Pharmacotherapy of MDR TB

PHARMACOTHER
APY OF
RESISTANT TB
Dr. Sumit Ourasang
Junior resident III
06/29/2024 Department of Pharmacology & Therapeutics

Outline of the Seminar
Introduction Resistance to TB drugs
Classification based on drug

Epidemiology
resistance
History Newer anti-TB drugs
Pathogenesis Algorithmic approach
Diagnosis of TB Current regimens- PMDT
Classification of Anti-TB drugs Summary

Introduction
A lethal airborne infection caused by

Mycobacterium tuberculosis
The global outbreak of Tuberculosis in

1993 led the “World Health
Organization” to announce TB as a
matter of high priority
Khawbung JL, Nath D, Chakraborty S. Drug resistant Tuberculosis: A review. Comparative Immunology, Microbiology
06/29/2024 Department of Pharmacology & Therapeutics and Infectious Diseases. 2020 Nov 16:101574.
Epidemiology
 10 million new
cases
 1.6 million deaths
1. J. Furin, H. Cox, M. Pai, Tuberculosis, Lancet 393 (10181) (2019) 1642–1656. [4] W.H. Organization, World
Health Organization Multidrug and Extensively Drug resistant TB
2. (M/XDR-TB): 2010 Global Report on Surveillance And response, World Health Organization, Geneva,
06/29/2024 Department of Pharmacology & Therapeutics Switzerland, 2010.
Global and national magnitude of DR-TB problem
• A half million new cases of rifampicin resistant TB (RR-TB) occurred in 2019

with 78% of them having confirmed MDR-TB . Estimated number of MDR/RR-TB
cases in India is 124 000 (9.1/lakh population) .
• The first national anti-tuberculosis drug resistance survey (NDRS) revealed that
28% of TB patients were resistant to any drugs (22% among new and 36.82%
among previously treated) and 6.19% had MDR-TB (2.84% among new and
11.62% among previously treated).
• Any Isoniazid (H) resistance (16% in all with 11.6% in new and 25% in PT) being
driver for RR-TB.
Chaudhuri AD. Recent changes in guidelines on programmatic management of drug resistant tuberculosis in India
2019: a paradigm shift in tuberculosis control. The Journal of Association of Chest Physicians. 2020 Jul 1;8(2):53.
History

Pathogenesis
Tb Bacilli
Alveoli
LTBI &
macrophages Cure
Reactivation
Phagolysosome
Oxidative & Ph Granuloma

induced formation
destruction
Release of
bacilli from Spread to other
died system
macrophage
[1] A.A. Agyeman, R. Ofori-Asenso, Tuberculosis—an overview, J. Public Health Emerg. 1 (2017), 7-7.
[2] J. Armstrong, P.A. Hart, Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli.
Reversal of the usual nonfusion pattern and observations on bacterial survival, J. Exp. Med. 142 (1) (1975) 1–16.
[3] Z.A. Malik, G.M. Denning, D.J. Kusner, Inhibition of Ca2+ signaling by Mycobacterium tuberculosis is associated with
06/29/2024 Department of Pharmacology & Therapeutics reduced phagosome–lysosome fusion and increased survival within human macrophages, J. Exp. Med. 191 (2)
(2000) 287–302.
Diagnosis of TB

Molecular Diagnosis of TB
MacLean E, Kohli M, Weber SF, Suresh A, Schumacher SG, Denkinger CM, Pai M. Advances in molecular diagnosis of
06/29/2024 Department of Pharmacology & Therapeutics tuberculosis. Journal of Clinical Microbiology. 2020 Sep 22;58(10).
Methods for drug Growth-based
susceptibility testing phenotypic drug
Rapid molecular Drug
Resistance Testing (DRT) − susceptibility testing
Genotype (DST)
Nucleic Acid First-line drugs:

Line Probe Assay
Amplification Test R, H, E, Z
(LPA)
(NAAT)
Second-line
cartridge based Gene- drugs: S, Lfx,
First line (H & R), Mfx, Km, Cm,
Xpert platform,
Am
Other drugs:
chip based TruNAAT Second line (Lfx, Mfx, Lzd, Cfz, Bdq,
platform Km, Cm, Am) Dlm PAS etc.,
Chaudhuri AD. Recent changes in guidelines on programmatic management of drug resistant tuberculosis in India 2019: a
06/29/2024 Department of Pharmacology & Therapeutics paradigm shift in tuberculosis control. J Assoc Chest Physicians 2020;8:53-63
Current Management

