fluoroquinolone, and at least
one of the other three injectable anti-TB drugs: amikacin, kanamycin, or capreomycin. As a
result, XDR TB needs up to 2 years of extensive drug treatment and is the most challenging to
treat (World Health Organization 2012).

IV. ETIOLOGY
4.1 Causative organism:
Tuberculosis is an infection caused by the rod-shaped, non–spore-forming, aerobic
bacterium Mycobacterium tuberculosis.Mycobacteria typically measure 0.5 μm by 3 μm, are
classified as acid-fast bacilli, and have a unique cell wall structure crucial to their survival. The
well-developed cell wall contains a considerable amount of a fatty acid, mycolic acid, covalently


attached to the underlying peptidoglycan-bound polysaccharide arabinogalactan, providing an
extraordinary lipid barrier. This barrier is responsible for many of the medically challenging
physiological characteristics of tuberculosis, including resistance to antibiotics and host defense
mechanisms. The composition and quantity of the cell wall components affect the bacteria’s
virulence and growth rate. The peptidoglycan polymer confers cell wall rigidity and is just
external to the bacterial cell membrane, another contributor to the permeability barrier of
mycobacteria. Another important component of the cell wall is lipoarabinomannan, a
carbohydrate structural antigen on the outside of the organism that is immunogenic and
facilitates the survival of mycobacteria within macrophages.The cell wall is key to the survival
of mycobacteria, and a more complete understanding of the biosynthetic pathways and gene
functions and the development of antibiotics to prevent formation of the cell wall are areas of
great interest.
The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis,
M. africanum, M. canetti, and M. microti. M. africanum is not widespread, but it is a significant
cause of tuberculosis in parts of Africa. M. bovis was once a common cause of tuberculosis, but
the introduction of pasteurized milk has largely eliminated this as a public health problem in
developed countries. M. canetti is rare and seems to be limited to the Horn of Africa, although a
few cases have been seen in African emigrants. M. microti is also rare and is mostly seen in
immunodeficient people, although the prevalence of this pathogen has possibly been
significantly underestimated.
Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter
two species are classified as "nontuberculous mycobacteria" (NTM). NTM cause neither TB nor
leprosy, but they do cause pulmonary diseases that resemble TB (Harsh Mohan 2006).
4.2 Pathophysiology:
Infection with M tuberculosis results most commonly through exposure of the lungs or mucous
membranes to infected aerosols. Droplets in these aerosols are 1-5 μm in diameter; in a person
with active pulmonary TB, a single cough can generate 3000 infective droplets, with as few as 10
bacilli needed to initiate infection.


When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The
organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to
elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test.
Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response.
Their antigenicity is due to multiple cell wall constituents, including glycoproteins,
phospholipids,

and

wax

D,

which

activate

Langerhans

cells,

lymphocytes,

and

polymorphonuclear leukocytes.
When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths,
most of which do not lead to actual TB. The infection may be cleared by the host immune system
or suppressed into an inactive form called latent tuberculosis infection (LTBI), with resistant
hosts controlling mycobacterial growth at distant foci before the development of active disease.
Patients with LTBI cannot spread TB.
The lungs are the most common site for the development of TB; 85% of patients with TB present
with pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late,
generalized infection. An extrapulmonary location may also serve as a reactivation site;
extrapulmonary reactivation may coexist with pulmonary reactivation.
The most common sites of extrapulmonary disease are as follows (the pathology of these lesions
is similar to that of pulmonary lesions):
Mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes - The most common site
of tuberculous lymphadenitis (scrofula) is in the neck, along the sternocleidomastoid
muscle; it is usually unilateral and causes little or no pain; advanced cases of tuberculous
lymphadenitis may suppurate and form a draining sinus
Vertebral bodies
Adrenals
Meninges
GI tract


Infected end organs typically have high regional oxygen tension (as in the kidneys, bones,
meninges, eyes, and choroids, and in the apices of the lungs). The principal cause of tissue
destruction from M tuberculosis infection is related to the organism's ability to incite intense host
immune reactions to antigenic cell wall proteins.
Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary
systemic tubercular infection. There is some debate with regard to whether molecular mimicry,
as well as a nonspecific response to noninfectious tubercular antigens, provides a mechanism for
active ocular inflammation in the absence of bacterial replication (Harsh Mohan 2006).
4.3 TB lesions:
The typical TB lesion is an epithelioid granuloma with central caseation necrosis. The most
common site of the primary lesion is within alveolar macrophages in subpleural regions of the
lung. Bacilli proliferate locally and spread through the lymphatics to a hilar node, forming the
Ghon complex.
Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating the
following features:
A central caseation necrosis
An inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with
lymphocytes
An outer cellular zone of lymphocytes, plasma cells, and immature macrophages
A rim of fibrosis (in healing lesions)
Initial lesions may heal and the infection become latent before symptomatic disease occurs.
Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve
tubercles and larger lesions are surrounded by a fibrous capsule. Such fibrocaseous nodules
usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation.
Some nodules calcify or ossify and are seen easily on chest radiographs.


Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low
oxygen tension, all of which inhibit growth of the tubercle bacillus.
If the host is unable to arrest the initial infection, the patient develops progressive, primary TB
with tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with
large numbers of acid-fast bacilli can be found in sputum and tissue. Subserosal granulomas may
rupture into the pleural or pericardial spaces and create serous inflammation and effusions.
With the onset of the host immune response, lesions that develop around mycobacterial foci can
be either proliferative or exudative. Both types of lesions develop in the same host, since
infective dose and local immunity vary from site to site.
Proliferative lesions develop where the bacillary load is small and host cellular immune
responses dominate. These tubercles are compact, with activated macrophages admixed, and are
surrounded by proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular
killing of mycobacteria is effective, and the bacillary load remains low.
Exudative lesions predominate when large numbers of bacilli are present and host defenses are
weak. These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation
necrosis are sites of mycobacterial growth. Without treatment, these lesions progress and
infection spreads (Harsh Mohan 2006, World Health Organization 2012 ).
V. Latent TB Infection and TB Disease
Not everyone infected with TB bacteria becomes sick. As a result, two TB-related conditions
exist: latent TB infection and TB disease
5.1 Latent TB Infection:
TB bacteria can live in the body without making you sick. This is called latent TB infection. In
most people who breathe in TB bacteria and become infected, the body is able to fight the
bacteria to stop them from growing. People with latent TB infection do not feel sick and do not
have any symptoms. People with latent TB infection are not infectious and cannot spread TB


bacteria to others. However, if TB bacteria become active in the body and multiply, the person
will go from having latent TB infection to being sick with TB disease.
5.2 TB Disease:
TB bacteria become active if the immune system can't stop them from growing. When TB
bacteria are active (multiplying in your body), this is called TB disease. People with TB disease
are sick. They may also be able to spread the bacteria to people they spend time with every day.
Many people who have latent TB infection never develop TB disease. Some people develop TB
disease soon after becoming infected (within weeks) before their immune system can fight the
TB bacteria. Other people may get sick years later when their immune system becomes weak for
another reason.
Person with LTBI (Infected)

Person with TB Disease (Infectious)

Has a small amount of TB bacteria in his/her

Has a large amount of active TB bacteria in

body that are alive, but inactive

his/her body

Cannot spread TB bacteria to others

May spread TB bacteria to others

Does not feel sick, but may become sick if the

May feel sick and may have symptoms such as

bacteria become active in his/her body

a cough, fever, and/or weight loss

Usually has a TB skin test or TB blood test

Usually has a TB skin test or TB blood test

reaction indicating TB infection

reaction indicating TB infection

Radiograph is typically normal

Radiograph may be abnormal

Sputum smears and cultures are negative

Sputum smears and cultures may be positive

Should consider treatment for LTBI to prevent

Needs treatment for TB disease

TB disease
Does not require respiratory isolation

May require respiratory isolation

Not a TB case

A TB case
Table. no 5.2a. Deference between LTBI and TB Disease


Persons at Increased Risk
• Persons infected with HIV;
• Children younger than 5 years of age;
• Persons who were recently infected with M. tuberculosis (within the past 2 years);
• Persons with a history of untreated or inadequately treated TB disease, including persons with
fibrotic changes on chest radiograph consistent with prior TB disease;
• Persons who are receiving immunosuppressive therapy such as tumor necrosis factor-alpha
(TNF) antagonists, systemic corticosteroids equivalent to/greater than 15 mg of prednisone per
day, or immunosuppressive drug therapy following organ transplantation;
• Persons with silicosis, diabetes mellitus, chronic renal failure, leukemia, or cancer of the head,
neck, or lung;
• Persons who have had a gastrectomy or jejunoileal bypass;
• Persons who weigh less than 90% of their ideal body weight;
• Cigarette smokers and persons who abuse drugs and/or alcohol; and
• Populations defined locally as having an increased incidence of disease due to M. tuberculosis,
including medically underserved, low-income populations.
Table. no 5.2b. Persons at Increased Risk for Progression of LTBI to TB Disease
For people whose immune systems are weak, especially those with HIV infection, the risk of
developing TB disease is much higher than for people with normal immune systems (World
Health Organization (2012).
5.2.1 Signs and Symptoms of TB Disease:
Symptoms of TB disease depend on where in the body the TB bacteria are growing. TB bacteria
usually grow in the lungs (pulmonary TB). TB disease in the lungs may cause symptoms such as
A bad cough that lasts 3 weeks or longer
pain in the chest
coughing up blood or sputum (phlegm from deep inside the lungs)
Other symptoms of TB disease are


weakness or fatigue
weight loss
no appetite
fever
sweating at night
VI. Transmission:
Mycobacterium tuberculosis is spread by small airborne droplets, called droplet nuclei, generated
by the coughing, sneezing, talking, or singing of a person with pulmonary or laryngeal
tuberculosis. These minuscule droplets can remain airborne for minutes to hours after
expectoration. The number of bacilli in the droplets, the virulence of the bacilli, exposure of the
bacilli to UV light, degree of ventilation, and occasions for aerosolization all influence
transmission. Introduction of M tuberculosis into the lungs leads to infection of the respiratory
system; however, the organisms can spread to other organs, such as the lymphatics, pleura,
bones/joints, or meninges, and cause extrapulmonary tuberculosis (Harsh Mohan 2006, World
Health Organization 2012 ).

