This document discusses extensively drug resistant tuberculosis (XDR TB). It defines XDR TB as resistance to at least rifampin and isoniazid among first-line drugs, plus resistance to any fluoroquinolone and at least one second-line injectable drug. Globally, an estimated 9.7% of MDR TB cases have XDR TB. XDR TB has been reported in 105 countries as of 2014, with the highest rates in several Eastern European and Southern African countries. Treatment of XDR TB requires utilizing the few drugs the infection remains susceptible to in a lengthy 24-30 month regimen.

1. XDR TB
(EXTENSIVELY DRUG RESISTANT TB)
- DR. PRAPULLA CHANDRA

2. DEFINITION
• XDR TB is defined as "resistance to atleast rifampicin and
isoniazid among the first line-anti tubercular drugs in
addition to resistance to any fluroquinolones and atleast
one of three injectable second line anti tubercular drugs
i.e. amikacin, kanamycin and capreomycin”.

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4. EPIDEMIOLOGY
• Globally, 3.3% of the new cases and 20% of the previously
treated cases have MDR TB.
• And an estimated 9.7% of the MDR TB pts have XDR TB.
(9% in 2013 & 9.6% in 2012)
• XDR TB has been reported by 105 countries by the end of
2014.
• 14 of these countries reported > 10 XDRTB cases.
• Highest in Belarus (29%), Latvia(19%),Georgia (15%) and
Lithuania (15%)
-GLOBAL TB REPORT 2015

5. • In 2014, 49 countries reported treating people with XDR TB.
• Globally, 4044 pts with XDR TB were enrolled on
treatment.(3284 in 2013).
• Most of the cases in 2014 were notified from
India – 1262 (392 in 2013)
Ukraine – 657
South Africa -562
Belarus – 431
Kazakhstan – 318
GLOBAL TB REPORT 2015

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8. MECHANISM
OF
DRUG RESISTANCE

9. NATURAL RESISTANCE
• M. tuberculosis is naturally resistant to many antibiotics
• the highly hydrophobic cell envelope acting as a
permeability barrier
• many potential resistance determinants encoded in the
genome.
• hydrolytic or drug-modifying enzymes
• b-lactamases
• aminoglycoside acetyl transferases,
• M. bovis isolates are naturally resistant to pyrazinamide

10. M. Tuberculosis Bacillary population
in different TB lesions
• TB Sm+ 107-109 Bacilli
• Cavitary* 107-109 Bacilli
• Infiltrates 104-107 Bacilli
• Nodules 104-106 Bacilli
• Adenopathies 104-106 Bacilli
• Extrapul. TB 104-106 Bacilli
High chance of resistant mutants in cavitary and smear positive

11. Acquired Resistance to Anti-tuberculosis
Drugs
• Resistance to anti-tuberculosis drugs in M. tuberculosis is
caused by spontaneous chromosomal mutation.
• These mutations affect the genes through which the anti-
TB drugs act.

12. M.Tubeculosis RESISTANCE
• Anti-Tubercular drugs do not cause resistance per
se but they SELECT the resistant mutants.

13. M. tuberculosis Resistance
Selection of resistant mutants
• If Smear positive TB is treated with just ONE drug (H), for
each million bacilli, it will kill 999,999, but it will select the
resistant mutant (1 individual) that exists.
• If this TB has a minimum of 1,000 million (109) organisms,
in 2-8 weeks it will have selected the 1,000 mutant bacilli (1
per million) that are resistant in this population.
• These 1,000 bacilli are insufficient to cause clinical
symptoms or to be smear +.
• But these 1,000 soon will become 109.

14. Probability of drug-resistant mutants in unselected
populations of Mycobacterium tuberculosis
• The highest proportions of mutants observed in
• Isoniazid 1 in 106
• Streptomycin 1 in 106
• Rifampicin 1 in 108
• Ethambutol 1 in 104
• Pyrazinamide 1 in 102 - 104
• The larger the bacterial population, the higher was the
probability that resistant mutants were present.

15. Probability of drug-resistant mutants in unselected
populations of Mycobacterium tuberculosis
• As each drug has a different target to attack the bacilli, the
genomic mutation that causes the resistance is different for each
one of them
• The probability of finding a bacillus with 2 genetic mutations,
that express resistance to 2 drugs, is equal to the exponential sum
of their respective mutation rates:
• 1014 for INH+RIF ( INH106 x RIF108 = 106+8 = 1014)
• 1020 for INH+RIF+EMB

16. PRIMARY DRUG RESISTANCE
• Drug resistance observed in new cases
• -Patient has never been exposed to TB drugs in the past (or
less than 1 month)
• Resistance to anti-TB drugs from the outset prior to anti-
tuberculosis treatment
-Caused by transmission of drug-resistant bacilli
• INH resistance – 16-20%
• MDR ~ 3%

17. Drug Resistance among Previously Treated
Tuberculosis Cases
• Resistance in patients who have been treated for TB in the
past (1 month or more)
• Considered as a proxy for truly acquired resistance
• Mixed group and includes
• Patients who have acquired resistance
• Patients have been primarily infected with a resistant
strain and subsequently failed therapy
• Patients who have been re-infected.

18. Organisms in
Pansusceptible
new case
Development
(creation)
Transmission (spread)
Development and Spread of Drug Resistance
INH,SM:10-5-6
RIF:10-6-7
EMB:10-4-5
New cases
with Primary
drug resistance
Drug resistant
mutants
Treatment failure
with Acquired
drug resistance
Programmatic Errors
Mismanagement Delay in diagnosis and
treatment
Modified SJ Kim

19. TRANSIENT DRUG RESISTANCE
• During treatment with good bacteriological evolution there is an isolated
positive culture
• Usually small number of colonies (<20)
• Resistance on DST
• No clinical or bacteriological significance
• D.S.T. performed during treatment should be interpreted with much caution.
• Repeat culture
• Negative  Not significant: keep the same regimen
• Positive  Probably is a “fall and rise” and amplification of
resistance must be suspected

20. Transient drug resistance
Transient resistance

21. TYPES OF DRUG RESISTANCE
• Mono resistance: resistant to one drug
• Poly resistance: resistant to 2 or more drugs
• Multidrug-resistant tuberculosis (MDR-TB)- resistant to at least
isoniazid and rifampin
• Pre- XDR TB –
MDR TB + resistance to a fluoroquinolone or a 2nd line
injectable drug
• Extensively Drug Resistant TB (XDR TB) –
MDR-TB + resistance to a fluoroquinolone and a second line
injectable (amikacin/ kanamycin/capreomycin)
• Totally Drug Resistant TB (TDR-TB) ???

22. Totally drug-resistant tuberculosis
- In 2007, two patients with strains having resistance to all first and
second-line anti-TB drugs tested were reported from Italy
- In 2009, 15 TB patients in Iran were reported to be resistant to all
anti-TB drugs tested
- In December 2011, clinicians in Mumbai, India, described four
patients with “TDR-TB”
- A few weeks later, the Times of India reported another eight cases in
Mumbai.

23. 1. No. of drugs the patient is resistant to will depend on the drugs
tested which varies widely between laboratories.
2. Cross-resistance among different drugs within a class of drugs
(e.g. fluoroquinolones) or closely related classes of drugs (e.g.,
aminoglycosides and polypeptides) is not 100%.
3. DST for several anti-TB drugs is not sufficiently reproducible
or reliable- invitro vs invivo.
4. Availability of newer drugs.

24. DIAGNOSIS

25. • All pts diagnosed with MDR-TB should preferably be tested for
XDR-TB.
• The two strongest risk factors for XDR-TB are :
- Failure of an MDR-TB treatment regimen, which contains
2nd line drugs including an injectable agent and a fluoroquinolone.
- Close contact with XDR-TB pt or with a failed MDR-TB
treatment patient.

