1. G u i d e d b y,
M r. S . G . P a t i l
D e p t . o f P h a r ma c e u t i c s
S c h o o l o f
P h a r ma c y, S . R . T. M . U . N a n d e d
Seminar on
DRUG RESISTANCE TUBERCULOSIS
P re s e n t e d b y,
M r. R a v i ka n t V. K a d a m
D e p t . o f P h a r ma c e u t i c s
S c h o o l o f
P h a r ma c y, S . R . T. M . U . N a n d e d

2. Contents
 Introduction
 Transmission of TB
 Pathogenesis of TB
 Drug-Resistant TB (MDR and XDR)
 Factors that Create Resistance
 Treatment
 Special Situations

3. Introduction
It is mainly caused by Mycobacterium tuberculosis
Tuberculosis is an ancient disease & it remains the leading cause of death of
human being.

4. USAID Report on Tuberculosis in India
 India has more new tuberculosis (TB) cases annually than any other country,
ranking first among the 22 high-burden TB countries worldwide, according to
the World Health Organization’s (WHO’s) Global TB Report 2009. TB
remains one of the leading infectious causes of mortality in India, causing
more than 331,000 deaths in 2007. There were approximately 1.96 million new
TB cases in India in 2007, representing more than 21 percent of all TB cases
worldwide

5. Transmission of TB
 M. tuberculosis is carried in airborne particles, called droplet nuclei, of 1– 5
microns in diameter.
 Infectious droplet nuclei are generated when persons who have pulmonary or
laryngeal TB disease cough, sneeze, shout, or sing. Depending on the
environment, these tiny particles can remain suspended in the air for several
hours.
 M. tuberculosis is transmitted through the air, not by surface contact.
Transmission occurs when a person inhales droplet nuclei containing M.
tuberculosis, and the droplet nuclei traverse the mouth or nasal passages, upper
respiratory tract, and bronchi to reach the alveoli of the lungs

6. Transmission of TB

7. Pathogenesis of TB
 Infection occurs when a person inhales droplet nuclei containing tubercle
bacilli that reach the alveoli of the lungs.
 These tubercle bacilli are ingested by alveolar macrophages; the majority of
these bacilli are destroyed or inhibited.
 A small number may multiply intracellularly and are released when the
macrophages die. If alive, these bacilli may spread by way of lymphatic
channels or through the bloodstream to more distant tissues and organs
(including areas of the body in which TB disease is most likely to develop:
regional lymph nodes, apex of the lung, kidneys, brain, and bone).
 This process of dissemination primes the immune system for a systemic
response.

8. Pathogenesis of TB
 Droplet nuclei containing tubercle
bacilli are inhaled, enter the
lungs, and travel to the alveoli.

9. Pathogenesis of TB
 Tubercle bacilli multiply in the
alveoli.

10. Pathogenesis of TB
 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 the
brain, larynx, lymph node,
lung, spine, bone, or kidney).

11. Pathogenesis of TB
 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).

12. Pathogenesis of TB
 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

13. Drug-Resistant TB
 Drug-resistant TB is caused by M. tuberculosis organisms that are
resistant to the drugs normally used to treat the disease . Drug-resistant
TB is transmitted in the same way as drug-susceptible TB, and is no
more infectious than drug-susceptible TB. However, delay in the
recognition of drug resistance or prolonged periods of infectiousness
may facilitate increased transmission and further development of drug
resistance.

14. Drug-Resistant TB
 Drug resistant TB
 Mono resistance
 Poly resistance
 Multi Drug Resistant TB(MDR- TB)
 Extensive Drug Resistant TB (XDR-TB)
 Total Drug Resistance (TDR – TB)

15. Drug-Resistant TB
 Mono Drug Resistance
 (Resistance to single first line ATT)
 Poly Drug Resistance
 (Resistance to two or more first line ATT except MDR-TB)

16. Drug-Resistant TB
Multi-drug resistant tuberculosis (MDR TB) is defined as resistance to
isoniazid and Rifampicin (a laboratory diagnosis).
Extensively drug resistant TB (XDR-TB) is MDR + resistance to any
fluoroquinolone + resistance to at least one 2nd-line injectable drug
(amikacin, kanamycin, or capreomycin

17. TDR: Total Drug Resistance
 Resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs
(SLD) that were tested.

18. Drug-Resistant TB

19. EPIDEMIOLOGY
 In our country

20. Global Data

21. MECHANISMS & FACTORS

23. Mechanism of resistance
 INH
 Chromosomally mediated
 Loss of catalase/peroxidase
 Mutation in mycolic acid synthesis
 Regulators of peroxide respo