Classification of Anti-TB drugs
•Isoniazid (H)
•Rifampicin (R)
First line •Pyrazinamide (Z)
•Ethambutol (E)
Anti- •Streptomycin
TB
Second line Thioacetazone
Ethionamide
Cycloserine
• Fluoroquinolones Amikacin/Kanamycin
• Prothionamide P-aminosalicylic acid
• Terizidone
• Rifabutin/Rifapentine
• Capreomycin
Goodman, L., Gilman, A. and Brunton, LEllis R. Levin, Wendy S. Vitek, and Stephen R. Hammes Goodman & Gilman's
06/29/2024 Department of Pharmacology & Therapeutics manual of pharmacology and therapeutics.13th edition. Antitubercular drugs. New York: McGraw-Hill Medical. P809-830
First line drugs

Drugs MOA Antibacterial activity Adverse effects
Against M.TB and one Peripheral neuritis,

Act by inhibiting
Isoniazid atypical mycobacteria M. Hepatotoxicity, allergic
mycolic acid synthesis
kansasii reaction, xerostomia etc
Acts by inhibiting DNA- Red discoloration of

Active against M.TB and body fluids, Fatal
dependent RNA
Rifampicin M.leprae, Staph. Aureus hepatitis, Flu like
polymerase thereby
etc syndrome
blocking RNA synthesis
Hepatotoxicity
Act by inhibiting Hyperuricaemia
Pyrazinamide Active against M.TB
mycolic acid synthesis GI upset
Inhibit Arabinosyl Active against M.TB Retrobulbar Neuritis
Ethambutol transferase, thereby inhibit And M. Avium Gouty Arthritis
cell wall synthesis intracellulare GI intolerance

Daily dose regimen
Treatment regimen Treatment regimen

Type of TB case
in IP in CP
New (2) HRZE (4)HRE
Previously Treated (2) HRZES+(1) HRZE (5) HRE

Weight band for daily dose regimen
Department of Pharmacology & Therapeutics Park K. Park's Textbook of Preventive Medicine 25th edition. Jabalpur: m/s Banarasidas Bhanot; 2019. p. 188-221.
Resistance to TB drugs
MTB
Intrinsic Acquired
Complex structure of mycolic acid Chromosomal mutation of the drug target-

genes
Phenotypic resistance
Rv1698 and Rv1973
P.E. Almeida Da Silva, J.C. Palomino, Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical
06/29/2024 Department of Pharmacology & Therapeutics and new drugs, J. Antimicrob. Chemother. 66 (7) (2011) 1417–1430.
Resistance to First line drugs

Rifampicin Rpo B
Isoniazid KatG & inhA
Pyrazinamide panC
Ethambutol embB & ubiA

Khawbung JL, Nath D, Chakraborty S. Drug resistant tuberculosis: a review. Comparative Immunology, Microbiology
06/29/2024 Department of Pharmacology & Therapeutics and Infectious Diseases. 2021 Feb 1;74:101574.
Second line drugs

Antibacterial
Drugs MOA Therapeutic effects Adverse effects
activity
Inhibits inhA inhibits mycobacterial Anorexia, nausea
gene.Blocks Tuberculostatic growth by inhibiting the Vomiting,
Ethionamide
mycolic acid (0.6-2.5ug/ml) activity of the inhA gene Neurotoxicity
synthesis product (15-20mg/kg/day) Hepatitis
Anti- Tuberculocidal In conjunction with other

Ototoxicity
Capreomycin mycobacterial M.TB, M.kansasi, drugs
Nephrotoxicity
cyclic peptide MAC 15-30 m/k/d
Tuberculocidal
Kanamycin Bind to 30s 2nd choice after Ototoxicity
Disseminated
Amikacin ribosomal unit streptomycin /capreomycin Nephrotoxicity
MAC
Fluoroquinolon
e Tuberculocidal GI disturbances,
Used in combination
Cipro (750 Inhibit DNA Inhibit 90-95% Neurological
regimes (MDR/MAC in
mg/bd) gyrase strains of manifestation,
AIDS )
0floxacin(400 susceptible bacilli tendon rupture
mg bd)
Drugs Mechanism of Antibacterial Therapeutic Adverse effects
Action activity effects
250-500 mg
inhibits reactions in Tuberculocidal / Peripheral
twice daily.
which D-alanine is static depending on neuropathy
Cycloserine Retreatment/
involved in cell conc. At infection Dizziness tremors
MDR TB
wall synthesis aite Psychotic changes
Renal TB
Skin rash
Viz to Rifampin. Viz to Rifampin Latent tb
Rifabutin GI intolerance
Less potent inducer Better activity infections
Hepatitis
of cyt p450. Less against MAC. Tb in HIV
Red orange
interactions with M. leprae / M. patients.
Rifapentin discoloration of
PI/NNRTI fortitum 300mg/day
urine
GI intolerance
Inhibits folic acid Bacteriostatic
HS reactions
Aminosalicylic acid synthesis of Highly specific to 10-12g daily.
Hematological
bacteria M. TB
Abnormalities
Resistance to Second line drugs

