DRUG RESISTANT

TUBERCULOSIS

 Tuberculosis is a bacterial infection caused by

Mycobacterium TB

The disease primarily affects lungs(pulmonary TB)

Other organs include intestine, meninges, bones and
joints, lymph glands and skin

DRUG RESISTANCE
Temporary/permanent capacity of the organism
& their progeny to remain viable/to multiply in
the presence of the concentration of the drug
that would normally destroy/inhibit the growth
of other cells

Types of Drug Resistant TB

MDR TB does not simply mean resistance to more than one
drug, it specifically means resistance to at least both
isoniazid (H) and rifampin (R)
XDR-TB is a rare type of MDR-TB that is resistant to INH &
rifampicin, plus any fluoroquinolone and at least one of
three injectable second-line drugs(amikacin, kanamycin or
capreomycin)
TDR-TB refers to M.TB clinical strains that strains that
show in vitro resistance to all first and second line drugs

Emergence of drug resistance

Streptomycin was introduced in 1946 for the treatment of TB

and the first case of SM-resistant TB was reported in 1947

INH was introduced in 1952 and was used alone or in
combination with SM/ PAC by the British Medical Research
council
The first case of MDR-TB was reported in 1990 with
resistance to INH and rifampicin in NewYork
The first case of XDR-TB was reported in 2006
Upto the end of 2012, XDR-TB was reported in 92 countries
with an estimated 45000 new cases per year

 The presence of TDR-TB was first observed in two patients

in Italy in 2003, the second report came from Iran
In jan 2012 there was a report of 4 cases of TDR-TB in
India

As per WHO, about 3.7% of new TB patients in the world

have MDR-TB.
About 9% of MDR-TB cases have resistance to two other
classes of drugs, or are extensively drug resistant TB(XDRTB)
By March 2013, 84 countries had reported at least one XDRTB case
WHO estimates that there were about 0.5 million new MDRTB cases in the world in 2011
About 60% of the cases occurred in Brazil, China, India,
Russia & South Africa alone (BRICS countries)
48% of patients with MDR-TB and 22-28% of XDR-TB
enrolled on treatment in 2009 were reported to have been
successfully treated

Genesis of MDR-TB

Resistance is a man-made amplification of a natural

phenomenon.
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.

Development of anti-tuberculosis drug resistance

Wild M. TB strain
Spontaneous mutation

Strains with genetic

drug resistance
Selection: inadequate treatment

Acquired drug
resistance
Transmission

Primary drug
resistance

Pablos-Mendez et al. WHO, 1997

Mechanism of resistance
INH

Chromosomally mediated
Loss of catalase/peroxidase
Mutation in mycolic acid synthesis
Regulators of peroxide response
Rifampin

Reduced binding to RNA polymerase

Clusters of mutations at Rifampin Resistance
Determining Region (RRDR)
Reduced Cell wall permeability

Anti-TB Drugs
FirstLine
(H)
Isoniazid

(R) Rifampin
(Z)
Pyrazinamide
(E)
Ethambutol

Second-Line
Streptomycin
Cycloserine
Ethionamide
Amikacin
Ciprofloxacin

Prevalence of drug-resistant TB
in India
Initial MDR-TB is probably very low
MDR-TB is more common in previously treated TB
patients
Acquired resistance to Rifampicin -33-35% &
Acquired resistance to INH-50-55%
Strains resistant to Rifampicin are usually resistant to
INH whereas vice versa may not be always true

Drug-Resistant TB
Drug-resistant TB is transmitted the same way as

drug-susceptible TB
Drug resistance is divided into two types:

- Primary resistance refers to cases initially

infected with resistant organisms

- Acquired resistance develops during TB therapy

 Initial resistance- presence of drug resistance

to one/more anti-TB drugs in a new TB patient
who presents to a TB centre

Chronic patient- patient who remains smear

positive after completing a WHO retreatment
regimen under supervision

Persons at Increased Risk for

Drug Resistance

History of treatment with TB drugs

Contacts of persons with drug-resistant TB
Smears or cultures remain positive despite 2

months of TB treatment

Received inadequate treatment regimens for

>2 weeks

Clinicians experience many challenges in the management

of patients with DR-TB . Success of treatment depends on

1. Quality diagnosis & testing

2. Medications , S/E and drug regimens
3. The patient and the programme

Clinical significance of drugresistant TB

Treatment failure rate is 5-6 fold
In case of resistance to INH/ Streptomycin , the TB can be
successfully treated with 6 months of short course
chemotherapy
Resistance to rifampicin is a serious problem
About 70-90% of INH & Rifampicin resistant bacilli did
not respond/relapsed to treatment with short course
chemotherapy

Diagnosis of drug-resistant TB

Fail to respond / deteriorate

Clinical criteria to confirm failure / relapse after 2 courses of

chemotherapy at least one of which is directly observed

Confirm whether the diagnosis was correct
Repeat sputum AFB and CXR
If the diagnosis is confirmed and patient fully compliant with
treatment MDR-TB suspected
To confirm resistance sputum culture & drug sensitivity test
to be done in an intermediate reference lab accredited to
perform sputum culture & drug sensitivity as per DOTS-plus
guidelines

Management of drug resistant TB

(DOTS-plus regime)
The regimen should include at least 3 drugs for which the
patients organism have proven in-vitro susceptibility &
preferably that have not been used to treat the patient before
After diagnosis, the treatment of MDR-TB is initiated at
designated DOTS-Plus sites, which are established in tertiary
care centres (MC/large speciality hospitals)
Pre-treatment evaluation since the drugs used are known to
produce adverse effects

Pre-treatment evaluation
1. Detailed history
2. Height, weight
3. CBC
4. Blood sugar
5. LFT
6. TFT
7. Urine R/E & microscopy
8. Pregnancy test
9. CXR

Regimen for MDR-TB

INTENSIVE PHASE(6-9months)
Kanamycin, levofloxacin, ethionamide, pyrazinamide,
ethambutol, cycloserine
CONTINUATION PHASE(18 months)
Levofloxacin, ethionamide, ethambutol, cycloserine

 As single daily dose under supervision

On sundays, the oral drugs will be administered
unsupervised whereas injection Kanamycin will be omitted
If any intolerance occurs, ethionamide, cycloserine and
PAS may be split into two, the morning doses taken under
supervision & evening doses self-administered

Regimen for XDR-TB

INTENSIVE PHASE(6-12 MONTHS)
capreomycin, moxifloxacin, PAS, high dose INH,
clofazimine, linezolid and amoxyclav
CONTINUATION PHASE(18 MONTHS)
PAS, moxifloxacin, high dose INH, clofazimine, linezolid,
amoxyclav

 All drugs are to be given on a daily basis

Inj. Capreomycin are to be given for 6 days / week (not on
Sunday)
All morning doses are to be supervised by the DOT
providers except on sundays
Oral medicines for are given on Saturday to be taken by
the patient at home
Empty blisters of medicines taken on Sunday are to be
collected by DOT provider

 Direct observation of treatment remains even more

important in XDR-TB as this is the last chance at
successful treatment that these patient will have
Because of the use of drugs with different toxicity
profiles, XDR-TB requires more intensive monitoring
during follow up
1. CBC
2. RFT
3. LFT
4. CXR

Treatment of TB during pregnancy

Treated with INH, Rifampicin and Ethambutol for 2 months,

followed by INH & Rifampicin for an additional 7 months

If susceptible to INH & Rifampicin, ethambutol can be stopped
after the first month
Pyrazinamide should be used only if resistance to other drugs
are documented
Streptomycin is C/I in pregnancy as it may cause congenital
deafness
Those taking INH should receive pyridoxin 10-25 mg orally
once a day to prevent peripheral neuropathy