Figure. no 6.1. Mode of Transmission of TB bacilli



VII. Diagnosis:
7.1 The Standard:
Definitive diagnosis of tuberculosis requires the identification of M tuberculosisin a culture of a
diagnostic specimen. The most frequent sample used from a patient with a persistent and
productive cough is sputum. Because most mycobacteria grow slowly, 3 to 6 weeks may be
required for detectable growth on solid media. However, a newer, alternative method in which
high-performance liquid chromatography is used to isolate and differentiate cell wall mycolic
acids provides confirmation of the disease in 4 to 14 days. Conventionally, 3 sputum samples
were also used for culture diagnosis, but the use of 2 specimens, as mentioned earlier for smears,
also applies for cultures.
After medications are started, the effectiveness of the therapy is assessed by obtaining sputum
samples for smears. Once again, the traditional requirement of 3 sputum smears negative for M
tuberculosis may be unnecessary when determining if respiratory isolation can be discontinued.
A patient is considered to have achieved culture conversion when a culture is negative for the
mycobacteria after a succession of cultures have been positive; culture conversion is the most
important objective evaluation of response to treatment (World Health Organization 2012 ).
7.2 Alternatives:
Unfortunately, not all patients with tuberculosis can be detected by culture of sputum specimens,
a situation that can lead to delayed or missed diagnosis. Additionally, many critically ill patients
have trouble producing the necessary material from the lungs and instead produce saliva or
nasopharyngeal discharge. For patients who have difficulty generating sputum, inhalation of an
aerosol of normal saline can be used to induce sputum for collection. However, if sputum
specimens are still inadequate, or the index of suspicion for tuberculosis is still high despite
cultures negative for M tuberculosis, alternative approaches are available.
Bronchoscopy with bronchial washings or bronchoalveolar lavage can provide sputum for
diagnosis. In bronchial washing, a fiberoptic bronchoscope is inserted into the lungs, and fluid is
squirted in and then collected, essentially washing out a sample of cells and secretions from the
alveolar and bronchial airspaces. Aliquots obtained from subsequent lavages constitute
bronchoalveolar lavage specimens.


In patients with involvement of intrathoracic lymph nodes, as indicated by adenopathy
suggestive of tuberculosis, who have sputum smears negative for M tuberculosis, culture of
specimens collected by transbronchial needle aspiration can be used to accurately and
immediately diagnose the disease. With this technique, specimens are collected by inserting a
19-gauge flexible histology needle through a bronchoscopy tube; patients are sedated but
conscious, and computed tomography scans are used for guidance (Centers for Disease Control
and Prevention 2012).

7.3 Technological Advancements:
Newer diagnostic techniques for faster detection of M tuberculosis include nucleic acid
amplification tests. In these tests, molecular biology methods are used to amplify DNA and
RNA, facilitating rapid detection of microorganisms; the tests have been approved by the Food
and Drug Administration. One method is the polymerase chain reaction assay, which can be used
to differentiate M tuberculosis from other Mycobacteria on the basis of genetic information and
provides results within hours. Although the test can provide rapid confirmation of
M.tuberculosis in sputum specimens positive for acid-fast bacilli, it has limitations, including
high cost, low sensitivity, and low availability. A polymerase chain reaction assay positive for M
tuberculosis in conjunction with a sputum smear positive for the organism indicates true
tuberculosis, but in a patient with a sputum smear negative for the organism, the positive
polymerase chain reaction assay should be considered carefully along with clinical indicators.
The results of these assays cannot be relied on as the sole guide for isolation or therapy (Centers
for Disease Control and Prevention 2012).
7.4 Diagnosing latency:
Once patients recover from a primary M tuberculosis infection and the infection becomes latent,
sputum specimens are negative for the organisms, and findings on chest radiographs are typically
normal. These patients also do not have signs or symptoms of infection, and they are not
infectious to others. Tuberculin skin testing is the most common method used to screen for
latent M tuberculosis.
7.4.1 The tuberculin skin test is performed by intradermally injecting 0.1 mL of intermediatestrength purified protein derivative (PPD) that contains 5 tuberculin units. After 48 to 72 hours,


the injection site is examined for induration but not redness . Although the test is useful because
the PPD elicits a skin reaction via cell-mediated immunity when injected in patients previously
infected with mycobacteria, it is limited because it is not specific for the species of mycobacteria.
Many proteins in the PPD product are highly conserved in various species of mycobacteria. Also,
the test is of limited value in patients with active tuberculosis because of its low sensitivity and
specificity. False-negatives can occur in patients who are immunocompromised or malnourished,
because these patients cannot mount an immune response to the injection, and in 20% to 25% of
patients who have active tuberculosis, because there is a time lag of 2 to 10 weeks between
infection and the T-lymphocyte response required for a positive skin reaction. False-positives
can occur in patients who have infections caused by mycobacteria other than M tuberculosis or
who have been given BCG vaccine.

The tuberculin skin test was the only test available to detect latent tuberculosis until an
interferon-release assay, called QuantiFERON-TB test, was approved by the Food and Drug
Administration in 2001. Then, in 2005, a new interferon-assay, called QuantiFERON-TB Gold
was approved and is intended to replace the QuantiFERON-TB test, which is no longer
commercially available. In both tests, the cell-mediated reactivity to M tuberculosis is
determined by incubating whole blood with an antigen and then using an enzyme-linked
immunosorbent assay to measure the amount of interferon-γ released from white blood cells. In
the QuantiFERON-TB Gold test, 2 synthetic antigenic proteins specific in PPD are used rather
than a PPD admixture, making this test more sensitive than its predecessor. QuantiFERON-TB
Gold provides results in less than 24 hours and can be used to detect both active and latent
tuberculosis. The results of the QuantiFERON-TB Gold test are similar to those of the tuberculin
skin test, and the Centers for Disease Control and Prevention now recommend that the
QuantiFERON-TB Gold test be used in all instances in which the tuberculin skin test formerly
would have been used ( www.cdc.gov/tb).



