Multi drug resistant tuberculosis

Approach and Updates on MDR TB Mgt

1. Presenter:Dr.Melaku Y.(Year I Resident) Moderator:Dr.Bekele HordoFA (Assistant Professor, Consultant Internist) ADAMA HOSPITAL MEDICAL COLLEGE Department of Internal Medicine Seminar on Multi-Drug Resistant Tuberculosis(MDR-TB) 2/11/2020 1

2. Outline Introduction Definition Epidemiology Mechanism Causes Diagnosis Treatment Follow UP XDR TB 2/11/2020 2

3. Introduction On March 24,1882 ,Dr.Robert Koch announced the discovery of M.TB His discovery was the most important step taken toward the control and elimination of this deadly disease 2/11/2020 3

4. Drug-Resistant tuberculosis TB is considered drug-resistant (DR) when the TB causative agent (mycobacterium tuberculosis) is not killed by one or more of the available anti-TB drugs. Mono-resistance: Rresistance to one anti-tuberculosis drug. Poly-resistance: Resistance to more than one anti-tuberculosis drug, other than Isoniazid and Rifampicin . 2/11/2020 4

5. Drug resistant TB… Multidrug-resistance (MDR)-TB: Resistance to at least isoniazid and rifampicin Extensive drug-resistance (XDR-TB): Resistance to any of the fluoroquinolones , and at least one of the three injectable Second Line Medicines ( capreomycin , kanamycin and Amikacin ), in addition to resistance to INH and rifampicin Total drug-resistance (TDR-TB): resistance to all anti TB medicines 2/11/2020 5

6. Epidemiology Globally, an estimated 10.0 million people fell ill with TB in 2018. Though the burden of disease varies enormously among countries, the global average is around 130. There were an estimated 1.2 million TB deaths among HIV-negative people in 2018 and 60% reduction among HIV- positive 2/11/2020 6

7. Epidemiology… Geographically, most TB cases in 2018 were in the WHO regions of South-East Asia (44%), Africa (24%) and the Western Pacific (18%), smaller percentages in the Eastern Mediterranean (8%), the Americas (3%) and Europe (3%) 2/11/2020 7

8. Epidemiology… Drug-resistant TB continues to be a public health threat. In 2018, there were about half a million new cases of rifampicin-resistant TB Globally, 3.4% of new TB cases and 18% of previously treated cases had multi-drug resistant TB or rifampicin-resistant TB (MDR/RR-TB), 2/11/2020 8

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11. Epidemiology… Tuberculosis (TB) strains with drug resistance (DR-TB) are more difficult to treat than drug-susceptible ones Threaten global progress towards the targets set by the End TB Strategy of the World Health Organization (WHO) 2/11/2020 11

12. How is drug resistance generated? Drug resistance is generated at the molecular level through spontaneous mutation The prevalence of resistant mutants associated with each first-line drug used to treat TB has been estimated Within wild-type populations, resistance to more than one TB drug is even rarer 2/11/2020 12

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14. Selected anti-tuberculosis drugs and prevalence of resistant mutants 2/11/2020 14

15. What causes drug resistance? 2/11/2020 15

16. Does MDR-TB have Classic/Peculiar clinical Picture ? 2/11/2020 16

17. Risk assessment for drug resistance The most important predictors of drug-resistant TB are: Previous episode(s) of TB treatment Worsening clinical and/or radiographic findings while on TB therapy Origin from, history of residence in, or frequent travel to a region or country with a high prevalence of drug-resistant TB Exposure to an individual with known (or highly suspected) infectious drug-resistant TB, or exposure to individuals in congregate settings where drug resistance has been documented 2/11/2020 17

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19. How do you diagnose MDR? AFB Smear Xpert MTB/RIF Xpert MTB/RIF ultra Sputum culture(conventional and liquid) 2/11/2020 19

20. How do you diagnose… Line probe assay Gene sequencing CXR? 2/11/2020 20

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22. How do you diagnose… 2/11/2020 22

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24. Treatment of MDR TB 2/11/2020 24

25. Regimens for isoniazid -resistant tuberculosis(Hr-TB) T reatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months I t is not recommended to add streptomycin or other injectable agents to the treatment regimen 2/11/2020 25

26. Hr-TB… The overall aim of TB treatment is to achieve cure without relapse in all patients, interrupting M. tuberculosis transmission and preventing the acquisition (or amplification) of additional drug resistance. 2/11/2020 26

27. Hr-TB… Support and close monitoring of patients are needed in order to maximize treatment adherence Repeat DST for rifampicin and the fluoroquinolones, preferably with Xpert MTB/RIF or LPA, is indicated in the presence of non-response 2/11/2020 27

28. Hr-TB… The recommended Hr-TB treatment regimen does not have an intensive and a continuation phase, Simplified the delivery and monitoring of treatment 2/11/2020 28

29. The composition of longer MDR-TB regimens 2/11/2020 29

30. Longer MDR-TB Regimens All three Group A agents and at least one Group B agent should be included If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it 2/11/2020 30

31. Longer MDR-TB Regimens The likelihood of treatment success in MDR-TB patients on longer regimens depends upon patient level/strain factors (including severity of disease, resistance patterns and co-morbidities), access to health care (e.g. regimens with sufficient effective agents, medications of good quality, management of AEs and other patient support). Longer MDR-TB regimens with sufficient effective agents are known to increase the likelihood of cure and lower the risk of death . The composition of longer regimens is governed by the selection of individual medicines considered to be effective and also by a need to combine sufficient medicines to maximize the likelihood of relapse-free cure without increasing toxicity 2/11/2020 31

