Recent advances in MDR TB

1. Drug Resistant TB
- Recent Updates
Dr. Gyanshankar Mishra
MD (Pulmonary Medicine), DNB (Respiratory Diseases), MNAMS
Assistant Professor ,
Department of Respiratory Medicine,
GMC Nagpur

2. Drug resistance - Types & Definitions
Epidemiology
Diagnostics update – (emphasis on Gene
expert/LPA)
Management of Drug resistant TB update
Principles in brief
History of global guidelines/changes/updates
Implications on our current national guidelines
Shorter MDR TB regime
Bedaquiline

3. Drug Resistant
TUBERCULOSIS
Types & Definitions

4. 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)

5. 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)

6. 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)

7. 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)

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

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

11. 2012

12. Drug Resistant
TUBERCULOSIS
EPIDEMIOLOGY

13. 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.

14. 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

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

16. 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 /Pediatric TB.

18. In an Ideal setting..

19. 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.

20. 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

21. Diagnosis – Accredited laboratory

22. 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.

23. 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.

24. Which test to do ?

25. Uses of Mycobactrium culture
 To establish a definite diagnosis
 Determine susceptibility: MDR
 To identify the species

26. Mycobacterial culture
ADVANTAGES
 Only test that confirms definite TB
 More sensitive (detects 10 bacilli / ml)
 DST can be done
DISADVANTAGES
 Very Slow Growth (3-8 Weeks)
 Less accessible than microscopy
 More expensive than microscopy
Pivotal in the diagnosis and follow-up of MDR TB

27. Methods for Detection of Drug Resistance:
Conventional methods
 Solid medium: L. J. Medium
 Advantages:
 Lower contamination rates
 Can recognize mixed cultures
 Morphology can be observed
 Colony count can be performed
 Much lower occupational health risk
33

28. Modern culture methods
(Automated)
 BACTEC 460TB (B&D)- Radiometric detection of
14CO2 when 14C labeled palmitic acid in 7H12 is
metabolized – growth index.
 BACTEC MGIT 960 (B&D) - fluorometric technology
which measures accurate O2 utilization- 7H9 media,
PANTA antibiotics.
 MB/BACT(biomeriux)- colorimetric technology

29. Negative Culture
Little or No Fluorescence
Positive Culture
FF
FO2
FO2
FO2FO2
FO2
F
FO2FO2
CO2
O2
O2
O2 O2
O2
O2
O2
O2
CO2
CO2
O2
F
F F
F
FO2
FO2
F
F
F F
CO2
O2
O2
O2
O2
O2
Strong Fluorescence
Sensor
Broth
Head
space
MGIT Detection System
Free
flouroscent
molecules
AFB bacilli

30. Non-Conventional Methods and New Techniques in TB Diagnosis
Liquid Culture Media
 Advantages
 Greater sensitivity than solid
mediums
 Faster growth detection
 Disadvantages
 Higher contamination rates
 Difficult to recognize mixed cultures
 Morphology can not be observed
 Colony count can not be performed
 Much higher occupational health
risk: need Biosafety level II/III Lab

31. Genotypic tests
 These tests detect genetic mutations
linked with drug resistance
 Xpert MTB/RIF (CBNAAT)
 Line probe assay (LPA)
 Inno-Lipa
 Tested and validated for culture isolates
 Genotype MDR TB Assay (Hain’s test)
 Tested and validated for culture isolates and
direct sputum

32. Genotypic tests

33. Rapid Molecular Detection of
Tuberculosis and Rifampin Resistance
 Xpert MTB/RIF, an automated, PCR based, molecular
test for M tb.and resistance to rifampin (RIF), with fully
integrated sample
NEJM Downloaded from www.nejm.org on September 1, 2010

34. Boehme,C et al NEJM 2010
Gene Xpert MTB/RIF:
Total processing
time = 2 hours
Reportable result:
Positive/negative TB
Resistance yes/no to
Rifampicin

35. How good is Xpert?
 Systematic review with 27 studies, 9558 participants
 Reference standard for detecting pulm TB was solid/liquid
culture
 Reference standard for Rif resistance was phenotypic DST
 For S+ C+ TB, the pooled sensitivity of Xpert
MTB/RIF was 98% , Specificity 99%
 For S- C+ TB, the pooled sensitivity was 68% ,
Specificity 98%
 For rifampicin resistance pooled sensitivity was 95%,
specificity was 98%
 In HIV patients pooled sensitivity was 79%