Table.no7.4.1a.TST reaction for diagnosis of TB

VIII. Drug-resistance Tuberculosis
8.1 Types of drug resistance:
The three types of drug resistance are primary, secondary, and naturally occurring resistance.
8.1.1 Primary resistance:
Primary resistance occurs if the organisms transmitted are resistant to one or more TB drugs.
8.1.2 Secondary resistance:
Secondary resistance occurs if new resistance develops during treatment.
8.1.3 Naturally occurring drug resistance:
There is a degree of naturally occurring resistance to anti-TB drugs. This resistance varies from
drug to drug. The approximate rates of development of resistant organisms in vitro are:
10-3 for ethionamide, capreomycin, cycloserine and thiocetazone
10-5–10-7 for isoniazid, streptomycin, ethambutol, kanamycin and para-aminosalicylic acid
10-9 for rifampicin
10-14 for combined isoniazid and rifampicin.


Cavities contain approximately 108–109 bacilli and there is a significantly higher risk of naturally
resistant organisms being present in cavitating TB. Due to the occurrence of naturally occurring
drug resistant TB it is essential that TB is treated with multiple drugs (www.cdc.gov/tb)
8.1.4 Suspected drug resistance:
Additional drugs may be necessary in re-treating TB in people previously treated. If MDR-TB is
a possibility and immediate treatment is clinically necessary, sufficient drugs should be used
initially to avoid the development of further resistance should the isolate subsequently prove to
be resistant to all first-line agents. In practice, this may necessitate use of an MDR regimen at
the outset.
Treatment of TB caused by drug-resistant organisms should be done by or in close consultation
with an expert in the management of these difficult cases. Second-line regimens often present
the patient’s best hope for cure and thus inappropriate management of a drug-resistant case can
have life threatening consequences.

The management of drug-resistant TB is often complicated by drug toxicities and long duration
of therapy. Successful treatment outcomes for drug-resistant TB are often difficult to achieve
compared with drug-susceptible disease, especially when multidrug-resistance is present (World
Health Organization 2012)
The most important predictors of drug-resistant TB are:
a previous episode of TB treatment
progressive clinical and/or radiographic findings while on TB treatment
origin from, history of residence in or frequent travel to a region/country with high rates of
drug resistance
exposure to an individual with infectious drug-resistant TB.
Multidrug-Resistant Tuberculosis (MDR TB):


MDR TB is a form of drug-resistant TB in which TB bacteria can no longer be killed by at least
the two best antibiotics, isoniazid (INH) and rifampin (RIF), commonly used to cure TB. As a
result, this form of the disease is more difficult to treat than ordinary TB and requires up to 2
years of multidrug treatment.
People may get MDR TB in two ways:
Directly, if they spend time with an MDR TB patient and breathe in the MDR TB bacteria
If they already have active TB and do not properly follow their prescribed treatment regimen or
TB medicine is not reliably available to them.
The inconsistent use of TB antibiotics gives the bacteria enough time to evolve and evade the
first-line anti-TB medicines, and regular TB may then progress to MDR TB, which is more
challenging to treat.
Extensively Drug-Resistant Tuberculosis (XDR TB):
XDR TB is a less common form of multidrug-resistant TB in which TB bacteria have changed
enough to circumvent the two best antibiotics, INH and RIF, as well as most of the alternative
drugs used against MDR TB. These second-line drugs include any fluoroquinolone, and at least
one of the other three injectable anti-TB drugs: amikacin, kanamycin, or capreomycin. As a
result, this form of the disease needs up to 2 years of extensive drug treatment and is the most
challenging to treat.
People may get XDR TB in two ways:
Directly, if they spend time with an XDR TB patient and breathe in the XDR TB bacteria, and
If they already have MDR TB or active TB, and do not properly follow their prescribed
treatment regimen or TB medication is not reliably available to them.
The inconsistent use of TB antibiotics gives the bacteria enough time to evolve and evade most if
not all TB drugs, making it extremely difficult or impossible to treat XDR TB (World

Health

Organization 2012)

IX. Treatment of drug-resistant TB
The duration of treatment needs to be re-evaluated when drug resistance is encountered. The
following treatment periods are a guide and represent the minimum duration of treatment


(Table).

A daily dosing schedule should be used for all patients with drug-resistant TB.

Intermittent dosing schedules must not be used.
It is essential that exemplary infection control practices are maintained in all case of drug
resistant TB ( ttp://www.theunion.org/index.php/en/what-we-do/tuberculosis/multidrug-resistanttb-mdr-tb, www.ncbi.nlm.nih.gov )

Pattern

of Suggested regimen

Minimum duration Comments

drug

of

resistance

(months)

H (+/- S)

R,Z and E

6–9*

treatment

A

fluoroquinolone

may

strengthen the regimen for
patients

with

extensive

disease
H and Z

R, E and moxifloxacin

9–12*

A

longer

duration

of

treatment should be used for
patients

with

extensive

disease
H and E

R, Z and moxifloxacin

9–12*

A

longer

duration

of

treatment should be used for
patients

with

extensive

disease
R

H, E, moxifloxacin plus 12–18*

An

injectable

at least two months of Z

patients

with

agent

may

extensive

disease


R and E (+/- H, Z, moxifloxacin plus 18

A longer course (six months)

