This document provides information on multi-drug resistant tuberculosis (MDR-TB). It discusses the epidemiology and definitions of drug-resistant TB. It describes how to diagnose DR-TB through tests like Xpert MTB/RIF, line probe assay, and culture and drug susceptibility testing. Treatment options for DR-TB are also outlined, including shorter standardized treatment regimens and longer regimens. Criteria for determining appropriate treatment regimens and defining treatment outcomes are also summarized.

1. MULTI-DRUG RESISTANCE
TUBERCULOSIS
Preceptor : Dr Alok singh
Head of Department,
Internal Medicine
Presenter : Dr Parash Mani Bhatta
1ST year Resident
Internal Medicine

2. Duration : 30 minutes
Objectives : At the end of session , participants will be able to
know how to approach and manage Multi Drug Resistance
Tuberculosis.

3. CONTENT
1. Epidemiology
2. Key Definitions
3. Diagnosis of DR TB
4. Treatment of DR TB
5. Multi-Drug Resistance in Special Situations
6. Infection Control.
7. Modified STR regimen and future options

4. Epidemiology
Global TB burden

5. Epidemiology in Nepal
• 1500 TB cases annually,
• 350-450 MDR TB cases are notified annually.
• 2017/2018 = 420 cases were notified.
Table 1 : Estimates of MDR-TB burden in Nepal for 2016
% of MDR-TB cases among new TB cases 2.2(1.3-3.8)
% of MDR-TB cases among retreatment TB cases 15.4(10-23)
Number of MDR-TB cases among notified new TB cases 540(320-930)
Number of MDR-TB cases among notified retreatment cases 620(410-920)

6. Key Definitions
Poly resistance
Multidrug resistance (MDR): resistance to isoniazid and
rifampicin.
Extensive drug resistance(XDR) : MDR+ resistance to
fluoroquinolones ( at least one) + second line injectables(
capreomycin, kanamycin, amikacin)

7. Isoniazid resistance TB (Hr-TB): resistance to isoniazid only.
Pre-XDR : Resistance to either fluroquinolones or Second line
injectable drugs but not to both in addition to MDR.
Rifampicin resistance(RR-TB): resistance to rifampicin detected
using phenotypic or genotypic methods with or without
resistance to other anti TB drugs
SLD= second line injectable drug
MDR = multi drug resistance

8. Conversion : culture considered negative when 2
consecutive cultures taken 30 days apart found negative.
Reversion : culture considered to reverted to positive, after
initial conversion 2 consecutive culture, taken at least 30
days apart are found positive.

9. • Drug resistance – spontaneous chromosomal point mutation
in specific gene targets.
• Primary resistance: resistance to ATT before treatment
• Resistance to two or more drugs is caused by sequential
mutations in different genes

10. Causes of resistance

11. How to prevent drug resistance :
4 principal ways-
Early detection and high quality treatment of drug susceptible
and drug resistant tuberculosis.
Effective implementation of infection control measures.
Strengthening and regulation of health systems.
Addressing underlying risk factors and social determinants.

12. Diagnosis of DR-TB
Following categories of TB patients at risk of having DR-TB and
need to be screened for drug resistance:
1. Close contact of DR-TB cases.
2. Previously treated who either –
-failed,
-relapsed,
-returned after loss to follow up.

13. 3. Smear positive at 2 months or subsequent follow up during
first line treatment.
4. Getting worse during continuation phase of first line
treatment with frequent interruptions and irregular first line
drugs
5. Health care workers with presumptive TB
6. PLHIV,DM and other immunocompromised , migrants and
refugees.
PLHIV= people living with HIV
DM= diabetes mellitus

14. Management of presumptive DR-TB
1) Perform a Xpert MTB/RIF test.
2) What to do if Xpert MTB/RIF test shows rifampicin resistance (RR)
- treat according to guidelines.
3)Patient with low risk of DR-TB :
- If RR result in xpert test , then it is necessary to repeat the test
because of presumption of TB and not a presumption of DR –TB .
TB= tuberculosis
DR-TB = drug resistant tuberculosis

15. DIAGNOSTIC TESTS
• Direct microscopy- To monitor treatment progress.

16. Xpert MTB/RIF test:
Test takes 2 hours.
Molecular test.
Very high sensitivity and specificity.
Identifies presence of DNA from the tubercle bacillus and
Occurrence of mutations in the DNA that cause
rifampicin resistance.

17. • If presence of Mycobacterium Tuberculosis (MTB) is detected ,
look for RR .
WHY??