26. DRUG SUSCEPTIBILITY TESTING
• Resistance should be confirmed by doing DST
• Never make the diagnosis on clinical or radiological basis
• Types of DST
• Phenotypic
• Genotypic

27. RELIABILITY OF DST RESULTS
• First line drugs (H,R,Z,E,S)
- Good reliability for H & R
- less reliable for S & E
- Z needs to be tested by liquid method
• Second line drugs (FQ, SLI, Eto, Cs, PAS)
- Good reliability for FQs and Second Line Injectables (Am, Km
and Cm)
- Not reliable for Eto, Cs and PAS

28. CROSS RESISTANCE
• Rifamycins
rifampicin and rifabutin have high level of cross resistance
• INH
• High level of cross resistance with Eto (especially if there
is inhA mutation
• Second line injectables (Am, Km and Cm)
• Am and Km have high cross-resistance (both
aminoglycosides)
• Am/Km may have cross-resistance with Cm (Polypeptide)
• Sm has low cross-resistance with Am, Km and Cm

29. • 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
• Mfx should be tested at both 0.5 and 2 mcg
• Thioamides
• Eto and Pto have complete cross-resistance

30. GENOTYPIC TESTS
• These tests detect genetic mutations linked with drug resistance
• 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
• Xpert MTB/RIF (Genexpert)

32. PRE TREATMENT
EVALUATION

33. • The patient should be hospitalised for pre-treatment evaluation and treatment initiation. It includes
Detailed history
Clinical examination
Weight and height
Complete blood picture with platelet count
Blood sugar levels
Liver function tests
Renal function tests
TSH levels
Urine examination
Chest X-Ray
HIV counselling and testing
pregnancy test
• ECG
• S. Electrolytes
• Surgical evaluation

34. TREATMENT
STRATEGIES

35. • CHEMOTHERAPY WITH ATT
- STANDARDIZED REGIMEN
- INDIVIDUALIZED REGIMEN
• SURGERY

36. WHO classification of anti TB drugs
Group Drugs
Group 1. First line oral drugs Isoniazid, Rifampicin
Ethambutol, Pyrazinamide
Rifabutin, Rifapentine
Group 2. Injectable anti-TB drugs Streptomycin (First line)
Kanamycin, Amikacin, Capreomycin
Group 3. Fluoroquinolones Ofloxacin, Levofloxacin
Moxifloxacin
Group 4. Oral bacteriostatic second-line anti-TB
drugs
Ethionamide, Prothionamide
Cycloserine, Terizidone
Para-aminosalicylic acid
Group 5. Anti-TB drugs with limited
data on efficacy and/or long term
safety in the treatment of drug-resistant
TB
Bedaquiline
Delamanid
Linezolid
Clofazimine
Amoxicillin/ clavulanate
Imipenem/cilastatin; Meropenem
High-dose isoniazid
Thioacetazone
Clarithromycin

37. RNTCP GUIDELINES

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39. • INTENSIVE PHASE (6-12 MONTHS) :
capreomycin + PAS + moxifloxacin + high dose INH +
Clofazamine + Linezolid + Amoxyclav
• CONTINUATION PHASE (18 MONTHS) :
PAS + moxifloxacin + high dose INH + Clofazamine +
Linezolid + Amoxyclav

41. DURATION OF REGIMEN
• It is of 24-30 months duration, with 6-12 months IP & 18
months CP.
• The change from IP to CP will be done only after
achievement of culture conversion i.e., 2 consecutive
negative cultures taken atleast 1month apart.

42. MONITORING & FOLLOW UP
• CBP with platelet count : weekly in first month, then
monthly to rule out bone marrow suppression and anemia as a
side effect of LINEZOLID.
• RFT – monthly creatinine & s. electrolytes – inj capreomycin
• LFT – monthly in IP, 3 monthly in CP
• CXR – 6 monthly & whenever clinically indicated
• Follow up smear & cultures at the end of months of
3,4,5,6,7,9,12,15,18,21 and 24.