S)

an injectable agent for

of the injectable agent may

at least the first 2–3


months

patients

with

extensive

disease
R and Z (+/- H, E, moxifloxacin plus 18


S)

an injectable agent for


at least the first 2–3


months

patients

with

extensive

disease
H, E, Z (+/- R, moxifloxacin plus an 18


S)

oral second-line agent,


plus an injectable agent


for the first 2–3 months

patients

with

extensive

disease

Table.no 9.1. Suggested regimens for mono- and poly-drug resistance (when further acquired

resistance is not a factor and laboratory results are highly reliable)
Isoniazid-resistant tuberculosis:
Resistance to isoniazid is reported at 0.1 mcg/mL (low level) and 0.4 mcg/mL (high level). If
low-level resistance is present, isoniazid should be continued as part of a regimen containing at
least three other effective drugs. This is because the determination of isoniazid resistance is
based on minimal inhibitory concentrations (MICs), and in practice the serum level could exceed
the in vitro MIC.
Rifampicin-resistant tuberculosis:
Isolated resistance to rifampicin is uncommon and should raise the suspicion of MDR-TB. The
loss of rifampicin from the treatment regimen requires a longer duration of treatment.


Resistance to rifampicin is associated in most cases with cross-resistance to rifabutin. It is not
clear whether laboratory-reported rifabutin susceptibility in the presence of rifampicin resistance
is sufficiently reliable to allow use of rifabutin as a substitute for rifampicin. It is recommended
that a regimen similar to that used for rifampicin resistance be used.
Pyrazinamide-resistant tuberculosis:
Mycobacterium bovis (or BCG related disease) is naturally resistant to pyrazinamide.
2RHE/7RH (or 9RH for minor extent of disease) is appropriate for treatment of patients with
isolated pyrazinamide-resistant TB (www.ncbi.nlm.nih.gov)
X. Tuberculosis facts
Tuberculosis (TB) is an infection, primarily in the lungs (apneumonia), caused by bacteria
called Mycobacterium tuberculosis. It is spread usually from person to person by breathing
infected air during close contact.
TB can remain in an inactive (dormant) state for years without causing symptoms or
spreading to other people.
When the immune system of a patient with dormant TB is weakened, the TB can become
active (reactivate) and cause infection in the lungs or other parts of the body.
The risk factors for acquiring TB include close-contact situations, alcohol and IV drug
abuse, and certain diseases (for example,diabetes, cancer, and HIV) and occupations (for
example, health-care workers).
The most common symptoms and signs of TB are fatigue, fever,weight loss, coughing,
and night sweats.
The diagnosis of TB involves skin tests, chest X-rays, sputum analysis (smear and culture),
andPCR tests to detect the genetic material of the causative bacteria.
Inactive tuberculosis may be treated with an antibiotic, isoniazid (INH), to prevent the TB
infection from becoming active.


Active TB is treated, usually successfully, with INH in combination with one or more of
several drugs, including rifampin (Rifadin), ethambutol (Myambutol),pyrazinamide, and
streptomycin.
Drug-resistant TB is a serious, as yet unsolved, public-health problem, especially in
Southeast Asia, the countries of the former Soviet Union, Africa, and in prison populations.
Poor patient compliance, lack of detection of resistant strains, and unavailable therapy are
key reasons for the development of drug-resistant TB.
The occurrence of HIV has been responsible for an increased frequency of tuberculosis.
Control of HIV in the future, however, should substantially decrease the frequency of TB
(www.ncbi.nlm.nih.gov).

XI. TUBERCULOSIS MANAGEMENT
Tuberculosis treatment refers to the medical treatment of the infectious tuberculosis (TB).
The standard "short" course treatment for TB is isoniazid (along with pyridoxal phosphate to
obviate peripheral neuropathy caused by isoniazid), rifampicin (also known as rifampin in the
United States), pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin
alone for a further four months. The patient is considered cured at six months (although there is
still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine
months of isoniazid alone.
If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and
pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol
need not be used.
First-line drugs
Isoniazid (INH)
Rifampin (RIF)
Rifabutin
Rifapentine


Pyrazinamide (PZA)
Ethambutol (EMB)
Second-line drugs
The second line drugs are considered as the reserved therapy for tuberculosis treatment.
These drugs are often used in special conditions. When situations like resistance to first line
therapy,

extensively

drug-resistant

tuberculosis

(XDR-TB)

or

multidrug-resistant

tuberculosis (MDR-TB) arise, the second-line drugs are implemented for the treatment of
tuberculosis.[2] There are six classes of second-line drugs (SLDs) used for the treatment of
TB. A drug may be classed as second-line instead of first-line for one of three possible
reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it
may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing
countries (e.g., fluoroquinolones):
Cycloserine
Ethionamide
Streptomycin
Amikacin/kanamycin
Capreomycin
P-Amniosalicylic acid (PAS)
Levofloxacin
Moxifloxacin
Gatifloxacin

11.1 Multi-drug resistant TB:
MDR-TB is defined as TB that is resistant to rifampicin and isoniazid. Resistance to other drugs
may or may not be present.
Key recommendations for the treatment of MDR-TB include:
drug-resistant TB should be promptly diagnosed and appropriate therapy initiated


patients with MDR-TB should always be treated with a minimum of four or more drugs to
which the patient has not been previously exposed and to which the isolate is susceptible
drug susceptibility testing (DST) should generally be used to guide therapy, however do not
depend on DST in individual regimen design for ethambutol, pyrazinamide and group 4 and 5
drugs
ciprofloxacin should not be used as an anti-tuberculosis agent
treatment should be continued for at least 18 months past culture conversion
adverse effects should be treated immediately and adequately
daily DOT is mandatory for all patients with MDR-TB.
WHO classifies five different groups of drugs available for use for the treatment of MDR-TB.
These groups provide a systematic method for allocating drugs to an MDR treatment regimen
(Table 11.1a ). Treatment regimens should be designed with a consistent approach based on the
hierarchy of the five groups of anti-tuberculosis drugs (Centers for Disease Control and
Prevention 2012).

