The presentation covers the salient aspects of MDR Tuberculosis.

1. MDR TUBERCULOSIS
- An overview
Dr. Gyanshankar Mishra
MD (Pulmonary Medicine), DNB (Respiratory Diseases)
Assistant Professor ,
Department of Pulmonary Medicine,
GMC Nagpur

3. Drug resistance - Types & Definitions
Epidemiology
Mechanism & Causes of drug resistance
Management of MDR TB
Clinical case illustration

4. Drug Resistant
TUBERCULOSIS
Types & Definitions

5. Drug resistance - types
When drug resistance is demonstrated in a patient who
has never received anti-TB treatment previously, it is
termed primary (Initial) resistance, i.e. TB patient’s initial
M.TB population resistant to drugs
 Secondary (Acquired) resistance is that which occurs as
a result of specific previous treatment, i.e. Drug-resistant
M. TB in initial population, selected by inappropriate drug
use (inadequate treatment or non-adherence)

6. DRUG RESISTANT –TB (DR-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)

7. DRUG RESISTANT- TB(DR-TB)
Mono Drug Resistance
(Resistance to single first line ATT)
Poly Drug Resistance
(Resistance to two or more first line ATT except MDR-TB)

8. DRUG RESISTANT- TB(DR-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)

9. MDR TB
 Single Isoniazid or Rifampicin resistance is not MDR – TB.
 MDR TB is a laboratory diagnosis, Not a Clinical assumption.

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

12. 2012

13. Drug Resistant
TUBERCULOSIS
EPIDEMIOLOGY

14. In our country…

15. Global Data

17. India MDR TB Data
State representative community based
drug resistance surveys estimate the
prevalence of Multidrug resistant TB (MDR-TB)
to be ~3% among new TB cases and
12-17% among previously-treated TB
cases.

18. India XDR TB data
 *NDTB center, 18400 isolates, 0.89% of all MDR were
XDR
 **Hinduja Hospital, Mumbai, 3204 samples, 32%
MDR, 8% of MDR were XDR
 *** KGMU, Lucknow: Among 68 MDR, 5 (7.4%) were
XDR
* Ind J Tub 2008; 55:104
**Sushil Jain et al ATS 2007 meet Abstract 1398
***Mondal R et al. Em. Inf. Dis 2007; 13:9

19. Drug Resistant
TUBERCULOSIS
MECHANISMS & FACTORS

20. Mechanisims of Drug Resistance in Tuberculosis

21. DRUG RESISTANCE : MOLECULAR BASIS
DRUG RESISTANT ISOLATES SHOW
MUTATION IN GENES
 INH : kat g, inhA
 RIFAMPICIN : rpoB
 STREPTOMYCIN : rpsL
 ETHIONAMIDE : inhA
 FLUOROQUINOLONES : gyrA, gyrB
DNA probes using genetic information have
been devised

22. 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

23. Remember the correct doses of anti TB Drugs!

24. Why are correct doses important?
Ref: Mishra G, Mulani J. Tuberculosis Prescription Practices In
Private And Public Sector In India. NJIRM. 2013; 4(2): 71-78.

25. Why are correct doses important?
Ref: Mishra G, Mulani J. Tuberculosis Prescription Practices In
Private And Public Sector In India. NJIRM. 2013; 4(2): 71-78.

26. WHAT CAN BE DONE?
 Treatment:
 Daily regime / Once a day dosing/ Dose as per weight/Baseline LFT, KFT
 New TB cases:
 2(EHRZ) + 4(HR)
 Retreatment TB cases:
 2(SHERZ)+1(EHRZ)+5(HRE)

27. What can be done?..
 Treatment….
 Daily Dose (mg/kg) as per weight (WHO Recommended):

28. 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

29. Why this information?
 Suspect MDR TB if:
 There is extensive tuberculosis at the start of treatment.
 The patient is suffering from immunocompromised state like HIV.
 The patient has received ATT in suboptimal dosing.

30. FACTORS RESPONSIBLE FOR
DEVELOPMENTOF DRUG RESISTANCE
 SOCIOLOGICAL FACTORS :
 Irregular intake
 inadequate duration
 Neglect of disease
 Ignorance

31. What can be done?
Patient counseling at the
start of treatment

32. 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.

33. Drug Resistant
TUBERCULOSIS
MANAGEMENT PRINCIPLES
Suspicion, Diagnosis & Treatment

34. Suspicion of MDR TB
 When should we suspect drug resistant TB?
A close contact of Drug Resistant TB case.
 Treatment failures.
All retreatment cases.
 No sputum conversion after initial 2 months of ATT.
 Extensive disease at start of treatment.
All HIV patients with TB.
 Extrapulmonary TB not responding to standard ATT regime.