Fluoroquinolone gyrA and gyrB
Kanamicin, gene rrs and tylA
capreomycin, gene
amikacin, viomycin
Para-amino salicylic dfrA
acid (PAS)
Ehionamide ethA, ethR and
inhA,
Macrolides emr37
Clofazimine transcriptional
repressor Rv0678
Mechanism of Resistance to TB drugs
Classification based on drug
resistance
Mono-resistance(MR): Poly-Drug resistance(PDR):
One first line anti-TB drug > 1 first line anti-TB drug
only other than both H/R
Multi-Drug Extensive-Drug
Rifampicin
Resistance(MDR): resistance(XDR):
Resistant to both H/R
Resistance (RR):
MDR TB case whose
with/without resistance Resistance to R
biological specimen is
to other 1st line drugs, with/without resistance
additionally resistant to
(results from a quality to other anti-TB drugs
FQs and SLI anti TB
assured laboratory) (excluding H)
drug
https://www.who.int/tb/areas-of-work/drug-resistant-tb/types/en/
06/29/2024 Department of Pharmacology & Therapeutics https://www.tbcindia.gov.in/showfile.php?lid=3590
Intensive Continuation
Type of TB
Phase Phase Total duration
cases
(IP) (CP)
H (mono)/Poly drug
(6-9) Lfx R E Z 6-9 months
resistance
06/29/2024 Department of Pharmacology & Therapeutics https://www.who.int/docs/default-source/searo/tuberculosis/rglc-mission-report-india-2019.pdf?sfvrsn=9e4cf828_2

Grouping of o Ethambutol (E)
Anti-TB o Delamanid (Dlm)
o Pyrazinamide (Z)
drugs o Amikacin (Am)
(or streptomycin)
(S)
Group A Group B Group C
o Imipenem-cilastatin
(Ipm-Cln) or
o Levofloxacin (Lfx) Meropenem (Mpm)
o Clofazimine (Cfz)
or Moxifloxacin o Cycloserine (Cs) o Ethionamide (Eto) or
(Mfx) Prothionamide (Pto)
o Bedaquiline (Bdq) or terizidone (Trd)
o P-aminosalicylic acid
o linezolid (Lzd) (PAS)
Chaudhuri AD. Recent changes in guidelines on programmatic management of drug resistant tuberculosis in India 2019: a
06/29/2024 Department of Pharmacology & Therapeutics paradigm shift in tuberculosis control. J Assoc Chest Physicians 2020;8:53-63
Bedaquiline
By FDA- 2012
Diarylquinoline → Targets mycobacterial ATP Synthase

(not active against human ATP synthase)
The WHO in 2013 have issued guidelines for use of

BDQ in drug resistant TB,
following which the RNTCP (2016) has introduced BDQ

in India for MDR-TB at selected centers through its
conditional access program
Conditional access program BDQ
 Waiver of local clinical trials, 6 centers in India (KEM)
 BDQ added when:

 Effective treatment regimen containing 4 2nd line drugs (with Z) cannot
be designed
 Documented evidence of resistance to any FQ with MDR
 Pretreatment initiation at DR-TB centres as per RNTCP PMDT guidelines

which includes Second Line Drugs Sensitivity Test (SLDST)
 While waiting for results, initiate standard MDR-TB regimen