Group

Drug

Group 1 – first line agents (oral)

Isoniazid, rifampicin, ethambutol, pyrazinamide

Group 2 – injectable agents

Streptomycin, amikacin, kanamycin, capreomycin

Group 3 – Fluoroquinolone group

Moxifloxacin, ofloxacin, levofloxacin, gatifloxacin

Group 4 – Other, second line agents

Ethionamide, protionamide, cyloserine, PAS

(bacteriostatic)
Group 5 – Agents of uncertain efficacy (not

Clofazamine, amoxicillin-clavulanate,

routinely recommended)

clarithromycin, linezolid

Table. no 11.1a . WHO classification of anti-TB drugs


Group 1: Ethambutol and pyrazinamide can be used if there is laboratory evidence of
susceptibility but previous use potentially means that these drugs may be less effective. If the
laboratory demonstrates low-level isoniazid resistance then high dose isoniazid may be
beneficial.
Group 2: An injectable agent should be given to all MDR patients.
Group 3: A fluoroquinolone antibiotic should be included if susceptible. Moxifloxacin is the
preferred fluoroquinolone. Ciprofloxacin is no longer recommended for the treatment of TB.
Group 4: Protionamide (or ethionamide) and cycloserine are the two most commonly used agents
from this group. Para-aminosalicylic acid (PAS) is the next choice if a third drug is required.
Group 5: The effectiveness of drugs in this group is unclear. They should only be considered
when drug options are limited.

11.2 Extensively drug-resistant TB:
Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB that is resistant to one or more
of the fluoroquinolones and injectable agents.
Treatment of XDR-TB will involve Group 5 agents and management should always be in
consultation with an expert in the management of drug-resistant TB.
XDR-TB has a very high mortality rate, especially in the setting of HIV co-infection, and a low
cure rate (Centers for Disease Control and Prevention 2012).

XII. FDA Grants Accelerated Approval for SIRTURO (bedaquiline) as Part
of Combination Therapy to Treat Adults with Pulmonary Multi-Drug
Resistant Tuberculosis
"The accelerated approval of SIRTURO is a significant step in the fight against MDR-TB, which
is a more difficult to treat form of TB that affects approximately 630,000 people in the world .


"This is the first time a new drug is being introduced specifically for MDR-TB, for which the
current needs are so great," said Lee Reichman, M.D., Executive Director, New Jersey Medical
School Global Tuberculosis Institute. "It is an important step in the development of new
compounds for this serious and contagious disease."
The FDA accelerated approval of SIRTURO was based on data from TMC207-C208 Study 1
and Study 2. The primary endpoint was time to sputum culture conversion, defined as the
interval in days between the first dose of study drug and the date of the first of two consecutive
negative sputum cultures collected at least 25 days apart during treatment.
TMC207-C208 Study 1 is a placebo-controlled, double-blind, randomized trial conducted in
newly diagnosed patients with multi-drug resistant pulmonary Mycobacterium tuberculosis.
Patients were randomized to receive treatment with either SIRTURO and other drugs used to
treat MDR-TB (SIRTURO treatment group) (n=79) or placebo plus other drugs to treat MDRTB (placebo treatment group) (n=81): the other drugs used to treat MDR-TB consisted of
a combination of five other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide,
ofloxacin, and cycloserine/terizidone or available alternative). SIRTURO was administered as
400 mg once daily for the first two weeks and as 200 mg three times per week for the following
22 weeks. After the 24 week study drug (SIRTURO or placebo) treatment phase patients
continued to receive their other drugs used to treat MDR-TB until a total treatment duration of
18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture
(FDA Advisory http://www.sarpam.net ).
12.1 THE SIRTURO TREATMENT group had decreased time to culture conversion and
improved culture conversion rates compared to the placebo treatment group at week 24. Median
time to culture conversion was 83 days for the SIRTURO treatment group, compared to 125 days
for the placebo treatment group.
At week 24, culture conversation status results were:
77.6 percent of patients in the SIRTURO treatment group reached treatment success
vs. 57.6 percent of patients in the placebo treatment group (p=0.014).