36. In new version of GeneXpert poor predictive
Value for low Rif resistance may not be true

37. - 18 studies  4461 samples.
- Xpert sensitivity (versus culture) differed substantially between sample
types.
- In lymph node tissues or aspirates: 83.1% (95% CI 71.4–90.7%)
- In cerebrospinal fluid, 80.5% (95% CI 59.0–92.2%)
- In pleural fluid, 46.4% (95% CI 26.3–67.8%)

38. Xpert in Extra-pulmonary TB

39. Xpert MTB/RIF in India
 New case of PTB:
 Do not start MDR-TB treatment based on
single positive report of GeneXpert
 Repeat GeneXpert and MGIT culture
 If repeat Gene Xpert pos: start Cat IV
 If repeat Gene Xpert neg: start Cat I &
review later
 In retreatment case: start MDR-
TB treatment based on single
positive report

40. Xpert in near future…
•Xpert® for HIV-1 Viral Load
(< 2houres, until 400 resulta/day)
•GeneXpert Omni (“point of care”,
smalles, mobile, low consume, also for
HPV, HCV, ebola…. )
•Xpert MTB/Rif Ultra (more sensitive, similar to
liquid culture)
•Xpert XDR (in a near future)

41. LPA (Genotype MDR TB Plus assay)
 Detects both H (katG, inhA) and R (rpoB)
resistance
 Results available on the same day (within 8
hours)
 Good sensitivity and specificity
 RIF: Sensitivity: 98.1%; Specificity: 98.7%
 INH: Sensitivity 84.3%; Specificity: 99.5%
 Limitations
 Lab infrastructure and skilled personnel
 Can be done only on smear positive samples
 Low sensitivity for H res
 Does not distinguish between live and dead
bacilli

42. 57
Line Probe Assay procedure overview
1 DNA Extraction 2 Amplification (PCR)
3 Hybridization (Detection) 4
Result interpretation

43. How do you interpret LPA?
 If LPA shows R and H resistance treat as MDR
 Ask for the type of mutation
 If only kat G- patient has high level resistance to INH but
will be sensitive to Eto/Pto
 If only inh A – patient can be given high dose INH but he
has high probability of resistance to Eto/Pto
 If LPA shows only R resistance?
 Start MDR-TB treatment, add H
 Send Phenotypic DST & take action later
 If LPA shows only H resistance treat accordingly

44. The Cochrane Library 2014, Issue 10

45. LPA for second line drugs
Cochrane review 2014
 Genotype MDRTBsl assay for FQ & SLID
 Pooled sensitivity 83.1% pooled specificity
was 97.7%
 Genotype MDRTBsl assay for FQ & SLID
 It is good rule in test, can’t rule out resistance
 Can miss 1 in 5 cases of FQ resistance
 Can miss 1 in 4 cases of SLID resistance
 Among SLID Poorest sensitivity for kanamycin

46. LPA for second line drugs….
 In smear negative the indeterminate results are higher
 The sensitivity for quinolones and SLI differs hence the
accuracy of a diagnosis of XDR-TB overall is reduced
 Quinolones
 High correlation between oflox and levoflox resistance
on LPA with phenotypic resistance
 Correlation of mutations with phenotypic resistance to
moxifloxacin and gatifloxacin is unclear
 SLI
 High correlation between SLI resistance on LPA with
phenotypic resistance
 Conventional phenotypic DST to be used in the evaluation of
patients with a negative SL-LPA result

47. NS
nts
WHO
RECOMMENDATIONS
ON THE USE OF THE SL-LPA
http://www.who.int/tb/areas-of-work/laboratory/policy_statements
POLICY RECOMMENDATION
WHO recommends the use of the SL-LPA for patients
ESTABLISHING SL-LPA AT COUNTRY LEVEL
Countries with existing LPA capacity can
MOLECULAR LINE-PROBE ASSAY
FOR THE DETECTION OF RESISTANCE TO
SECOND-LINE ANTI-TB DRUGS (SL-LPA)
TUBERCULOSIS DIAGNOSTICS
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is a
public health crisis and a global health security
risk carrying grave consequences for those
affected.
An estimated 480 000 people developed MDR-
TB in 2014 and 190 000 people died as a result
of it.
Early detection of people with MDR-TB is one of
the major bottlenecks in tackling this epidemic.
Of the 480 000 MDR-TB cases estimated to have
occurred in 2014, only about a quarter –
123 000 – were detected and reported to
national authorities.
In May 2016, WHO issued new
recommendations on the use of a rapid
diagnostic test – a line probe assay to detect
resistance to second-line anti-TB drugs (SL-LPA).
WHO recommends this rapid diagnostic test for
identifying those MDR- or rifampicin-resistant
TB patients who can be placed on the shorter
MDR-TB regimen. The results of this test will
also be critical in placing patients on targeted
conventional MDR-TB regimens with improved
outcomes.
BENEFITS OF THE SL-LPA
The SL-LPA produces results in just 24-48 hours, a
vast improvement over the 3 months or longer
currently required.
It allows quick triage of confirmed rifampicin-
resistant or MDR-TB patients into either the shorter
MDR-TB regimen or the conventional longer
regimen.
Excluding second-line drug resistance a critical
prerequisite for identifying patients who can be
placed on the shorter MDR-TB regimen.
Detection of any second-line resistance by the SL-
LPA means that MDR-TB patients should not be
enrolled on the shorter regimen as this could
jeopardise their treatment outcome and fuel the
development of XDR-TB.
Photo credit: FIND

48. LPA for second line drugs ….
 In 2016 version 2 of the SL-LPA launched
 Probes for gyrB and eis in addition to gyr A and rrs;
sensitivity has increased
 WHO gave new recommendations
 Done on sputum samples For patients with
confirmed Rif resistance or MDR-TB, SL-LPA may
be used as the initial test instead of phenotypic
culture-based DST, to detect resistance to
fluoroquinolones and second line injectables
 Samples (direct) or culture isolates (indirect)
from pulmonary and extra-pulmonary sites
 Smear status can be positive or negative

49. 69
LPA report

50. 70
Soon to come in India PMDT ver. 2

51. Cross-resistance
 Fluoroquinolones
 Variable cross-resistance
 Later generation FQs (Lfx, Mfx, Gfx) may be
effective in case of oflox resistance
 In case of Lfx resistance Mfx may be effective
 Mfx and Gfx have nearly complete cross
resistance
 Test isolates for resistance to both Lfx and Mfx
 Mfx should be tested at both 0.5 and 2 mcg
 Thioamides
 Eto and Pto have complete cross-resistance

52. Drug Resistant Tuberculosis-
Treatment updates

54. 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 in a hierarchical
order.
5. Monitor and manage adverse effects of drugs.
6. Never add a single drug to failing regime.

55. 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.

56. WHO 2006

57. WHO 2006

58. WHO 2008

59. WHO 2008

60. WHO 2011

61. WHO 2011

62. WHO 2014

63. WHO 2014

64. WHO 2014

65. IUATLD

66. IUATLD 2004

67. www.thelancet.com/infection Vol 10 September 2010

72. Eur Respir J 2015; 46: 887–893 | DOI: 10.1183/13993003.00432-2015

74. WHO 2016

75. Expert Panel WHO 2016 guidelines

76. GROUP A
Fluoroquinolones
Levofloxacin
Moxifloxacin
Gatifloxacin
GROUP B
Second-line injectable agents
Amikacin
Capreomycin
Kanamycin
(Streptomycin)
GROUP C
Other Core Second-line Agents
Ethionamide / Prothionamide
Cycloserine / Terizidone
Linezolid
Clofazimine
GROUP D
Add-on agents
(not core MDR-TB regimen components)
D1
Pyrazinamide
Ethambutol
High-dose isoniazid
D2
Bedaquiline
Delamanid
D3
p-aminosalicylic acid
Imipenem-Cilastatin
Meropenem
Amoxicillin-Clavulanate
(Thioacetazone)

77. W.H.O. Treatment Guidelines for Drug-Resistant TB.
2016 Update. RECOMMENDATIONS

78. 2. Conventional MDR-TB regimens for adults & children
2a) In patients with rifampicin-resistant or multidrug-resistant TB, a
regimen with at least five effective TB medicines during the
intensive phase is recommended, including pyrazinamide and
four core second- line TB medicines – one chosen from group A, one
from group B, and at least two from group C
(conditional recommendation, very low certainty in the evidence).
If the minimum of effective TB medicines cannot be composed as
above, an agent from group D2 and other agents from D3 may
be added to bring the total to five.
W.H.O. Treatment Guidelines for Drug-Resistant TB.
2016 Update. RECOMMENDATIONS