43. MANAGEMENT OF TREATMENT
INTERRUPTIONS FOR M/XDR TB PTS

46. INDIVIDUALIZED
REGIMENS

47. BEFORE STARTING TREATMENT
• Establish that the patient definitely has drug resistance through
• DST by a WHO recommended method
• Phenotypic – Solid, Liquid
• Genotypic – LPA, Xpert
• By an accredited/proficient laboratory
• Radiological and clinical evidence only is not confirmatory of drug
resistance
• In some cases empirical diagnosis and treatment for drug resistance can be
initiated only if DST is not available or feasible

48. • DST for all drugs is not reliable or of clinical value
• DST is reliable for
• Rifampicin
• INH
• Fluoroquinolones (Ofx, Lfx, Mfx)
• Second line injectables (Am, KM, Cm)
• DST is not reliable for
• Emb, Pzm, Sm, Eto/Pto, Cs, PAS
• Cfz, Lzd, Amx/Clv, Clarithromycin, Bdq, Delaminid

49. BASIC PRINCIPLES IN DESIGNING
THE REGIMEN
• Patient has not received the drug earlier
• The drug was not part of an earlier failed regimen
• DST indicates susceptibility to the drug
• Reliability in case of certain second line drugs
• No known cross-resistance
• No known close contacts with resistance to the drug
• Choose effective drugs from all groups

50. CHOICE OF ANTI-TB DRUGS
Group
1 First line drugs • Choose as many effective
• Rifampicin- resistant
• INH- usually resistant; low level res- high dose
• Pyrazinamide- should include
• Ethambutol- can be considered
2 Second line injectable • Core drug
• Kanamycin, Amikacin, Capreomycin
• Choose 1
3 Fluoroquinolones • Core drug
• Levofloxacin /Moxifloxacin
• Choose 1
4 Others • Preferably Ethionamide and Cycloserine
• PAS (If Eto or Cs cannot be used)
• Choose till 4 effective drugs
5 Reinforcement drugs • Add if 4 effective drugs not available (group 1-4)

51. XDR TB TREATMENT REGIMEN
• Choose injectable
• If patient is sensitive to any injectable (including Sm) add
that
• If patient is resistant to all injectables, add the agent which
patient has not received earlier (Cm)- Do not count as
effective drug
• Choose FQ
• If only Oflox resistant use Lfx
• If resistant to Ofx and Lfx use Mfx
• If resistant to all exclude

52. XDR TB
• Group 4
• Add all agents as effective drugs (Eto, Cs and PAS)
• Group 1
• Use Z and any other agent which may be effective.
• Group 5
• Add 2 or more group 5 drugs
• Bdq/delamanid preferred if available
• Consider high dose INH if low level resistance or absence of KatG

53. • Confidence in all three Group 4 drugs: add one more Group 5 drug
• Confidence in only two Group 4 drugs: add two more Group 5
drugs
• Confidence in only one or none of the Group 4 drugs: add three
• Drug regimens :
• Bdq-Mfx-Lzd-Cfz-PAS-Cs-Cm-Z
• Mpm/Clav (Amx/Clav)-Mfx-Lzd-Cfz-PAS-H*- Z

54. EXAMPLE :
• A patient failed the standardized regimen of Z-Km-Lfx-Eto-Cs and
remained sputum smear positive after eight months of treatment. The
DST from a specimen taken 4 months ago revealed resistance to
HRZE-S-Km-Cm-Lfx and susceptible to Eto.
• Recommended regimen –
• Z-Mfx-PAS-Lzd-Mpm/Clv-Cfz
• Z-Mfx-PAS-Lzd-Amx/Clv-Cfz
• Z-PAS-Bdq-Lzd-Mpm/Clv-Cfz
• Z-PAS-Dlm-Lzd-Mpm/Clv-Cfz

55. PRE-XDR TREATMENT REGIMEN
• Pre XDR – MDR + resistance to any FQ or any second line injectable
(SLI)
1. FQ resistance
• If Oflox resistance-
• Add levoflox/Moxiflox (do not count as effective drug)
• Add PAS
• Add 1 drug from group 5- Linezolid/Clofazimine
• Km-Mfx-Eto-Cs-PAS-Lzd-Z
• If resistant to all FQs
• Add PAS
• Add 2 drugs from group 5 –Linezolid and Clofazimine
• Km-Eto-Cs-PAS-Lzd-Cfz- Z
• Continue injectable for 12 months