22.4 percent of patients in the SIRTURO treatment group experienced treatment failure
vs. 42.4 percent of patients in the placebo treatment group.
7.5 percent of patients in the SIRTURO treatment group vs. 24.2 percent in the placebo
treatment group experienced lack of conversion.
Discontinuation rates were 14.9 percent for SIRTURO treatment group vs. 18.2 percent
for the placebo treatment group.
At week 72, culture conversation status results were:
70.1 percent of patients in the SIRTURO treatment group reached treatment success vs.
56.1 percent of patients in the placebo treatment group (p=0.092).
29.9 percent of patients in the SIRTURO treatment group experienced treatment failure
vs. 43.9 percent of patients in the placebo treatment group.
4.5 percent of patients in the SIRTURO treatment group vs. 10.6 percent in the placebo
treatment group experienced lack of conversion.
Discontinuation rates were 25.4 percent for SIRTURO treatment group vs. 33.3 percent
for placebo treatment group.
TMC207-C208 Study 2 is a smaller, placebo-controlled study designed similarly to Study 1
except that SIRTURO™ or placebo was given for only 8 weeks instead of 24 weeks. Patients
were randomized to either SIRTURO

and other drugs used to treat MDR-TB (SIRTURO

treatment group) (n=23) or placebo and other drugs used to treat MDR-TB (placebo treatment
group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and
23 patients randomized to the placebo treatment group had confirmed MDR-TB based on
subjects' baseline M. tuberculosis isolate obtained prior to randomization. The SIRTURO
treatment group had a decreased time to culture conversion and improved culture conversion
rates compared to the placebo treatment group at week 8. At weeks 8 and 24, the differences in
culture

conversion

proportions

were

38.9

percent

and

15.7

percent,

respectively

(http://www.who.int/tb/challenges/mdr/en/).



12.1.1 Two Phase 2 Clinical Trials:
The FDA looked at two Phase 2 clinical trials to determine Sirturo's safety and efficacy.
In the first trial, patients were randomly selected to be treated with Sirturo alongside other TB
medications, or a placebo alongside other TB medications.
In the second trial patients received Sirturo plus other TB medications. This study is ongoing.
In both studies, the aim was to determine how long it took for the patient's sputum to be free
ofM. tuberculosis.
In the first trial, the Sirturo-combination therapy patients' sputum became M. tuberculosis free in
83 days, versus 125 days for those on placebo. The second trial has so far supported the results of
the first trial.
During the two trials, the most commonly reported side effects included headache, joint
pain and nausea ( Diacon AH et al June 2012 , http://www.who.int/tb/challenges/mdr/en/).

12.2 MECHANISM OF ACTION OF BEDAQULINE:
The FDA approved Bedaquiline (as the fumarate salt; trade name: Sirturo; (for Bedaquiline
Fumarate), and TMC-207 (for Bedaquiline)), a novel, first-in-class diarylquinoline
antimycobacterial drug indicated for the treatment of pulmonary multi-drug resistant tuberculosis
(MDR-TB) as part of combination therapy in adults.

Tuberculosis is an infectious disease caused by the mycobacteria Mycobacterium tuberculosis,
which usually affects the lungs. MDR-TB occurs when M. tuberculosis becomes resistant to the
two most powerful first-line treatment anti-TB drugs, Isoniazid and Rifampin . Bedaquiline is the
first anti-TB drug that works by inhibiting mycobacterial adenosine 5'-triphosphate (ATP)
synthase , an enzyme essential for the replication of the mycobacteria.



Figure.no 12.2.a The Mycobacterial ATP synthase

ATP is the most commonly used energy currency of cells for most organisms. ATP synthase
produces ATP from adenosine di phosphate (ADP) and inorganic phosphate using energy from a
transmembrane proton-motive force generated by respiration. The above figure depicts a model
of the mycobacterial ATP synthase. ATP synthase has two major structural domains, F0 and F1,
that act as a biological rotary motor. The F1 domain is composed of subunits α3 (Uniprot: ), β3
(Uniprot:), γ3 (Uniprot:), δ and ε (Uniprot:); the F0 domain includes one a subunit (Uniprot), two
b subunits (Uniprot) and 9 to 12 c subunits (Uniprot) arranged in a symmetrical disk. The F0 and
F1 domains are linked by central stalks (subunits γ and ε) and peripheral stalks (subunits b and
δ). The proton-motive force fuels the rotation of the transmembrane disk and the central stalk,
which in turn modulates the nucleotide affinity in the catalytic β subunit, leading to the
production of ATP (FDA Advisory http://www.sarpam.net ).

It has been shown that mutation in the atpE gene, which encodes the c subunit, of the
mycobacterial ATP synthase, confers resistant to Bedaquiline, suggesting that Bedaquiline binds
crucially to this target (although almost certainly other components of the complex are required


for a competent binding site), inhibiting the proton pump of M. tuberculosis and therefore
interfering with the rotation properties of the transmembrane disk, leading to ATP depletion
 Another notable feature is the high specificity of Bedaquiline for Mycobacteria. This is

due to the fact that there is very limited sequence similarity between the mycobacterial
and human atpE proteins.
12.2 .1 STRUCTURE OF BEDAQUILINE :

Figure.no12.2.1a . The structure of Bedaquiline

Bedaquiline is a diarylquinoline antimycobacterial drug, which displays both planar hydrophobic
moieties and hydrogen-bonding acceptor and donor groups. It has a molecular weight of 555.50
Da (671.58 for the fumarate salt), an ALogP of 6.93, 4 hydrogen-bond acceptors and 1
hydrogen-bond donor, and therefore not fully rule-of-five compliant.[13][14]
IUPAC Name: (1R, 2S)-1-(6-bromo-2 methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1naphthalenyl)-1-phenyl-2-butanol
The recommended dosage of Bedaquiline is 400 mg once daily for 2 weeks followed by 200
mg 3 times per week for 22 weeks with food.


