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 m a c e u t i c s

S c h o o l o f P h a r m a c y, S . R . T. M . U . N a n d e d

Seminar onDRUG RESISTANCE TUBERCULOSIS

P r e s e n t e d b y,

M r. R a v i k a n t V. K a d a m

D e p t . o f P h a r m a c e u t i c s

S c h o o l o f P h a r m a c y, S . R . T. M . U . N a n d e d

Contents

IntroductionTransmission of TBPathogenesis of TBDrug-Resistant TB (MDR and XDR)Factors that Create ResistanceTreatment Special Situations

Introduction

It is mainly caused by Mycobacterium tuberculosis Tuberculosis is an ancient disease & it remains the leading cause of death of

human being.

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

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

Transmission of TB

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.

Pathogenesis of TB

Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to the alveoli.

Pathogenesis of TB

Tubercle bacilli multiply in the alveoli.

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).

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).

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

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.

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)

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)

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

TDR: Total Drug Resistance

Resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested.

Drug-Resistant TB

EPIDEMIOLOGY

In our country

Global Data

MECHANISMS & FACTORS

Mechanism of resistance

INH Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide respo

Mechanism of resistance

Rifampin Reduced binding to RNA polymerase

Clusters of mutations at “Rifampin Resistance Determining Region” (RRDR)

Reduced Cell wall permeability

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

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

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

FACTORS RESPONSIBLE FOR DEVELOPMENT OF DRUG RESISTANCE

SOCIOLOGICAL FACTORS :

Irregular intake inadequate duration Neglect of disease Ignorance

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.

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

Drugs in MDR TB Management

Less efficacious and poorly tolerated

Most efficacious and best tolerated

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.

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.

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

DOTS PLUS DAILY REGIME

Nausea and vomiting - Eto, PAS, Z, EGiddiness - Aminoglycosides, Eto, Fq and/or ZOcular toxicity - ERenal toxicity - AminoglycosidesArthralgia - Z and/or FqCutaneous reactions - pruritis or rash- any of the drugs

used.Hepatitis - Z & Eto

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.

THANK YOU…………..!