18. • Sample: 2-3 ml of single
early morning sputum
sample
• Testing of blood, urine or
stool is not recommended
but testing of an
appropriate specimen can
be very helpful
• Pleural fluid not very
sensitive

19. Result of Xpert MTB/RIF test
Label Result and interpretation Action to be taken
T MTB detected, rifampicin
resistance not detected
Diagnosis of TB confirmed. Treat with first-line
TB drugs
RR MTB detected, rifampicin
resistance detected
If presumptive MDR-TB case : DR-TB center.
If new TB case : Consider repeat Xpert MTB/RIF
test
TI MTB detected, rifampicin
resistance intermediate
Diagnosis confirmed. Treat with first-line TB
regimen.
Send new sample for repeat test, if result is RR
, then send to RR Centre.
N MTB not detected Additional investigations required to exclude TB
I Invalid/no result/error Send new sputum specimen to repeat the test.

20. Line Probe Assay (LPA)
Nucleic Acid Amplification Test (NAAT) using the PCR.
2 specimen required , one sample for culture and other for rapid
molecular testing by line probe assay(LPA)
First line LPA detects mutation in
rpoB gene ( resistance to R ) and katG and inhA genes
(resistance to H).
• KatG- High level resistance.
• inhA- Low level resistance

21. Second line LPA detects mutation In
• gyrA ad gyrB genes ( resistance to fluoroquinolones {FQ} and
• rrs and eis genes { resistance to second –line injectable drugs
(SLID) Amikacin and Capreomycin }

22. • If no resistance to FQ AND SLID, patient can continue initial
prescribed TB regimen, either SSTR or long course regimen (LR1).
• If resistance to FQ is detected, irrespective of SLID, patient will be
put on LR 2 regimen.
SSTR= shorter standardized TB regimen
FQ = Floquinolones
SLID : second line injectables

23. Culture and Drug Susceptibility Testing(DST)
• Identifying viability of Mycobacterium
• Carrying out phenotypic Drug susceptibility Testing.
• Confirming the results where direct LPA testing is not possible.
Culture test are also used to monitor response.
LPA=line probe assay

24. Specimens collected for culture and DST in
presumptive Extrapulmonary(EP) DR-TB
Type of EP TB Specimen Quantity to
be collected
Tuberculous pleuritis Pleural Fluid 10-15 ml
Tuberculous meningitis Cerebrospinal fluid 2 ml
TB of peripheral lymph adenitis Pus and/or excision biopsy 2ml
Musculoskeletal TB, Osteo-articular TB Intra-articular fluid biopsy
samples
2ml
TB pericarditis Pericardial fluid 2ml
TB peritonitis Ascitic fluid 10-15 ml
Genito-urinary TB Urine
Endometrial biopsy
100-200ml

25. Culture Result
• Culture will be performed on both samples which will be
inoculated onto a solid culture medium ( Lowenstein-Jensen)
and/or MGIT.
• If no growth appeared till 8 weeks , culture considered
negative.
• If bacilli are present in the sample , colonies start to grow on
the medium after 4-6 weeks in solid culture and nearly 2
weeks in MGIT.

26. Colonies have typical shape:
brownish, granular, and with rough surface.
Solid cultures: Colony growth will be graded according to
number of colonies observed :

27. • Liquid culture ; Growth of bacteria, including mycobacteria, is
indicated by fluorescence which increases proportionally as
oxygen decreases in tube.
• Instrument detects the fluorescence in medium using UV
light.
• Interpretation : either positive or negative.

28. Drug susceptibility testing
DST in Solid Media
Turn over time : 4 weeks
DST in Liquid Media
Turn over time : 2 weeks
1st line drugs :
-rifampicin
-isoniazid
-Ethambutol
2nd line drugs :
- Levofloxacin
- Moxifloxacin
- Amikacin
- Streptomycin
1st line drugs:
- Isoniazid
- Rifampicin
- Ethambutol
- Pyarazinamaide
- 2nd line drugs:
- Levofloxacin
- Moxifloxacin
- Bedaquilline
- Linezolid
- Clofazimine
- Amikacin
- Delaminid
- streptomycin

29. Xpert MTB/RIF Ultra assay :
-Xpert MTB/RIF is neverthless suboptimal, in specimen with low
number of bacilli.
So Xpert MTB/RIF ultra assay is developed to overcome this limitation
Next Generation sequencing(NGS) :
Nucleotide sequence of whole genome (i.e Whole genome sequencing
(WGS) or part of genome ( i.e targeted NGS) in a single biochemical
reaction volume.