Bedaquiline shows
volume of distribution of approximately 164 L and a plasma binding protein of > 99.9%.
Bedaquiline is primarily subjected to oxidative metabolism by CYP3A4 leading to the
formation of the N-monodesmethyl metabolite (M2),
which is 4 to 6 times less active in terms of antimycobacterial potency. It is mainly
eliminated in feces and the mean terminal half-life T1/2 of Bedaquiline and M2 is
approximately 5.5 months ( Diacon AH et al June 2012).
XIII. Warnings and Precautions:
Increased Mortality: An increased risk of death was seen in the SIRTURO treatment group.
QT Prolongation: SIRTURO prolongs the QT interval. An electrocardiogram (ECG) should be
obtained before initiation of treatment, and at least 2, 12 and 24 weeks after starting treatment
with SIRTURO. Serum potassium, calcium, and magnesium should be obtained at baseline and
corrected if abnormal. Discontinue SIRTURO and all other QT prolonging drugs if the patient
develops clinically significant ventricular arrhythmia or a QTcF interval of > 500 ms (confirmed
by repeat ECG).
The following may increase the risk for QT prolongation when patients are receiving SIRTURO
and therefore ECGs should be monitored closely: use with other QT prolonging drugs including
fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine;
a history of Torsade de Pointes; a history of cogenital long QT syndrome; a history of
hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure, serum calcium,
magnesium, or potassium levels below the lower limits of normal (www.fda.gov,
http://www.sarpam.net ).
SIRTURO has not been studied in patients with ventricular arrhythmias or recent myocardial
infarction.
Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were
reported with the use of SIRTURO plus other drugs to treat TB compared to other drugs used to
treat TB without the addition of SIRTURO. Alcohol and other hepatotoxic drugs should be


avoided while on SIRTURO , especially in patients with diminished hepatic reserve. Monitor
liver-related laboratory tests. Discontinue SIRTURO if aminotransferase elevations are
accompanied by total bilirubin elevation > 2xULN; aminotransferase elevations are > 8xULN;
aminotransferase elevations persist beyond 2 weeks.
Drug Interactions: Co-administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or
other strong systemic CYP3A4 inducers should be avoided. Co-administration with strong
systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate
clinical monitoring for SIRTURO™-related adverse reactions is recommended.
HIV-TB Co-Infected Patients: There are no clinical data on the combined use in HIV/MDR-TB
co-infected patients and only limited clinical data on the use in HIV/MDR-TB co-infected
patients who were not receiving antiretroviral therapy.
Treatment Failure: SIRTURO should be administered by directly observed therapy.
SIRTURO™ should only be administered in combination with at least 3 drugs active against the
patient's TB isolate. Non-adherence to the treatment regimen could result in failure or resistance.
Adverse Reactions:
The most common adverse drug reactions reported in greater than or equal to 10% of
patients treated with SIRTURO compared to the placebo treatment group are nausea (38% vs.
32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%) and additional adverse events
reported in greater than or equal to 10% of patients are hemoptysis (17.7% vs. 11.1%) and chest
pain (11.4% vs. 7.4%) ( Diacon AH et al June 2012).

.



XIV. APPENDIX
TABLES:
TABLE.NO

NAME OF THE TABLE

Table.no 5.2a

Deference between LTBI and TB Disease

Table.no 5.2b

Persons at Increased Risk for Progression of
LTBI to TB Disease

Table.no7.4.1a

TST reaction for diagnosis of TB

Table.no9.1

Suggested regimens for mono- and poly-drug
resistance (when further acquired resistance is
not a factor and laboratory results are highly
reliable)

WHO classification of anti-TB drugs

Table.no11.1a

FIGURES:
FIGURE.NO

NAME OF THE FIGURE

Figure.no 6.1

. Mode of Transmission of TB bacilli

Figure.no 12.2a

The Mycobacterial ATP synthase

Figure.no 12.2.1a

The structure of Bedaquiline


XV. REFERENCES:
1.

http://en.wikipedia.org/wiki/Tuberculosis

2.

http://www.cdc.gov/tb/

3.

http://www.who.int/topics/tuberculosis/en/

4.

World Health Organization (2009). "Epidemiology".Global tuberculosis control: epidemiology, strategy,
financing. pp. 6–33. ISBN 978-92-4-156380-2. Retrieved 12 November 2009.

5.

Harsh Mohan p.no.149-156.(2006) Text book of pathology (p.no.149-156.)

6.

Centers for Disease Control and Prevention (2006). "Emergence of Mycobacterium tuberculosis with Extensive
Resistance to Second-Line Drugs — Worldwide, 2000–2004".MMWR Weekly 55 (11): 301–05.

7.

Multidrug

and

extensively

drug-resistant

TB

(M/XDR-TB) Drugs

Used

in

the

Treatment

of

Tuberculosis.(WWW.Cdc.Com)

8.

http://www.medindia.net/patients/patientinfo/tuberculosis_treatment.html.

9.

. http://www.webmd.com/lung/understanding-tuberculosis-treatment.

10. .http://www.ncbi.nlm.nih.gov.
11. http://www.theunion.org/index.php/en/what-we-do/tuberculosis/multidrug-resistant-tb-mdr-tb.
12. FDA Advisory Committee recommends accelerated approval of bedaquiline for drug-resistant TB
(http://www.sarpam.net).

13. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.html.
14. http://www.who.int/tb/challenges/mdr/en/.

15. Diacon AH et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrugresistant

tuberculosis:

long-term

outcome,

tolerability,

and

effect

on

emergence

of

drug

resistance. Antimicrobial Agents and Chemotherapy 56, no. 6: 3271-3276, June 2012.


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