35. In an Ideal setting..

36. Culture dst of all 1st and 2nd line drugs prior to Treatment of
MDR TB. + Individualised treatment.
= Success rates of 68% …..Lung India. 31(4) Oct-Dec 2014.

37. Delay of culture dst : Patient’s all culture dst (1st and 2nd line ATT) available
7 years after initial diagnosis of PTB + Standardised Regime.
Success rate - patient not cured till date…IJME. Vol XI No 1 January-March 2014

38. Diagnosis – Accredited laboratory

39. Diagnosis…
 Tests available are:
 Conventional LJ culture DST – Gold standard
 DST- modified proportion method. (4 to 6 weeks for culture & 3 weeks post culture for dst).
 PCR based LPA (line probe assay) – DST result within 72 hours.
 Other methods – (Liquid cultures)BACTEC 460, MGIT 960 (14 days + 9 days
for dst) , etc.

40. The Xpert MTB/RIF
 The Xpert MTB/RIF is a cartridge-based,
automated diagnostic test
that can identify Mycobacterium
tuberculosis (MTB)DNA and
resistance to rifampicin (RIF)by
nucleic acid amplification
technique(NAAT )
Result within 2
hours.

41. Treatment – why important?

42. Treatment…
 “Recently, a letter to Clinical Infectious Disease Journal
in December 2011 described 4 patients from Mumbai,
India with “totally drug resistant” tuberculosis (coined
“TDR-TB” from earlier reports) i.e. resistant to all first line
and second-line drugs tested.”
 “A careful audit of their prescriptions revealed that these
3 patients had received erratic, unsupervised second
line drugs, added individually and often in incorrect
doses, from multiple private practitioners (on average
from 4 physicians during a 18-month period) in an
attempt to cure their multi-drug resistant (MDR)
tuberculosis.”

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

44. 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.

45. 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.

46. 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

47. DOTS PLUS DAILY REGIME

48. Be aware of the possible culprits in
case of ADR
 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

49. Be aware of the possible culprits in
case of ADR..
 Peripheral neuropathy - Cs, Eto
 Seizures - Fq and/or Cs
 Psychiatric disturbances – Cs, Fq and/or Eto
 Vestibulo-auditory disturbances - Aminoglycosides
 Hypothyroidism - PAS and/or Eto

50. Pre treatment evaluation for MDR TB
PMDT (Dots Plus)

51. CAT V- XDR TB
The Intensive Phase (6-12 months)
will consist of 7 drugs
Capreomycin (Cm), PAS,
Moxifloxacin (Mfx), High dose-
INH, Clofazimine, Linezolid, and
Amoxyclav
The Continuation Phase (18
months) will consist of 6 drugs –
PAS, Moxifloxacin (Mfx), High dose-
INH, Clofazimine, Linezolid, and
Amoxyclav

53. NEW DRUGS FOR MDR-TB
 Bedaquiline (diarylquinolone)and delamanid
(oxazole) are two new drugs for use in the
treatment of MDR-TBand WHO has developed
interim guidance on their use.
 No four 2nd line drugs in MDR + FQ resistance.
 bedaquiline be used for a maximum duration of 6
months and at suggested dosing (400 mg daily for
the first 2 weeks, followed by 200 mg three times per
week for the remaining 22 weeks
 Novel drug regimens for shortened treatment of
drug-resistant TB, including new or re-purposed
drugs, are under investigation.

55. Drug Resistant
TUBERCULOSIS
CASE ILLUSTRATION
Exercise

56. Clinical Case
 50 years old, 62 Kg patient
 H/o Irregular ATT treatment for 6-7 months
 Now sputum AFB smear Positive
 Put on 4 drug ATT (H 300mg, R 450 mg, E 800 mg and Z
1500 mg).

57. Clinical Case Contd...
 Sputum continues to be positive after 5 months of
treatment
 Sputum sent for AFB culture/sensitivity and inj.
kanamycin added.
 Sputum continues to be positive after 3 months

58. Clinical Case Contd...
 DST: MDR (resistance to H+R)
 INH and RIF stopped and ethionamide &
ofloxacin added
 After 4 months sputum is still positive
 DST: resistance to H, R, Kana, Oflox (XDR-TB)

59. Clinical Case Contd...
Lesson learnt from case
 Inadequate dosages.
 Wrong regime at the start .
 Lack of initial suspicion of MDR suspect and hence delay in
sending culture dst / and initiating correct regime.
 Adding only single drug to a failing regimen
 Improper regime of MDR TB: Regime did not include 4
reliable core drugs after diagnosis of MDR TB.
Can lead to MDR / XDR -TB

60. Better to Prevent MDR-TB
Regular Drugs
Appropriate Dosages
Full Duration
Health Education
Direct Supervision
Carry Home Message

62. Some useful resources on MDR TB