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
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.
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.
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
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
37.
38. References
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South Africa: theory and practice. PLoS Med 2007; 4(4):
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