32. Subgroup Considerations Extrapulmonary TB Meningitis Pregnancy HIV infection 2/11/2020 32

33. Longer MDR-TB Regimens The new recommendations signal an important departure from previous approaches to treat MDR/ RR-TB. Fully oral regimens should be prioritized and become the preferred option for most patients, And injectable agents are no longer among the priority medicines to consider when designing longer MDR-TB regimens. 2/11/2020 33

34. Longer MDR-TB Regimens Patients on longer MDR-TB treatment regimens need to be monitored for response to treatment and for safety using reasonable schedules of relevant clinical and laboratory testing . ensure appropriate action and an acceptable level of monitoring for and prompt response to AEs – alongside monitoring for treatment outcomes. Electrocardiography may be indicated as more regimens in future may have two or three agents that are expected to prolong the QT interval if given concurrently. Audiometry and specific biochemical tests should also be made available whenever certain agents are included in the regimens 2/11/2020 34

35. Longer MDR-TB Regimens Patients on longer MDR-TB treatment regimens need to be monitored for treatment response or failure and safety, using reasonable schedules of relevant clinical and laboratory testing . Response to treatment and toxicity is monitored through regular history-taking, physical examination, chest radiography, special tests such as audiometry , visual acuity tests, electrocardiography and laboratory monitoring. Using smear microscopy or culture to assess conversion of bacteriological status is an important means of assessing response and most patients are usually expected to have converted to a sputum-negative status within the first few months of starting treatment. Persistence of culture positivity beyond that point, or close to the expected end of the intensive phase when injectable agents are in use, is a trigger for a review of the regimen and performance of DST. 2/11/2020 35

36. Longer MDR-TB Regimens Social support to enable adherence to treatment is very important to ensure a patient- centred approach to the delivery of care. Implementation of active TB drug safety monitoring and management (aDSM) whenever any MDR-TB treatment is given is a standard of care that is recommended to improve early management of drug-related harms, and contribute to global knowledge on drug safety 2/11/2020 36

37. Longer MDR-TB Regimens Preventing treatment interruption is important to increase the likelihood of treatment success. Measures to support patient adherence, either by facilitating patient visits to health-care facilities or home visits by health-care staff 2/11/2020 37

38. Duration of … In MDR/RR-TB patients on longer regimens, a total treatment duration of 18–20 months is suggested for most patients; the duration may be modified according to the patient’s response to therapy In MDR/RR-TB patients on longer regimens, a treatment duration of 15–17 months after culture conversion is suggested for most patients; the duration may be modified according to the patient’s response to therapy In MDR/RR-TB patients on longer regimens containing amikacin or streptomycin, an intensive phase of 6–7 months is suggested for most patients; the duration may be modified according to the patient’s response to therapy 2/11/2020 38

39. standardized shorter MDR-TB regimen In MDR/RR-TB patients : who have not been previously treated for more than 1 month with second line medicines used in the shorter MDR-TB regimen in whom resistance to fluoroquinolones and second-line injectable agents has been excluded, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens 2/11/2020 39

40. Exclusion for Short MDR-TB regimen resistance to or suspected ineffectiveness of a medicine in the shorter MDR-TB regimen (except isoniazid resistance) 2. exposure to one or more second-line medicines in the regimen for >1 month (unless susceptibility to these second-line medicines is confirmed); 3. intolerance to any medicine in the shorter MDR-TB regimen or risk of toxicity from a medicine in the shorter regimen (e.g. drug–drug interactions); 2/11/2020 40

41. Exclusion for Short MDR-TB regimen 4. pregnancy; 5. disseminated, meningeal or CNS TB ; 6. any extrapulmonary disease in HIV patients. 2/11/2020 41

42. Subgroup Considerations People living with HIV Resistance in addition to isoniazid and rifampicin Pregnant women Exclusive extrapulmonary disease 2/11/2020 42

43. Longer or shorter? 2/11/2020 43

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45. Short regimen MDR-TB If the shorter regimen is used, the GDG recommended that: there be shared decision-making between the clinician and patient when choosing between a shorter and a longer regimen; 2. before the start of treatment, emphasis be placed on DST for fluoroquinolones and secondline injectable agents, as well as other regimen components where possible (e.g. pyrazinamide, mutations associated with isoniazid and ethionamide resistance); 3.kanamycin be replaced by amikacin (based on evidence from the comparative effectiveness of these two injectable agents) 4. other exclusion criteria be observed 2/11/2020 45

46. Short regimen MDR-TB DOT with patient support be implemented to help patients complete the shorter MDR-TB regimen by clinic staff or family members or other members of the community, depending on the local circumstances 2/11/2020 46

47. Monitoring patient response to MDR-TB treatment using culture In MDR/RR-TB patients on longer regimens, the performance of sputum culture in addition to sputum smear microscopy is recommended to monitor treatment response It is desirable for sputum culture to be repeated at monthly intervals. 2/11/2020 47

48. Monitoring… 2/11/2020 48

49. Monitoring patient response… Subgroup Considerations : Extrapulmonary disease HIV negative individuals Patients on the shorter MDR-TB regimen 2/11/2020 49

50. Monitoring Adverse Drug Reactions ADR Responsible drug Monitoring Gastrointestinal Pto/Eto, PAS, H, E, Z, Cfz, Bdq,Lzd,FQ Monthly AST,ALT and serum electrolyte,CBC,RFT Dermatologic rxns All Clinical Cardiac FQs, Bdq, Dlm , