XDR TB

Xdr TB

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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7. MECHANISM OF DRUG RESISTANCE

8. 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

9. M. Tuberculosis Bacillary population in different TB lesions TB Sm + 10 7 -10 9 Bacilli Cavitary * 10 7 -10 9 Bacilli Infiltrates 10 4 -10 7 Bacilli Nodules 10 4 -10 6 Bacilli Adenopathies 10 4 -10 6 Bacilli Extrapul . TB 10 4 -10 6 Bacilli High chance of resistant mutants in cavitary and smear positive

10. 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.

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

12. 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 (10 9 ) 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 10 9.

13. Probability of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis The highest proportions of mutants observed in Isoniazid 1 in 10 6 Streptomycin 1 in 10 6 Rifampicin 1 in 10 8 Ethambutol 1 in 10 4 Pyrazinamide 1 in 10 2 - 1 4 The larger the bacterial population, the higher was the probability that resistant mutants were present.

14. 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: 10 14 for INH+RIF ( INH10 6 x RIF10 8 = 10 6+8 = 10 14) 10 20 for INH+RIF+EMB

15. 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%

16. 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.

17. 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

18. 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

19. 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 Transient drug resistance

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 2 nd 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. No. of drugs the patient is resistant to will depend on the drugs tested which varies widely between laboratories. 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%. DST for several anti-TB drugs is not sufficiently reproducible or reliable- invitro vs invivo . 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 2 nd 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 )

31. PRE TREATMENT EVALUATION

32. 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

33. TREATMENT STRATEGIES

34. CHEMOTHERAPY WITH ATT - STANDARDIZED REGIMEN - INDIVIDUALIZED REGIMEN SURGERY

35. 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

36. RNTCP GUIDELINES

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38. 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

39. 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.

40. 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.

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

42. INDIVIDUALIZED REGIMENS

43. 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

44. 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

45. 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

46. 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)

47. 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

48. 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

49. 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 D rug regimens : Bdq - Mfx - Lzd - Cfz -PAS-Cs-Cm-Z Mpm / Clav ( Amx / Clav )- Mfx - Lzd - Cfz -PAS-H*- Z

50. 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

51. PRE-XDR TREATMENT REGIMEN Pre XDR – MDR + resistance to any FQ or any second line injectable (SLI) 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

52. 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

53. 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.

54. 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

55. 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 .

56. 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

57. 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.

58. TREATMENT OUTCOMES

59. 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

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

61. 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.

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