Management of multi drug resistant tuberculosis

1. Management of Multi-Drug Resistant
Tuberculosis with SIRTURO(Bedaquiline)
Mrs. Priyanka Namdeo
Assistant Professor
Department of Pharmacology

2. CONTENTS
 Introduction of TB
 Definitions
 Pathophysiology of Tuberculosis
 Diagnosis
 Management of TB
 What is SIRTURO
 Mechanism of Action
 SIRTURO Treatment

3. INTRODUCTION
 (Robert Koch) Discovered of Mycobacterium tuberculosis in 1885.
 24th March TB Day
 Discovery of staining technique that identified Tuberculosis bacillus
 Tuberculosis is called TB is chronic bacterial infection caused by
M. tuberculosis/ M. bovis
 It contains unusual cell wall. The cell wall has a high lipid content, resulting high
degree of hydrophobicity and resistance to alcohol, acids, alkalies and some
disinfectants.

4.  This organism usually attacks or affects almost any tissue and also affect the
CNS (meningitis), Circulatory System, Genito-urinary system, Bones, joints.
 It is characterized by the formation of nodular bodies or tubercles.
 Cough lasting > 3 wks and not respond to usual antibiotics, Production of purulent,
sometimes blood- stained sputum, Evening rise of temp.
 It is one of the most deadly and common major infectious disease today, more than 2
billion people have been suffering the world’s population
 1000 people have been dieing daily in India by TB.

5. Definitions
Multidrug-Resistant Tuberculosis (MDR TB)
 Multidrug-resistant TB (MDR TB) is TB that
is resistant
Isoniazid and Rifampicin
 These drugs are considered first-line drugs and
are used to treat all persons with TB disease

6. Mode of Transmission
 TB spread person to person through the air. Throat cough, laugh, sneeze, even
talk the germs that cause TB may be spread into the air, if another person
breaths in these germs there is a chance that they will be come infected with TB.
Symptoms of TB
 Unproductive cough, Difficulty breathing
 Feeling tired all time.
 Weight loss, loss of appetite, Night time sweating.
 Fever, Blood in cough
 Fatigue, night sweats, constant tiredness
Transmission of TB

7.  Chest x-ray examination reveals
changes like pleural effusion (increase
volume of pleural space), diffuse
infiltrates in lung parenchyma.
 Untreated cases may show systemic
secondary amyloidosis ( infiltration of
liver, kidneys, spleen and other tissues
with amyloid.

8. PATHOPHYSIOLOGY
 MTBC (M. tuberculosis complex)
M. bovis, M. africanum, M. microti
 Rod shaped, aerobic bacterium
mycobacterium tuberculosis
 Acid fast bacilli
 Cell wall is lipid rich with mycolic
acid which is essential & unique
component
Mycobacterium tuberculosis

9. Pathogenesis of TB
 M. Tuberculosis enter the Macrophages
 Once inside the macrophage, M Tuberculosis replicate within the
phagosome by blocking fusion of the phagosome and lysosome.
 Thus the earliest stage of primary tuberculosis (< 3 weeks ) in the
nonsesitized individual is characterized by proliferation of bacteria in the
pulmonary alveolar macrophage and airspaces, with resulting bacteremia
and seeding of multiple sites.

10. 3
1
2
4
Tubercle bacilli multiply
in the alveoli.
A small number of
tubercle bacilli enter the
bloodstream and spread
throughout the body.
The tubercle bacilli may
reach any part of the body
including areas where TB
disease is more likely to
develop (such as Brain,
larynx, lymph node, lung,
spine, bone, or kidney).
Within 2 to 8 weeks,
special immune cells
called Macrophages
ingest and surround
the tubercle bacilli
The cells form a
barrier shell, called
a Granuloma, that
keeps the bacilli
contained and under
control (LTBI).
If the immune system
cannot keep the tubercle
bacilli under control, the
bacilli begin to multiply
rapidly (TB disease).
This process can occur
in different areas in the
body, such as the lungs,
kidneys, brain, or bone

11. Stage in Pathogenesis of Tuberculosis

12. DIAGNOSIS
 Conventional Methods- Microscopy examination, Chest X-rays,
Culturing using Lowenstein- Jensen medium
 Immunological Methods- ELISA
Tuberculin skin test (TST) or blood tests
Interferon Gamma Determination
 Novel Diagnostic Methods-
 Automated BACTEC MGIT
Multiplex PCR
AMTD

13. MANAGEMENT OF TB
 TB involves screening those at high risk, early detection and treatment of cases and
vaccination with the bacillus Calmette- Guerin vaccine. Those at high risk
include household, workplace, and social contacts of people with active TB. Type of
T. B. Pulmonary Tuberculosis Extra pulmonary Tuberculosis.
 Anti-tubercular drugs are the agents which are used to treatment of tuberculosis.
 In 1938, Sulphanilamide was discovered and was found to possess bacteriostatic
action.
 Later Dapsone was developed, Although dapsone was effective it was not
considered for clinical use because it associated with toxicity.

14.  Streptomycin, PASA, Isoniazid, Ethambutol, Rifampicin
 The discovery of Rifampicin was a major break through in the treatment of Tuberculosis.
 This is because combination of Isoniazid, Ethambutol and Rifampicin required
Comparatively less time for producing effective results than the individual drugs Used alone.
 The Three drugs have acquired prime importance in the treatment of tuberculosis.
 Drug-resistant TB disease can develop in two different ways, called
 HIV infection is the greatest for the development of TB disease in persons with
LTBI, due to a weakened immune system.