Bedaquiline
Indication  MDR & XDR TB
400mgX 2wks f/b 200mg thrice a week X 22 wks =24wks
Background regimen of Km or Am, Ofx with/without E
Well absorbed orally, fatty meal improves absorption
Cationic amphiphilic drug High accumulation in tissues
Highly plasma protein bound & extensively distributed in tissues.
t1⁄2 is very long (160 days).
RNTCP technical and operational guidelines for tuberculosis control in India 2016, central TB division, directorate
general of health services, New Delhi Chapter 4-Treatment of TB Part 1
Bedaquiline
Metabolized in liver, mainly by CYP3A4. Clinically significant
drug interactions occur with CYP3A4 inducers & inhibitors
Excreted mainly in faeces
No cross resistance with existing 1st & 2nd line TB drugs
Strong bactericidal and sterilizing activity against M. tuberculosis

in invitro tests and in animal models by killing both rapidly
multiplying as well as dormant bacilli
ADR- nausea. headache, arthralgia & prolongation of QTc interval
BDQ has the potential to cause hepatotoxicity
RNTCP technical and operational guidelines for tuberculosis control in India 2016, central TB division, directorate general of
health services, New Delhi Chapter 4-Treatment of TB Part 1
For increased risk
of arrhythmias, as
it may prolong the
QT interval
monitoring with a
baseline and
repeated ECG
QTcF of > 500ms or

a significant
ventricular
arrythmia
Bedaquiline
Patients eligible for BDQ administration-
MDR TB resistant to all fluroquinolones
XDR TB resistant to all newer fluroquinolones
Treatment failures of MDR
Treatment failures of XDR TB
Mixed pattern DR TB
RNTCP technical and operational guidelines for tuberculosis control in India 2016, central TB division, directorate general of
health services, New Delhi
Present recommendations for the use of BDQ…
 Only for pulmonary MDR-TB in adults (>18 yr)
 Non-pregnant & willing to remain so during BDQ use
 It should be used only in combination with at least 3

other ATT to which the bacilli are shown to be
susceptible in vitro
 when an effective regimen cannot be provided
 Each BDQ tablet should be swallowed whole with meals
 The background anti-TB drugs should be continued after

stopping BDQ
 BDQ is not to be used for drug-sensitive TB, or

extrapulmonary TB or for
nontubercular mycobacteria
RNTCP technical and operational guidelines for tuberculosis control in India 2016, central TB division, directorate general of health
services, New Delhi Chapter 4-Treatment of TB Part 1
Delamanid (Dlm)
Chemical class: nitroimidazole
Mechanism of Action: Bactericidal

1)By blocking the synthesis of mycolic acids (for cell walls).
2)By poisoning them with nitric oxide, which the drugs release
when metabolized
It was first approved by the European Medicines

Agency (EMA) in November 2014
Indication: treatment of MDR & XDR-TB
8131480597Guidelines for use of Delamanid for treatment of DR-TB in 39

Delamanid (Dlm)
Half-life: 36 hours
Each film-coated tablet contains 50 mg Delamanid
Tab. Delamanid 100 mg (2 tab of 50 mg) orally BD X 24 wks

In combination with an optimized background regimen (OBR)
Week 0–24 Delamanid 100 mg Orally BD + OBR
Week 25 (start of month 7) to end of treatment:

Continue other 2nd -line anti-TB drugs
only as per RNTCP recommendations.
8131480597Guidelines for use of Delamanid for treatment of DR-TB in

Delamanid (Dlm)
Criteria to receive Delamanid To be avoided in
1) Adult & adolescents 1) Children under 6 yrs

2) Patient with HIV 2) Pregnant & breast feeding
3) MDR/RR with resistance to women
any/all FQ Or any/all SLI 3) Repeated demonstration of
4) XDR TB QT interval>500ms
5) Mixed pattern DR TB 4) H/O torsades pointes OR
cardiac ventricular
arrhythmias
5) Hypersensitivity
8131480597Guidelines for use of Delamanid for treatment of DR-TB in

India
Delamanid (Dlm)
Resistance Continuation
Intensive Phase
Pattern Phase
Regimen with New drugs for MDR-TB:
(6-9) Km Eto Cs (18) Eto Cs Lzd Cfz

MDR TB
Z Lzd. Cfz + (6) Dlm
Regimen with New drugs for XDR-TB:
(6-12) Cm Eto (18) Eto Cs Lzd

XDR-TB Cs Z Lzd Cfz E + Cfz E
(6) Dlm
8131480597Guidelines for use of Delamanid for treatment of DR-TB in 42

India
Pretomanid (PA-824)
Bicyclic nitroimidazole-like molecule
Active against both replicating & non-replicating organisms
MOA: The aerobic killing mechanism which involve inhibition

of cell wall mycolic acid biosynthesis through an as yet
unknown molecular mechanism
Safe, Well tolerated, & efficacious at doses of 100-200mg daily
By FDA- August 2019

By DCGI- July 2020
https://www.tballiance.org/sites/default/files/assets/Pretomanid_Full-Prescribing-Information.pdf
 Pretomanid Tablets must be administered only as part of a
regimen in combination with bedaquiline and linezolid.
 contraindicated in patients for whom bedaquiline and/or
linezolid is contraindicated.
 Pretomanid Tablets are not indicated for patients with:
 Drug-sensitive (DS) tuberculosis
 Latent infection due to Mycobacterium tuberculosis
 Extra-pulmonary infection due to Mycobacterium
tuberculosis
 MDR-TB that is not treatment-intolerant or nonresponsive
to standard therapy
A shorter oral Bedaquiline-containing
MDR/RR-TB regimen
9-11 Months
(4-6) Bdq (6 m), Lfx, Cfz, Z, E,

(5) Lfx, Cfz, Z, E,
Hh, Eto

Inclusion Criteria
Rifampicin resistance
DST Based MDR/RR-TB with H resistance detected/inferred based

on InhA mutation only or based on KatG mutation only
(not both)
MDR/RR-TB with FQ resistance not detected

Exclusion Criteria
MDR/RR-TB patients with H resistance detected with
DST Based
both KatG and InhA mutation;
MDR/RR-TB patients with FQ resistance detected.

A shorter Injectable MDR/RR-TB
regimen
(4-6) Mfxh, Km/Am, Eto, Cfz, Z, Hh, E/ (5) Mfxh, Cfz,

Z, E

MDR/RR-TB in children
The principles for treatment of MDR/RR-TB in children is quite similar to adults

and uses the same second-line drugs
Principles for management of MDR/RR-TB in children

• Always treat in consultation with an expert, preferably paediatrician
available/linked to DRTBC.
• Include at least 4-5 effective medicines from group A and B to which the
Mycobacterium tuberculosis strain is known or likely to be susceptible.
• Do not add a single drug to a failing regimen to avoid amplification of resistance.
• Strict monitoring of treatment by clinical examination, radiology and culture
response to be undertaken by paediatrician/expert available/ linked to DR-TBC.

Treatment Regimens
<3 years (FLQ-R): Lzd-Cfz-Cs; Add one of Dlm, PAS or Eto Additional drugs if needed
(FLQ-S): Lfx-Lzd-Cfz-Cs Additional drugs if needed Dlm, PAS and Eto
<6 years (FLQ-R): Lzd-Cfz-Cs-Dlm; Additional drugs if needed PAS and Eto
(FLQ-S): Lfx-Lzd-Cfz-Cs Additional drugs if needed Dlm and PAS
>6 years (FQ-R): Bdq-Lzd-Cfz-Cs Additional drugs if needed Dlm and PAS
(FQ-S): Bdq-Lfx-Lzd-Cfz Additional drugs if needed Cs and Dlm

Longer oral M/XDR-TB regimen
o All three Group A agents and at least one Group B agent should be included to
ensure that treatment starts with at least four TB agents likely to be effective and
that at least three agents are included for rest of the treatment if Bdq is stopped.
o If only one or two Group A agents are used, both Group B agents are to be
included.
o If the regimen cannot be composed with agents from Groups A and B alone,
Group C agents are added to complete it as recommended by WHO.
(18-20) Lfx Bdq (6 month or longer) Lzd# Cfz Cs

Replacement of Drugs

CO-9
Nix-TB Pivotal Study Presented Opportunity to

Evaluate Novel Regimen with Transformative Potential
 BPaL = bedaquiline (B) + pretomanid (Pa) + linezolid (L)

 Each drug has potent preclinical and clinical anti-TB activity
 Minimal pre-existing resistance
 All 3 drugs contribute to bactericidal and curative activity
 In animal models, efficacy better than 1st line treatment for
drug-susceptible TB
https://www.fda.gov/media/128001/download
Department of Pharmacology & Therapeutics
CO-10
BPaL: All-Oral, Short, Fixed Regimen
 Breakthrough cure for extensively drug resistant or treatment

intolerant or nonresponsive multidrug resistant pulmonary TB
 “Highly-resistant TB”
 Cure = no clinical or bacteriologic evidence of TB ≥ 6 months
after completion of treatment
 6-month BPaL regimen cured approximately 90% of patients
 AEs manageable and as expected with regimen
 Majority able to complete therapy, achieve therapeutic success
CO-11
Overcoming Challenges in Treatment of