30. Registration category of DR-TB
• New : No or less than 1 month of anti-TB treatment.
• Relapse : Previously treated for TB and outcome was cured or
treatment completed and is subsequently diagnosed with a
recurrent episode of TB (either a true relapse or a new
episode of TB caused by reinfection).

31. • Failure: Previously treated TB patient who has received treatment and in
whom treatment has failed.
- After failure of first line treatment with FLD
- After failure of retreatment with FLD
- After failure of treatment with Hr TB regimen
- After failure of treatment with SLD
• Treatment after loss to follow up : previously treated for TB and was
declared Lost to follow up at the end of most recent course of treatment

32. Treatment of DR TB
Patient education :
1) Knowledge and understanding
2) Prevention of spread of DR TB
3) Information about possible side effects
4) Rights and responsibilities
5) Maintaining confidentiality
6) Psycho-social support throughout treatment.
Before treatment Active TB drug safety and monitoring and
management (aDSM) essential for all patients.

33. Key points for RR/MDR TB
• Drugs are limited, expensive, less effective, poorly tolerated ,
some side effects are very severe and difficult to recognize.
• Standardized shorter treatment Regimen (SSTR) of 9-12
months duration prescribed for uncomplicated RR/MDR TB
provided that eligibility criteria are met.
• All oral Longer treatment regimen( LTR) of 18-20 months
duration for those not eligible for SSTR.
Mainly two regimens - LR1 , LR2 for most RR/MDR TB patients .

35. Shorter Standardized Treatment
Regimen (SSTR)
Intensive phase: 4 months with 7 drugs followed by
Continuation phase of 5 months with 4 drugs
Intensive phase will be extended if smear conversion is not
achieved within 4 months, with a maximum of 6 months.

36. Source: DR-TB-Guidelines 2019

37. Ethionamide-ETO

39. Criteria to decide when the shorter MDR-TB regimen
may be offered

40. When to discontinue administration of Shorter
Standardized Treatment Regimen (SSTR)
• Severe toxicity due to Moxifloxacin :
Q-T interval increase and risk exceeding >500 msec .
• Adverse drug reactions.
• Pregnancy during treatment.
• Sputum smear remains positive up to 6 month.
• Culture is positive at 4 or 5 or 6 months depending on
duration of the intensive phase.
• After negative culture at end of intensive phase, 3 consecutive
cultures are positive during the continuation phase.
• Shorter Standardized Treatment Regimen

41. Treatment regimen of SSTR and failure
of SSTR (modified LR2)

42. Definition of outcome in SSTR
Cured: Treatment completed without evidence of failure AND
3 or more consecutive cultures taken at least 30 days apart are
negative after the intensive phase.
Treatment completed: without evidence of failure but no record.
• Shorter Standardized Treatment Regimen

43. Failure –
-acquired resistance to Fluoroquinolones and or injectable.
-Sputum smear positive at month 6 along with poor clinical
and radiological response by end of intensive phase.
-2 positive culture taken at least 30 days apart in continuation
phase of SSTR .
-One culture positive in last three months of treatment and
recent follow up months are also positive.

44. Longer RR/MDR TB regimen (LR1) should be given only in case
where SSTR cannot be initiated
Resistance pattern and
background history
Regimen
LR1 Standard longer RR/MDR TB
Regimen for adults and children 6
years and above
Non-eligible for SSTR and for
those whose fluoroquinolones
results unknown/ awaited/
sensitive.
Bedaquiline(6), 18
levofloxacin,
Linezolid,
Clofazimine,
Pyarazinamide Z
LR2 RR TB with risk of FQ
resistance/FQ resistance at
baseline (pre-XDR and XDR TB
Bedaquiline(12). 18
Linezolid,
Clofazimine,
Cycloserine,
pyrazinamide

45. Drug Formulation Daily dose
Moxifloxacin standard dose 400mg tab 7.5-10mg/kg
Moxifloxacin high dose 400mg tab
Levofloxacin( high dose upto
1500mg daily)
250 mg tab
500 mg tab,750 mg tab
15-25mg/kg/day
Amikacin <60 years -
>60 years-
500mg/2ml per vial -15mg/kg/day
-10 mg/kg/day
Ethionamide 250mg/day 15-20mg/kg/day
Clofazimine 100mg cap 100mg/day
Cycloserine 250mg cap 10-15mg/kg/day
Pyrazinamide 400mg tab 20-30mg/kg/day
Ethambutol 400mg tab 15-25mg/kg/day
Isoniazid high dose 300 mg tab 10mg/kg/day
PAS 4gm sachet 150-200mg/kg/day
Linezolid 600 mg tab 600mg/day
Delaminid 50mg tab 200mg/day
Clavulanic Acid 125mg with Amoxicillin
and Meropenem
250mg/day
Imipenem-cilastatin 500mg vial 4gm/day
Bedaquiline 100mg tab 400 mg once for 2 weeks followed by 200 mg
3 times per week for 22 weeks

