MDR/XDR TB poses a serious global public health threat. MDR TB is resistant to rifampicin and isoniazid, while XDR TB is also resistant to fluoroquinolones and second-line injectable drugs. Factors contributing to drug resistance include improper treatment, non-compliance, and exposure to drug-resistant TB patients. Diagnosis and treatment of drug-resistant TB is challenging due to long turnaround times for drug susceptibility testing and toxic second-line drug regimens of up to 2 years. Proper diagnosis, treatment monitoring, and surgical intervention where needed are critical to control the spread of drug-resistant TB.

1. MDR/XDR And Its Management
Dr. Arabil Reang

2. INTRODUCTION
• Although the global incidence of TB has been
slowly declining , TB remains out of control in
many parts of world.
• MDR TB comprises 6- 7% of total burden of TB.
• DR TB is associated with pulmonary morbidity
including chronic lung fibrosis, bronchiectasis &
Aspergillus associated lung disease.

3. • Several issue are critical to the control of DR TB
including-
1. reducing global level of proverty
2. overcrowding
3. HIV
4. cigarette smoking,
5. Alcohol and substance abuse,
6. biomass fuel exposure
7. diabetes.

4. • Tuberculosis (TB) strains with drug resistance (DR-
TB) are more difficult to treat than drug-
susceptible ones.
• WHO estimates that about half a million cases of
multi-drug or rifampicin resistant (MDR/RR-TB)
are estimated to occur each year.
• Only one third were estimated to have accessed
effective treatment and of those, just over half
had a successful treatment outcome.

5. Definitions
• MDR-TB: TB caused by Mycobacterium
Tuberculosis strains that are resistant to both
rifampicin and isoniazid.
• Extensively drug resistant TB (XDR-
TB): TB that is resistant to any fluoroquinolone
and to at least one of three second-line injectable
drugs, in addition to multidrug resistance.

6. • Rifampicin-resistant TB (RR-TB): TB
caused by M. tuberculosis strains resistant to
rifampicin..
• Rifampicin-susceptible, isoniazid-
resistant TB (Hr-TB): caused by M.
tuberculosis strains resistant to isoniazid but
susceptible to rifampicin.

7. • Mono-resistance TB (MR): A TB patient,
whose biological specimen is resistant to one
firstline anti-TB drug only.
• Poly-drug resistance TB (PDR): A TB
patient, whose biological specimen is resistant
to more than one first-line anti-TB drug, other
than both H and R.

8. • Drug susceptibility testing (DST): in vitro
testing using either molecular, genotypic techniques to
detect resistance-conferring mutations , or phenotypic
methods to determine susceptibility to a medicine.
• Serious adverse events: is an adverse
event that leads to death or a life-threatening
experience, to hospitalization or prolongation of
hospitalization, to persistent or significant disability, or
to a congenital anomaly.

9. Epidemiology
• Globally in 2016, there were an estimated
4.1% of new cases and 19% of previously
treated cases with MDR/RR-TB.
• Drug resistance surveillance data show that an
estimated 240 000 people died from MDR/RR-
TB in 2016.

10. • In spite of increased testing, the number of MDR/RR-
TB cases detected in 2016 only reached 153 000.
• In 2016, 8 000 patients with extensively drug-resistant
TB (XDR-TB) were reported worldwide.
• To date, 123 countries have reported at least one XDR-
TB case.
• More of the half MDR TB burden lies in INDIA, CHINA
and the Russian Federation

12. • In India, the estimated percentage of new and
retreatment cases with MDR/RR- TB was 2.2%
and 18%.
• In 2017, there were an estimated 135,000
incident MDR/RR – TB cases in india.

13. WHY THIS EMERGENCE:CAUSES
• MULTIPLE INEFFECTIVE TB REGIMENS
• DELAYED DIAGNOSIS
• WRONG DOSE
• NON COMPLIANCE
• WRONG DURATION OF TREATMENT
• POOR QUALITY OF DRUGS
• CONTACT WITH A DRUG RESISTANT TB PATIENT
• CO-MORBIDITIES– HIV POSITIVE

14. DEVELOPMENT OF ANTI-
TUBERCULOSIS DRUG RESISTANCE
• PRIMARY or PRE-TREATMENT RESISTANCE-When
drug resistance is demonstrated in a patient who
has never received anti-TB treatment previously,
it is termed primary resistance.
• SECONDARY or ACQUIRED RESISTANCE-Here the
bacteria were sensitive to the drug at the start of
the treatment but became resistant to the
particular drug during the course of the
treatment with it.

15. CAUSES OF DRUG RESISTANCE
• Microbial: In m. Tuberculosis, acquired drug
resistance is caused mainly by spontaneous
mutations in chromosomal genes, producing
the selection of resistant strains during sub-
optimal drug therapy.
• Clinical - Due to inadequate treatment.

16. Mechanism of drug resistance
• The TB bacteria has natural defenses against some
drugs, and can acquire drug resistance through genetic
mutations.
• Some mechanisms of drug resistance include:
• Cell wall- The cell wall of M. tuberculosis (TB) contains
complex lipid molecules which act as a barrier to stop
drugs from entering the cell.
• Drug modifying & inactivating enzymes: The TB
genome codes for enzymes (proteins) that inactivate
drug molecules. These enzymes usually phosphorylate,
acetylate, or adenylate drug compounds.

17. • Drug efflux system;- The TB cell contains
molecular systems that actively pump drug
molecules out of the cell.
• Mutations-Spontaneous mutations in the TB
genome can alter proteins which are the
target of drugs, making the bacteria drug
resistant.

18. MECHANISM OF RESISTANCE
ANTIMICROBIAL AGENT MECHANISM OF ACTION MECHANISM OF
RESISTANCE
ISONIAZID inhibition of mycolic acid
biosynthesis
-Mutations in katG -
overexpression of inhA -
ahpC mutation
RIFAMPICIN Inhibition of transcription Mutation of rpoB prevent
interaction with rifampicin
STREPTOMYCIN Inhibition of protein
synthesis
Mutation prevent
interaction with
streptomycin resistance
ETHAMBUTOL Inhibition of
arabinogalactan and
lipoarabinomannan
biosynthesis
Overexpression or
mutation of Emb B allow
continuation of arabinan
biosynthesis

19. ANTIMICROBIAL AGENT MECHANISM OF ACTION MECHANISM OF
RESISTANCE
PYRAZINAMIDE because of mutations in
pncA results in inactive
pyrazinamidase and
confers resistance to
pyrazinamide
FLUOROQUINOLONE Inhibition of the DNA
gyrase
Mutation in gyr A prevent
interaction with fluoro-
quinolones

22. CAUSES OF INADEQUATE TREATMENT
Providers/Programmes:
Inadequate regimens
Drugs: Inadequate
supply/quality
Patients: Inadequate drug
intake
• Absence of guidelines
or inappropriate
guidelines
• Non-compliance with
guidelines
• Inadequate training of
health staff
• No monitoring of
treatment
• Poorly organized or
funded TB control
programmes
• Non-availability of
certain drugs (stock-
outs or delivery
disruptions)
• Poor quality
• Poor storage conditions
• Wrong dosages or
combination
• Poor adherence (or
poor DOT)
• Lack of information
• Non-availability of free
drugs
• Adverse drug reactions
• Social and economic
barriers
• Mal-absorption
• Substance abuse

23. Causes of emergence and potential
threat of XDR-TB
• XDR-TB is human-made.
• Inadequate/interrupted treatment with second line anti-TB drugs.
• Indiscriminate use of second-line drugs.
• Non-adherence to national and/or international guidelines.
• Increasing use of fluoro-quinolones in combination with standard
first-line drugs esp. in new cases .
• Weak systems to ensure standardized regimens and treatment
adherence for MDR-TB

24. IMPACT OF DRUG RESISTANCE
• Huge individual as well as public health consequences in terms of-
• Prolonged illness
• Increased mortality
• Prolonged periods of infectiousness with increased risk of
transmission of resistant pathogens to others
• Indirect costs (prolonged absence from work, etc)
• Increased direct cost (longer hospital stay, use of more expensive 2
nd or 3rd line drugs)

25. Diagnosis of DR-TB
• Improving the diagnosis DR- TB is the most
effective intervention that can enhance the
clinical outcome of patients and limit the
emergence of new cases.
• However only two –third of the estimated 9
million cases of TB are diagnosed each year
and less than half of these undergo DST.

26. Methods for drug susceptibility testing
• Rapid molecular Drug Resistance Testing
(DRT)-
• Nucleic Acid Amplification Test (NAAT)-
1. cartridge based Gene-Xpert platform,
2. chip based TruNAAT platform

27. • (b) Line Probe Assay (LPA)-
• (1) First line (H & R),
• (2) Second line (Lfx, Mfx, Km, Cm, Am)
• Growth-based phenotypic drug susceptibility
testing (DST)-
• First-line drugs: R, H, E, Z
• Second-line drugs: S, Lfx, Mfx, Km, Cm, Am
• Other drugs: Lzd, Cfz, Bdq, Dlm PAS etc.,

28. CHOICE OF DIAGNOSTIC TECHNOLOGY

29. Turn around time
• Solid LJ media- of up to 84 days,
• Liquid Culture (MGIT) up to 42 days,
• LPA up to 72 hours,
• NAAT - 2 hours.