79. 2. Conventional MDR-TB regimens for adults & children
2b) In patients with rifampicin-resistant or multidrug-resistant TB, it is
recommended that the regimen be further strengthened with high-
dose isoniazid and/or ethambutol
(conditional recommendation, very low certainty in the evidence).
It is recommended that any patient – child or adult - with rifampicin-resistant
TB in whom isoniazid resistance is absent or unknown be treated with a
recommended MDR-TB regimen, either a shorter MDR-TB regimen, or if this
cannot be used, a conventional MDR-TB regimen to which isoniazid is added.
There is no change in the recommended use of the new TB drugs from those
defined by the WHO interim guidance on bedaquiline (2013) and delamanid
(2014). The two drugs now occupy a unique subgroup within the Add-on agents
used to treat MDR-TB.
W.H.O. Treatment Guidelines for Drug-Resistant TB.
2016 Update. RECOMMENDATIONS

81. 2 HRZE / 4 H R
Initial Res. H
Sm ( -) 2nd Month
Sm (+) 2nd M.
% CURE
Extend 1st Phase
Go to 2nd Phase
High Risk MDR-TB! but Susceptible ZE
Likelihood of generating MDR and XDR under NTP conditions

82. 2 HRZE/4 H R FAILURE
2. Initial Resistance to H (+%)
Risk of Resistance Amplification in Cat. I Failures receiving
Category II Regimen (1)
2 HRZE/4 H R MDR, but suscpt. Z+E
2HRZES/1HRZE/5H R E
Risk to Amplifying Resistance to E
(Avoidable if DST before 3rd Month)

83. What are the
implications on our
guidelines?

84. 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
Reserve drug: PAS/Moxiflox/Capreomycin

85. DOTS PLUS DAILY REGIME

86. 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
Reserve: Thiacetazone /
Clarithromycin

87. 20
treatment success than those who received longer conventional regimens (89.9% vs. 78.3% respectively when
success was compared with treatment failure/relapse/death (Table 5) and 83.4% vs. 61.7% when compared with
treatment failure/relapse/death/loss to follow-up; see also online Appendix 4). The number of relapses was
very low, although this may have been as a result of the relatively small number of patients followed up. As
expected, the treatment success was lower in patients with additional resistance to pyrazinamide and/or
fluoroquinolones on shorter MDR-TB regimens, even if in general it remained high and exceeded that in the
patients on individualised, conventional regimens (although the differences were not statistically significant).
Table 5. Treatment success in patients treated with a shorter MDR-TB regimen versus conventional MDR-TB
regimens10
Resistance pattern Shorter MDR-TB regimen Conventional MDR-TB regimen
N % (95% CI) N % (95% CI)
All cases regardlessof pyrazinamide
and fluoroquinolone susceptibility
1008/1116 90.3% (87.8%- 92.4%) 4033/5850 78.3% (71.2%- 84%)
Pyrazinamide resistant;
fluoroquinolone resistant
19/28 67.9% (47.6%-84.1%) 81/137 59.1% (50.6%-67.1%)
Pyrazinamide resistant;
fluoroquinolone susceptible
90/100 88.8% (47.3%-98.6%) 840/1075 81.4% (71.6%-88.4%)
Pyrazinamide susceptible;
fluoroquinolone resistant
12/15 80.0% (50.0%-94.1%) 72/120 64.4% (49.6%-76.9%)
Pyrazinamide susceptible;
fluoroquinolone susceptible
121/125 96.8% (77.3%-99.6%) 890/1119 83.5% (75.7%-89.2%)
10
treatment success (cured or treatment completed(14),(9)) versusfailure/relapse/death inpatientsnot previouslytreatedwithsecond-
line TB medications ; percentagesshown have been adjusted when possible (see online Appendix 4for more details)
W.H.O. Treatment Guidelines for Drug-Resistant TB.
2016 Update. RECOMMENDATIONS