46. • All diagnosed case should be placed on DST regardless of SSTR
or longer regimen.
• Basic principle of having at least 4 effective drugs in beginning
and at least 3 drugs to be continued after 6 months ( or when
Bdq/ Dlm is stopped ). At least 1 strong bactericidal should be
on board .
• Duration of treatment 18 months and can be extended based
on patient response to treatment.
dst= Drug susceptibility testing
Bdq-Bedaquiline/Dlm-Delaminid, SSTR=Shorter Standardized Treatment Regimen

47. • Regimens without injectable agent are considered not to have
an intensive phase .
• However, if injectable( amikacin or streptomycin) is to be
used, intensive phase 6 months
• Recommended duration of injectable guided by culture
conversion, can be used with at least four negative culture
and given that patient remains converted

48. Treatment outcome
• Cured – minimum 18 months with
16 months past culture conversion
without evidence of failure
AND 3 or more consecutive cultures taken at least 30 days
apart are negative.
• If there is one positive culture by end of treatment , this positive
culture should be followed by 3 negative culture

49. Treatment failed : Treatment terminated or need for permanent
regimen change of at least 2 anti TB drugs because of
• Lack of conversion by end of 6 months or in case of injectable
by end of intensive phase
• Reversion
• Adverse drug reaction
• Evidence of additional acquired resistance to
fluoroquinolones or second line injectable drugs

50. • If an MDR TB patient has 4 positive cultures and is on 6
month treatment , repeat LPA/DST to SLD and act accordingly.
There may be delayed response to treatment in XDR TB
patients.
LPA- line probe assay
DST-dryg sussceptibility testing
SLD- second line
injectable drugs

51. Treatment of INH Resistant TB
• 5.6 % monoresistance (DR survey 2011, Nepal)
• 5 to 11%( WHO regions , WHO 2017)
• Significant number of isoniazid (Hr TB) who remain undiagnosed
and inappropiately treated cannot be ignored .
• Diagnosis : 1st line LPA and DST
LPA- Line probe assay
DST- drug susceptibility testing

53. MDR in special situations
In pregnancy :
Start in 1st trimester or may be delayed upto 2nd because of
teratogenic effects during 1st trimester.
• Regimen is 18 levofloxacin, Clofazimine, Cycloserine,
Paraaminlosalicylic Acid and Pyrazinamide.
• After delivery switch back to original LR regimen.
• Duration same of MDR TB.
• Child should receive BCG vaccination.

54. Breast feeding:
No contraindication, but there is risk of exposure to MDR
TB.
DR-TB and HIV co-infection
ATT should be initiated first, followed by ART as soon as
possible within first 8 weeks of treatment.
HIV patient with profound immunosupression( CD4 less
than 50 cells/ mm3 should receive ART within 2 weeks of
initiating TB treatment.

55. Therapy is complicated by
• Drug toxicities
• Drug-drug interaction
• Co-infections exacerbating drug toxicity
• Malabsorption of drugs leading to treatment failure
• Paradoxical worsening of TB symptoms when ART is started.

56. Possible drug drug interactions between
antiretrovirals and the new TB drugs
DRUGS INSTRUCTIONS
ARV’s to avoid with
Bedaquiline
1. Efavirenz
2. Ritonavir
1.Substitute nevirapine or
integrase inhibitor instead
of Efavirenz.
2. ARV regimen with no
Protease inhibitors.
ARV’s to avoid with
Delaminid
None

57. Patient with DR TB with ExtraPulmonary TB
can be initiated in SSTR except
Those with severe form of Extrapulmonary TB –
TB meningitis,
Bone TB,
Miliary TB,
Disseminated TB ,
TB pericarditis and
Extrapulmonary TB with HIV

58. Patient with hepatitis :
Hepatitis is not contraindication of DR TB treatment unless liver
enzymes are raised i.e 5 fold increase in liver enzymes or active
jaundice.
Liver failure – longer course regimen with atleast 4 non
hepatotoxic drugs is required .
Drugs from group A and group B are safer to use
In severe hepatic and renal failure bedaquiline and Linezolid may
be avoided .