Highly-Resistant TB
Treatment Challenges Opportunities with BPaL
Too long: 18+ months 6-month regimen
Too complicated: ≥ 5 drugs,

3 drug, all oral, set regimen
some IM / IV, no defined
regimen
Highly toxic, leading to Manageable tolerability, few

discontinuations discontinuations
Poor efficacy: ~20% cure rate pre- 90% cure rate
bedaquiline
era in South Africa
Summary
TB is a lethal airborne infection caused by Mycobacterium tuberculosis
India has gathered experience of nearly two decades in planning and implementation
diagnosis and clinical management of DR-TB
From bacteriological perspective, the resistance is caused by a genetic mutation that
makes a drug ineffective against the mutant bacilli
Diagnostic algorithm provides an opportunity for upfront NAAT testing for certain
types of presumptive TB (such as PLHIV, presumptive EP-TB cases, presumptive
pediatric TB, contacts, smear-ve X-ray suggestive of TB and other vulnerable
groups)
Patients with drug resistant TB are managed with the support of a nation-wide
network of DR-TB centers

Pharmacotherapy of MDR TB

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Pharmacotherapy of MDR TB

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PHARMACOTHER

06/29/2024 Department of Pharmacology & Therapeutics

Introduction Resistance to TB drugs

Classification based on drug

History Newer anti-TB drugs

Pathogenesis Algorithmic approach

Diagnosis of TB Current regimens- PMDT

Classification of Anti-TB drugs Summary

06/29/2024 Department of Pharmacology & Therapeutics

A lethal airborne infection caused by

The global outbreak of Tuberculosis in

 1.6 million deaths

• A half million new cases of rifampicin resistant TB (RR-TB) occurred in 2019

06/29/2024 Department of Pharmacology & Therapeutics

Oxidative & Ph Granuloma

06/29/2024 Department of Pharmacology & Therapeutics

Nucleic Acid First-line drugs:

06/29/2024 Department of Pharmacology & Therapeutics

06/29/2024 Department of Pharmacology & Therapeutics

Against M.TB and one Peripheral neuritis,

Acts by inhibiting DNA- Red discoloration of

06/29/2024 Department of Pharmacology & Therapeutics

Treatment regimen Treatment regimen

New (2) HRZE (4)HRE

Previously Treated (2) HRZES+(1) HRZE (5) HRE

06/29/2024 Department of Pharmacology & Therapeutics

Complex structure of mycolic acid Chromosomal mutation of the drug target-

06/29/2024 Department of Pharmacology & Therapeutics

Isoniazid KatG & inhA

Ethambutol embB & ubiA

06/29/2024 Department of Pharmacology & Therapeutics

Anti- Tuberculocidal In conjunction with other

06/29/2024 Department of Pharmacology & Therapeutics

06/29/2024 Department of Pharmacology & Therapeutics https://www.who.int/docs/default-source/searo/tuberculosis/rglc-mission-report-india-2019.pdf?sfvrsn=9e4cf828_2

Diarylquinoline → Targets mycobacterial ATP Synthase

The WHO in 2013 have issued guidelines for use of

following which the RNTCP (2016) has introduced BDQ

 Waiver of local clinical trials, 6 centers in India (KEM)

 BDQ added when:

 Pretreatment initiation at DR-TB centres as per RNTCP PMDT guidelines

 While waiting for results, initiate standard MDR-TB regimen

Indication  MDR & XDR TB

400mgX 2wks f/b 200mg thrice a week X 22 wks =24wks

Background regimen of Km or Am, Ofx with/without E

Well absorbed orally, fatty meal improves absorption

Cationic amphiphilic drug High accumulation in tissues

Highly plasma protein bound & extensively distributed in tissues.

t1⁄2 is very long (160 days).

Excreted mainly in faeces

No cross resistance with existing 1st & 2nd line TB drugs

Strong bactericidal and sterilizing activity against M. tuberculosis

ADR- nausea. headache, arthralgia & prolongation of QTc interval

BDQ has the potential to cause hepatotoxicity

QTcF of > 500ms or

MDR TB resistant to all fluroquinolones

XDR TB resistant to all newer fluroquinolones

Treatment failures of MDR

Treatment failures of XDR TB

 Only for pulmonary MDR-TB in adults (>18 yr)

 Non-pregnant & willing to remain so during BDQ use

 It should be used only in combination with at least 3

 when an effective regimen cannot be provided

 Each BDQ tablet should be swallowed whole with meals

 The background anti-TB drugs should be continued after