31. Good quality specimen
• Volume of 2-5 ml.
• Preferably mucopurulent and not heavily blood stained or
contaminated.
• Collect the specimen in a sterile container (50 ml conical tube) after
thorough rinsing of the mouth with clean water.
• Specimens should be transported to the NAAT or CDST laboratory
as soon as possible after collection .
• • If a delay is unavoidable the specimens should be refrigerated to
inhibit the growth of unwanted micro-organisms.

35. Clinical Features
• Include cough, fever, weight loss,
haemoptysis and night sweats.
• The traditional culture based laboratory
diagnosis of DR TB results in long delay (
usually several weeks) in obtaining DST result,
DR TB is often diagnosed late when DS TB
treatment.

36. PRE-TREATMENT EVALUATION
• The pre-treatment evaluation will include the
following:
• 1. Detailed history (including screening for
mental illness, drug/alcohol abuse etc.)
• 2. Weight
• 3. Height
• 4. Complete Blood Count with platelets count
• 5. Blood sugar to screen for Diabetes Mellitus

37. • 6. Liver Function Tests
• 7. Blood Urea and S. Creatinine to assess the
Kidney function
• 8. TSH levels to assess the thyroid function
• 9. Urine examination – Routine and Microscopic
• 10. Pregnancy test (for all women in the child
bearing age group)
• 11. Chest X Ray

45. Inclusion criteria for new drugs
(Bdq/Dlm)
• Bdq/Dlm can be provided to the patient ≥ 18 yrs.
• Dlm can be provided to age group 6 to 17 years.
• Use of Bdq for 6 to 17 yrs and Dlm for 3 to 6 yrs may be
considered only after approval of DCGI.
• non-pregnant females or females not on hormonal birth
control methods are eligible.
• patients with controlled stable arrhythmia can be
considered after obtaining cardiac consultation.

46. Exclusion criteria for new drugs
(Bdq/Dlm)
• Pregnancy & lactating mother.
• currently having uncontrolled cardiac arrhythmia that
requires medication.
• history of additional risk factors for Torsade de Pointes, e.g.
heart failure, hypokalaemia, family history of long QT
syndrome.
• Hypokalaemia, hypomagnesaemia and hypocalcaemia
should be corrected prior to a patient receiving any QTc
prolonging drugs.

47. Regimen for XDR TB
• All XDR-TB patients should also be
subject to a repeat full pre-treatment
evaluation, but also including
consultation by a thoracic surgeon for
consideration of surgery.

48. XDR TREATMENT
Resistance
pattern DST
guided
regimen class Intensive
phase
Continuation
phase
Principle of
regimen design
XDR-TB (res to
both FQ and
SLI1 class)
XDR-TB (6-12) Cm Eto
Cs Z Lzd Cfz E +
(6) Bdq
(18) Eto Cs Lzd
Cfz E

49. Clinical monitoring
• After initiation of Rx from the DR-TB --
• Monthly intervals during the IP
• 3-monthly intervals during the CP until the end
of treatment.
• Assess clinical, microbiologic, and radiologic
response to treatment.
• Measure weight..
• Assess ADR..
• Encourage the patient …

52. Interim outcomes
• Culture conversion-- culture converted when
two consecutive cultures, taken at least 1 month
apart, are found to be negative.
Culture reversion:-- culture reverted when, after
an initial culture conversion, two consecutive
cultures, taken at least1 month apart, are found
to be positive.

53. • Smear conversion:-- smear converted when
two consecutive smears, taken at least 1
month apart, are found to be negative.
• Smear reversion-- smear reverted when,
after an initial smear conversion, two
consecutive smears, taken at least 1 month
apart, are found to be positive

54. Outcomes for MDR TB regimen
• Cured
• Treatment completed
• Treatment failed
• Died
• Lost to follow-up
• Not evaluated
• • Regimen changed

55. Role of surgery in management of DR-
TB
• DR-TB patients with localized disease, surgery,
as an adjunct to chemotherapy, can improve
outcomes.
• When unilateral resectable disease is present,
surgery should be considered in the following
cases.
• absence of clinical or bacteriological response
to chemotherapy despite six to nine months
of treatment with effective anti-TB drugs

56. • high risk of failure or relapse due to high degree of
resistance or extensive parenchymal involvement.
• morbid complications of parenchymal disease e.g.
haemoptysis, bronchiectasis, bronchopleural fistula or
empyema.
• recurrence of positive culture status during course of
treatment
• relapse after completion of anti-TB treatment

57. • THANKS