Childhood TB
TB in children is mainly d/t failure of TB control in adults
An infant whose mother has sputum smear positive PTB
has a high chance of becoming infected
Because of less developed immune system, children under
5 years of age are more prone to develop the disease
mostly within 2 years following infection
1-4 yrs

DOSAGE OF DRUGS

Rifampicin 10-12mg/kg
INH- 10mg/kg
Ethambutol- 20-25 mg/kg
PZA- 30-35mg/kg
Streptomycin- 15mg/kg

HIV & TB
The HIV virus damages the bodys natural defences- the
immune system-and accelerates the speed at which TB
progresses from harmless infection to life threatening condition
HIV & TB interact in several ways
Reactivation of latent infection 25-30 times more risk,
because of the stoppage of working of the immune system by
HIV
Primary infection HIV patients are at risk of being newly
infected with TB because their weakened immune system make
them more vulnerable

Recurring infection HIV patients who have been cured of

TB infection are more at risk of developing TB again
DIAGNOSIS OF TB IN HIV PATIENTS
In HIV patients at early stages, the symptoms of TB are similar
to those without HIV infection. However the diagnosis of TB
using the standard diagnostic tools can be difficult in the
advanced HIV infection because,
1. Sputum smear ve, sputum culture to confirm
2. Tuberculin test ve
3. Less cavitations in the CXR
4. Extra-pulmonary TB are more common in co-infection

DIAGNOSIS OF HIV IN TB PATIENTS

In areas where there is high prevalence of HIV, HIV
testing should be systematically offered to all TB
patients, including children
Serological testing
Patients should be counselled on behaviour risk and
methods to prevent transmitting or acquiring the infection

Bedaquiline a novel promising

discovery in MDR-TB
Discovered in 2004 by Johnson & Johnson via screening prototype of
more than 70,000 chemicals by inhibition of growth against
mycobacterium smegmatis, a more rapidly growing mycobacterium
compared to MTB
First described at the Inter science Conference on Antimicrobial
agents and chemotherapy (ICAAC) in 2004
MOA inhibit proton pump of ATP synthase in MTB. ATP synthase is
an enzyme that is essential for the generation of energy in MTB.
Bedaquiline binds to the c-subunit of ATP synthase inhibiting ATP
synthesis causing death of MTB

 Indication as a part of combination therapy in adults

with MDR-TB when other alternatives are not available

Dosage and administration initial dose of 400mg once

daily for 2 weeks followed by 200mg 3 times per week for
22weeks. It is supplied as 100mg tablets to be taken with
food and swallowed whole with water

Adverse effects nausea, arthralgia, diarrhoea, pain the

extremities and hyperuricemia

Acquired resistance of MTB to

Bedaquiline
Identified in 2014
Due to mutations in Rvo678 , a transcriptional repressor
of the genes encoding MmpS5-MmPL5 efflux pump. Efflux
based resistance was identified in paired isolates from
patients treated with BDQ as well as in mice, in which it
was confirmed to decrease the bactericidal efficacy. The
efflux inhibitors verapamil & reserpine decreases
minimum inhibitory concentration of BDQ but failed to
increase the bactericidal effect of BDQ in mice & was
unable to reverse the efflux based resistance in-vivo

 In addition to BDQ, delamanid and linezolid are approved

by the US Food and Drug Administration(FDA) and the
European Medicines Agency that may offer therapeutic
solution to TDR-TB

In a recent update on TDR-TB, 15 cases with resistance to

all drugs tested have been reported and 5 patients died

Prevention of DR-TB

Initial treatment with standardized regimens (HRZE)

Directly observed therapy (DOT)
Drug susceptibility testing for all retreatment cases
Infection control precautions
Monitor drug resistance through surveys
Effective contact management

STOP TB STRATEGY

Launched in 2006
It is to be implemented over the next 10 years as
described in the Global plan to stop TB in 2006-2015
It focuses on 5 principal indicators that are used to
measure the implementation and the impact of TB control
case detection, treatment, success, incidence,
prevalence and deaths