15.  First line drugs: kill active
bacteria, important in the
early stages of infection.
 Second line drugs: hinder
bacterial growth.
- Strengthen treatment
- Less efficient and
generally more toxic than
first line drugs.

16. Antitubercular drugs are also classified on the basis of Chemical
moiety as:-
1. Salicylic acid derivatives: Para amino salicylic acid
2.Pyridine derivatives: Isoniazid (Isonicotinic acid hydrazine) ,Ethionamide,
Prothionamide
3. Pyrazine derivatives: Pyrazinamide
4. Ethylene diaminobutanol derivatives: Ethambutol
5. Antibiotics: Streptomycin, Refampin (Refampicin), Kanamcin
6. Miscellaneous drugs: Fluoroquinolones: Ofloxacin ,Ciprofloxacin, Macrolides,
Clarithromycin, Azithromycin

17. ISONIAZID-
 Isoniazid, is an antibiotic used as a first-line agent for the prevention and treatment of both
latent and active tuberculosis.
 It is effective against mycobacteria, particularly Mycobacterium tuberculosis.
Mechanism ofAction-
 Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme in
Mycobacterium tuberculosis called KatG
 Appears to penetrate host cells readily and diffuses across the cell membrane.
 Reported to inhibit multiple essential cellular pathways including synthesis of nucleic acids,
phospholipids & NAD metabolism
 Primary pathway responsible for the killing activity is inhibition of mycolic acid synthesis by
inhibiting NADH dependent enoyl-ACP reductase, which is encoded by inhA.

19. PHARMACOKINETICS
Absorption
 Rapid and complete, rate can be slowed with food
 Peak Plasma Time: 1-2 hr Distribution
Distribution
 All body tissues and fluid including to CSF, Crosses placenta, enters breast milk
 Protein bound: 10-15%
Metabolism
 Hepatic ( fast, slow acetylators)
Elimination
 Half life elimination: slow acetylators 2-5 hr, may be prolonged with hepatic or severe renal
impairment
Excretion: Urine (75-95%), feces

20. Contraindications
 Previous INH hepatic injury or reaction, acute liver damage
 Hypersensitivity
Cautions
 Alcohol or illicit injectable drug use, severe renal impairment, chronic liver damage
Drug Interactions
 INH can increase CBZ concentrations and cause CBZ toxicity. This interaction occurs more often
with INH doses at >/=200 mg/day
 INH and ethionamide may cause a temporary increase in serum concentrations of INH.
 , decrease the absorption of INH by a reducing gastric emptying.Administration of
antacids is recommended.
 INH may inhibit valproic acid hepatic metabolism. Elevated valproic acid concentrations and
hepatotoxicity.

21. RIFAMPICIN
 Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by
Streptomyces mediterranei
 It is active against gram positive and gram negative cocci, some enteric bacteria mycobacteria
and chlamydia
Mechanism of Action
 Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase, the direct
blocking of Elomgating RNA and thereby inhibits RNA synthesis. Resistance results from any
one of several possible point mutations in repoB, the gene for the β subunit of RNA
polymerase.

22. Absorption
 Orally well absorbed, food may delay absorption
 Peak plasma time: 2-4 hr Distribution
Distribution
 Highly lipophilic, crosses blood-brain barrier well with or without inflammation
 Protein bound: 80%
Metabolism
 Metabolized by liver, undergoes enterohepatic recirculation
Elimination
 Half-life: 3-4 hr (prolonged in hepatic impairment), in end-stage renal disease.
Excretion
 Feces (60-65%) and urine (~30%) as unchanged drug
PHARMACOKINETICS

23. Contraindications and Cautions
 Hypersensitivity to rifamycins
 Administration of bacterial vaccines
 Contraindicated in patients receiving ritonavir-boosted saquinavir, because of increased risk of severe
hepatocellular toxicity
Precautions
 May decrease the effectiveness of oral contraceptive pills (OCPs)
 Discontinue therapy if patient develops any signs of hepatocellular damage, including
hyperbilirubinemia
Drug Interactions
 Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or
CYP2C19 metabolism, can accelerate phenytoin clearance, reduce the plasma concentrations and also
possibly the efficacy of phenobarbital.

24. SIRTURO
Sirturo (bedaquiline) has been approved by the FDA on Dec 2012, as part of
combination therapy for adults with multi-drug resistant tuberculosis. This is the
first TB medication to be approved, the FDA informed.

25. What is sirturo?
 Also known Bidaquiline or TMC207
 Is an diarylquinoline anti-tuberculosis drug.
 It was described for the first time in 2004 at the
Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC).
 Sirturo is used in combination with other
tuberculosis medicines in adults and children (aged
at least 5 years and weighing at least 15 kg).
 Sirturo is the first medicine specifically designed for
treating Multi-drug-resistant tuberculosis

26.  By inhibiting mycobacterial
adenosine 5-triphosphate
(ATP) synthase
 Inhibiting the proton pump of
M. tuberculosis and
therefore interfering with the
rotation properties of the
transmembrane disk, leading
to ATP depletion.
MACHANISM OF
ACTION

27. SIRTURO TREAETMENT
 SIRTURO was administered as 400 mg once daily for the first two weeks and
200 mg three times per week for the following 22 weeks
 The FDA looked at two Phase 2 clinical trials to determine Sirturos safety and
efficacy. In the first trial, patients were randomly selected to be treated with Sirturo
along side other TB medications.
 In the second trial patients received Sirturo plus other TB medications.
 In both studies, the aim was to determine how long it took for the patients sputum to
be free of M. tuberculosis.