88. THE SHORTER
MDR-TB REGIMEN
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is a
public health crisis and a global health security
risk carrying grave consequences for those
affected.
An estimated 480 000 people developed MDR-TB
in 2014 and 190 000 people died as a result of it.
MDR-TB cannot be treated with the standard 6-
month course of first-line medication which is
effective in most TB patients. Patients with
rifampicin-resistant or MDR-TB are treated with a
different combination of second-line drugs,
Countries using the shorter MDR-TB regimen
(excluding clinical trial sites)
resistant-TB, regardless of patient age or HIV status
Monitoring for effectiveness, harms and relapse will
be needed. Patient-centred care and social support
will be essential to enable patient adherence
Programmatic use is feasible in most settings
worldwide
Lowered costs and reduced patient loss expected
Exclusion criteria: 2nd
line drug resistance,
extrapulmonary disease and pregnancy.
REGIMEN COMPOSITION
4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose -E / 5 Mfx-Cfz-Z-E
Km=Kanamycin; Mfx=Moxifloxacin;
Pto=Prothionamide; Cfz=Clofazimine;
Z=Pyrazinamide; Hhigh-dose= high-dose Isoniazid;
sistant TB in
endation on
gimen under
ed to benefit
worldwide;
or worsening
appropriately
e randomized
engthen the
ore effective
who.int/tb
6
FEATURES OF THE
SHORTER MDR-TB REGIM
Standardized shorter MDR-TB
drugs and a treatment duration o
Indicated conditionally in MDR- o
resistant-TB, regardless of patien
Monitoring for effectiveness, har
be needed. Patient-centred care
will be essential to enable patien
Programmatic use is feasible in m
worldwide
Lowered costs and reduced patie
Exclusion criteria: 2nd
line drug re
extrapulmonary disease and preg
REGIMEN COMPOSITION
4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose -E
Km=Kanamycin; Mfx=Moxifloxacin
Pto=Prothionamide; Cfz=Clofazim
Z=Pyrazinamide; Hhigh-dose= high-do
E=Ethambutol
which is tolerable have been ongoing for several
years through various studies.
Recently, a standardized treatment regimen
lasting less than 12 months has been used in a
number of countries (see map). It has shown
promising results in selected MDR-TB patients
Based on data from these studies, WHO updated
its treatment guidelines for drug-resistant TB in
May 2016 and included a recommendation on
the use of the shorter MDR-TB regimen under
specific conditions.
This new recommendation is expected to benefit
the majority of MDR-TB patients worldwide;
however, there are serious risks for worsening
resistance if the regimen is used inappropriately
(e.g. in XDR-TB patients).
WHO encourages ongoing and future randomized
controlled clinical trials to strengthen the
evidence base for shorter and more effective
regimens.
For more information please visit: www.who.int/tb
© World Health Organization May 2016

90. WHO 2016 guidelines..
• Treatment regimens for isoniazid-resistant TB and M. bovis
• Owing to the lack of data to address directly the questions no clinically-useful
recommendations could be made by the group for these two forms of the disease.
• We need to look at our national guidelines then!

94. Koen Andries

95. Bedaquiline
• Diarylquinolone
• Inhibits of the proton pump of Mycobacterial ATP
synthase – which provides energy to MTB
• Strong bactericidal and sterilizing activity.
• Extended half life – remains in plasma upto 5.5
months after stopping.
• Currently available under conditional access
programme -PMDT

97. Be aware of…
• Prior to initiation:
• Adults / No rhythm disorder/ barrier contraceptive
• LFT/KFT/CBC (esp. Neutrophil/platelets)/Hb/ Lipase
• Eye examination (Lzd)
• QTcF >450 ms excluded
• Mg, Ca, K
• UPT

98. CAP..BDQ..Pre XDR/XDR..

99. BDQ..PMDT..
Dose: 400 mg od po x 2 weeks followed by
200 mg thrice weekly po x 22 weeks (100
MG TABLETS)

100. But remember..

101. 124
But the literature is full of
controversies on this point…
Choice of the Fluoroquinolone. QTc
Br J Clin Pharmacol. 2010 Apr; 69(4): 391–400

102. 125
Cross-resistance between clofazimine and bedaquiline

103. Cross-resistance Cfz-Bdq: myths & misconceptions
1. Patients with Rv0678 mutations are not more likely to fail treatment (current
data do not suggest an increased risk of failure in patients with low level
resistance)
2. Rv0678 mutations are not always due to prior use of Cfz or Bdq
3. Rv0678 mutations do not always lead to high MICs for both Cfz or Bdq
4. Use of Cfz may not result in Rv0678 mutations and cross resistance to Bdq 126

104. Only time will tell the future course
• If Bedaquiline will be elevated to a higher group eg.
Group C in the next WHO classification based on
evidences accumulating now?
• Will cure rates improve with bedaquiline based
regimes?
• Will bedaquiline resistance be a problem?

109. Carry home message
Drug resistant TB is a Lab diagnosis.
The best way to tackle it is to prevent it.
The earlier the diagnosis, the better is the outcome.
Manage drug resistant TB as per principles of
management of Drug resistant TB.
Bedaquiline is the drug of the future and has
revolutionized the ambitious possibility a shorter effective
regime for drug resistant TB.

111. Some useful resources on MDR TB