Targets

By 2015- the global burden of TB will be reduced by 50%

relative to 1990 levels. This means reducing prevalence to
150 per 100000 or lower and deaths to 15 per 100000 per
year or lower by 2015
The number of people dying from TB in 2015 should be
less than approximately 1 million including those
coinfected with HIV
By 2050- the global incidence of TB disease will be less
than or equal to 1 case per million population per year

COMPONENTS OF THE STRATEGY AND

IMPLEMENTATION APPROACHES
1. Pursuing high quality DOTS expansion and enhancement
. Political commitments with increased and sustained
financing
. Case detection through quality-assured bacteriology
. Standardized treatment with supervision and patient
support
. An effective drug supply and management system
. Monitoring and evaluation system and impact
measurement

2. Addressing TB/HIV, MDR-TB and other challenges

Implement collaborate TB/HIV activities
Prevent and control MDR-TB
Address prisoners, refugees, other high risk groups and
special situations
3. Contributing to health system strengthening
Actively participate in efforts to improve system wide policy ,
human resources, financing, management, service delivery
and information system
Share innovations that strengthen health systems, including
the practical approach to lung health(PAL)
Adapt innovations from other fields

4. Engaging all care providers

Public-public and public-private mix approaches
Implement international standards for TB care
5. Empowering people with TB and communities
Advocacy , communication and social mobilisation
Community participation in TB care
Patients charter for TB care
6. Enabling and promoting research
Programme based operational research
Research to develop new diagnostics, drugs and vaccines

RNTCP daily treatment regimen

Type of TB
cases
NEW
PREVIOUSLY
TREATED

Treatment
regimen IP

Treatment
regimen
CP
2HRZE
4HRE
2HRZES+1HRE 5HRE

Daily dosage schedule for adults

Weight
category

Number
of

25-39 kg
40-54 kg
55-69 kg

consumed
IP
HRZE
75/150/400
/ 275
mg/tab
2
3
4

tablets to
be
injection

CP
HRE
75/150/27
5 mg/tab
2
3
4

Gram

0.5 g
0.75 g
1g

streptomy
cin

THE END TB STRATEGY 2016-2035

VISION: A world free of TB
- Zero deaths, disease and suffering due to TB
GOAL: End the Global TB Epidemic
MILESTONES FOR 2025: 75% reduction in TB deaths (compared with 2015)
50% reduction in TB incidence rate (less than 55 TB cases per
100,000 population)
No affected families facing catastrophic costs due to TB
TARGETS FOR 2035: 95% reduction in TB deaths (compared with 2015)
90% reduction in TB incidence rate (less than 10 TB cases per
100,000 population)
No affected families facing catastrophic costs due to TB
PRINCIPLES: collaboration

Government stewardship and accountability, with monitoring and evaluation

Strong coalition with civil society organizations and communities
Protection and promotion of human rights, ethics and equity
Adaptation of the strategy and targets at country level, with global

 PILLARS AND COMPONENTS:

1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION

A. Early diagnosis of TB including universal drug susceptibility testing; and systematic screening
of contacts and high-risk groups
B. Treatment of all people with TB including drug-resistant TB; and patient support
A. Collaborative TB/HIV activities and management of comorbidities
B. Preventive treatment of persons at high-risk; and vaccination against TB

2. BOLD POLICIES AND SUPPORTIVE SYSTEMS

A. Political commitment with adequate resources for TB care and prevention
B. Engagement of communities, civil society organizations, and public and private care providers
C. Universal Health Coverage policy and regulatory frameworks for case notification, vital
registration,
quality and rational use of medicines, and infection control
D. Social protection, poverty alleviation and actions on other determinants of TB

3. INTENSIFIED RESEARCH AND INNOVATION

A. Discovery, development and rapid uptake of new tools, interventions and strategies
B. Research to optimize implementation and impact, and promote innovations

THANK YOU