59. Patient with renal failure:
Dosing of second line drugs adapted if creatinine clearance is
> 30ml/minute.
Patient with diabetes : Person with latent TB and diabetes have
increased risk of progression to active TB.
None of anti –TB drugs are contraindicated ,
if patient is on OHA , recommend to switch to insulin for
duration of MDR treatment.
Oral Hypoglycemic agents

60. Adjuvant therapies and interventions
• Pyridoxine- 100mg per day.
• Steroids – TB meningitis and TB pericarditis.
• Surgery – elective partial lung resection
( lobectomy or wedge resection)

61. Follow-up after end of treatment:
Treatment outcome is cured or treatment completed
• Patient must go to DR TB center every 6 months for 2 years.
• If patient has not become culture negative , but a clinical
decision was made to stop treatment because of drug
intolerance , follow-up every 3 months for 3 years.

62. INFECTION CONTROL

63. RESPIRATORS SURGICAL MASKS
Designed to filter out droplet nuclei from
being inhaled by health-care worker.
Should NOT be worn by the patient.
Designed to stop droplet nuclei from being
spread(exhaled) by the patient.
Should NOT be worn by health care worker.

65. Drug information

66. Name Mechanism Cross-
resistance
Adverse effects
Bedaquiline Bactericidal Clofazimine QTc prolongation, hepatitis (so
contraindicated in hepatic failure and
renal failure ),elevated amylase,
hemoptysis
Capreomycin Bactericidal Amikacin,
kanamycin
Nephrotoxicity, Ototoxicity
Clofazimine In vitro activity
against M.
Tuberculosis
Bedaquiline Pink/red discoloration of skin,
conjunctiva, body fluids
Cycloserine Bacteriostatic None CNS toxicity
Delaminid Bactericidal- Nitroimidaz
ole
Nausea vomiting , insomnia
Ethambutol Bacteriostatic None Retrobulbar neuritis( dose related-
exacerbated during renal failure)

67. Ethionamide Weakly
bactericidal
Isoniazid Gastrointestinal upset,
Metallic taste, hepatotoxicity
Gynecomastia, neurotoxicity
Reversible hypothyroidism
Isoniazid Bactericidal Ethionamide Hepatitis, peripheral neuropathy
Kanamycin Bactericidal Amikacin Nephrotoxicity, ototoxicity
Levofloxacin Bactericidal QTc prolongation, tendon rupture
Linezolid Invitro
bactericidal
None Myelosupression, optic and peripheral
neuropathy
Meropenem Invitro
activity
Imipenem Diarrhea, vomiting, seizure but rare
Amoxicillin-
clavulanic
acid
None diarrhea
Moxifloxacin Bactericidal Similar to levofloxacin
Para-
aminosalicylic
acid
Bacteriosta
tic
None Reversible hypothyroidism
Pyrazinamide Bactericidal None Hyperuricemia and arthralgia

68. Modified Shorter regimen and future STR options
Globally all studies are focusing on all oral STR with different
combination and searching for effective , safer and shorter
treatment options.
Nix TB clinical study- combination of Pretomanid, Bedaquiline
and Linezolid( 6-9 months) for MDR, Pre XDR and XDR showing
high treatment success rate.

69. 1. TB PRACTECAL- Bedaquiline, Pretomanid, with preexisting new
and repurposed drugs
2. End TB clinical Trial part 1: from 2015-2019
3. End TB clinical Trial part 2: 2017-2019
4. Bpal Trial : pretomanid plus Linezolid and bedaquiline

70. Modified shorter treatment regimen
1) 9 Bdq, 9-12 Lfx, Lzd, Cfz, Z( Destroy TB operational research)
-contains all best bactericidal, sterlizing activity and resistance
prevention characterstics with extended use of Bedaquiline(Bdq)
2) 6-8 Bdq, Lfx(high dose), Cfz, Cs, INHh, E,Z Mfxh, Cfz, Cs, Z, E
Bedaquiline can be extended to 8 months if delayed response
and if Bdq is stopped by month 6 then switch to Lfx to high dose
Mfx, Cs replaces Eto.
Levofloxacin-Lfx Linezolid-lzd Cfz-clofazimine, Z= pyrazinamide
Cs= cycoserine, INH= isoniazid, E = ethambutol, Mfx – moxifloxacin,

71. 3) 6-8 Bdq, Lfx(high dose), Cfz, Eto, INHh, E , Z/5 Mfxh, Cfz, Z, E
replacing injection with Bdq but after Bdq is stopped switch to Lfx to high
dose Mfx
Maximum duration for all 3 regimens is 12 months and the cost varies.

72. THANKYOU