24. Mechanism of resistance
 Rifampin
 Reduced binding to RNA polymerase
 Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)
 Reduced Cell wall permeability

25. Gene location associated Drug-Resistant M.tuberculosis
Drug Gene
Isoniazid Kat G, Inh A, Kas A
Rifampicin rpo B
Ethambutol emb B
Streptomycin rps L
Pyrazinamide pnc A
Fluoroquinolones gyr A

26. FACTORS RESPONSIBLE FOR DEVELOPMENT OF DRUG RESISTANCE
 CLINICAL / OPERATIONAL FACTORS
 Unreliable treatment regimen by doctors
 Lesser number of drugs
 Inadequate dosage / duration
 Addition of a single drug in failing regimen
 Easy availability of drugs in private sector
 Poor drug supply
 Poor quality of drugs : poor bioavailability

27. FACTORS RESPONSIBLE FOR DEVELOPMENT OF DRUG RESISTANCE
 BIOLOGICAL FACTORS :
 Initial bacillary population
 Local factors in host favourable for multiplication of bacilli
 Presence of drug in insufficient concentration

28. FACTORS RESPONSIBLE FOR DEVELOPMENT OF DRUG RESISTANCE
 SOCIOLOGICAL FACTORS :
 Irregular intake
 inadequate duration
 Neglect of disease
 Ignorance

29. Genesis of MDR TB
 Resistance is a man-made amplification of a natural
phenomenon. i.e. Selection & proliferation of pre existing mutants
due to man made factors leads to drug resistance.
 Inadequate drug delivery is main cause of secondary drug
resistance.
 Secondary drug resistance is the main cause of primary drug
resistance due to transmission of resistant strains.
 MDR due to spontaneous mutations is not possible as the
genes encoding resistance for anti TB are unlinked.

30. Treatment…
 The choice of drugs would be based on:
• The pattern of drug resistance
• Which drugs have been taken previously
• Whether the patient has underlying medical conditions
• The adverse effects associated with the drug

31. Drugs in MDR TB Management
Less efficacious and
poorly tolerated
Most efficacious and best
tolerated

32. Important principles of
MDR-TB regimen design
1. Use at least 4 reliable drugs .
2. Do not use drugs with cross resistance .
3. Eliminate drugs that are not safe for the patient.
4. Include drugs from Groups 1-5 in a hierarchical order.
5. Monitor and manage adverse effects of drugs.
6. Never add a single drug to failing regime.

33. General Treatment Principles
 Provide 18-24 months’ treatment, always with intensive phase of at
least 6 months ( current WHO guidelines -8 months).
 Provide DOT therapy.
 Warn patients about possible side-effects.
 Manage side-effects appropriately.
 Perform cultures monthly.

34. Regimen under DOTS Plus
Programme in India (PMDT)
INITIAL INTENSIVE PHASE : 6- 9 months
 Inj. Kanamycin
 Tab Ethionamide
 Tab Ofloxacin
 Tab. Pyrazinamide
 Tab. Ethambutol
 Cap Cycloserine
CONTINUATION PHASE : 18 months
 Tab Ethionamide
 Tab Ofloxacin
 Tab Ethambutol
 Cap Cycloserine

35. DOTS PLUS DAILY REGIME

36.  Nausea and vomiting - Eto, PAS, Z, E
 Giddiness - Aminoglycosides, Eto, Fq and/or Z
 Ocular toxicity - E
 Renal toxicity - Aminoglycosides
 Arthralgia - Z and/or Fq
 Cutaneous reactions - pruritis or rash- any of the drugs used.
 Hepatitis - Z & Eto

38. References
 Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a menace that threatens to
destabilize tuber-culosis control. Chest 2006; 130(1):261-272.
 Andrews J, Basu S, Scales D, Smith-Rohrberg Maru D, Subbaraman R. XDR-TB in
South Africa: theory and practice. PLoS Med 2007; 4(4):
e163.doi:10.1371/journal.pmed.0040163.
 Nature Volume 469 issue 7331 2011 [doi 10.1038%2Fnature09657] Koul, Anil; Arnoult,
Eric; Lounis, Nacer; Guillemont, Jerome; An -- The challenge of new drug discovery for
tuberculosis.sssss
 Nature Reviews Drug Discovery Volume 12 issue 5 2013 [doi 10.1038%2Fnrd4001]
Zumla, Alimuddin; Nahid, Payam; Cole, Stewart T. -- Advances in the development of
new tuberculosis drugs.