56. PRE XDR
2. SLI Resistance (sensitive to FQ)
• If resistant to Am and Km
• Cm may be effective
• Add PAS
• Add 1 drug from group 5- Linezolid/Clofazimine
• Cm-Lfx-Eto-Cs-PAS-Lzd-Z
• If resistant to all SLIs
• Use Sm if sensitive
• Add PAS
• Add 2 drugs from group 5 – Linezolid and Clofazimine
• Lfx-Eto-Cs-PAS-Lzd-Cfz-Z

57. - 29 MDR-TB treatment failure patients (16 had XDR; 13 had pre-XDR with resistance to any quinolone but
sensitive to injectables)
- All patients received daily unsupervised therapy with linezolid, one injectable agent, one fluoroquinolone
and two or more other drugs.
- Out of total 29 patients, 89.7% patients achieved sputum smear and culture conversion; 72.4% showed
interim favorable outcome; 10.3% died, 6.8% failed and 10.3% patients defaulted.
- Linezolid had to be stopped in 3 (10.3%) patients due to adverse reactions.
- The outcome of treatment of 16 XDR-TB patients was comparable to the other 13.

58. - Nine observational studies (6 MDR-TB and 3 XDR-TB).
- Using random effects meta-analysis, 65% (95%CI 52–79) of those with
MDR-TB and 66% (95%CI 42–89) of those with XDR-TB experienced
favorable treatment outcomes.
- High-quality prospective cohort studies and clinical trials examining the
effect of CFZ as part of drug-resistant TB treatment regimens are needed

59. J Antimicrob Chemother. 2014 Jun 30. pii: dku235. [Epub ahead of print]
Clofazimine in the treatment of extensively drug-resistant tuberculosis with
HIV coinfection in South Africa: a retrospective cohort study.
Padayatchi N, Gopal M, Naidoo R, Werner L, Naidoo K, Master I, O'Donnell MR.
• Between August 2009 and July 2011, eligible XDR-TB patients (n = 85) were initiated on treatment
for XDR-TB.
• Most patients (86%) were HIV-infected and receiving antiretroviral therapy (90%).
• Patients receiving a clofazimine-containing regimen (n = 50) had a higher percentage of
culture conversion (40%) compared with patients (n = 35) receiving a non-clofazimine
regimen (28.6%).
• On multivariate analysis, there was a 2-fold increase in TB culture conversion at 6 months
(hazard rate ratio 2.54, 95% CI 0.99-6.52, P = 0.05) in the group receiving a clofazimine-
containing regimen.
• Adverse effects due to clofazimine were minor and rarely life-threatening.

60. • Case-control study of meropenem and
clavunate plus linezolid containing regimens
• Associated with a smear conversion rate at 3
months of 87.5% vs 56% in controls

61. SURGERY
• The timing of surgery should be earlier in the course of the disease when
patient’s risk of morbidity and mortality are lower i.e., when it is
localized to one lung or a lobe. But not as a last resort.
• Lung Resection is considered as an adjunct to chemotherapy.
• Atleast 2 months of therapy is given prior to surgery to decrease bacterial
infection in the surrounding tissue.
• Even with successful resection, IP & total treatment duration should be
completed.

62. TREATMENT OUTCOMES

63. • Among 2685 XDR TB pts in 2012 of whom outcomes were
reported,
• completed treatment successfully – 682 (26%)
• died – 809 (30%)
• treatment failed – 510 (19%)
• lost to follow up – 684 (25%)
• High mortality is in South Africa (47%) likely to be associated
with high levels of HIV- coinfection.
• -GLOBAL TB REPORT 2015

64. Pooled treatment outcomes by extensively drug-
resistant tuberculosis (XDR-TB) patient group
Migliori GB et al. Eur Respir J 2013; 42: 169–179

65. • 13 observational studies covering 560 patients:
• 43.7% (95% CI, 32.8%–54.5%) favorable outcomes
• 20.8% (95% CI, 14.2%–27.3%) Died.
• Studies in which a higher proportion of patients received a later-
generation fluoroquinolone reported a higher proportion of favorable
treatment outcomes.

67. NEXT SEMINAR ON 22/06/2016
WEDNESDAY
ACUTE SEVERE ASTHMA
BY
Dr. SANDEEP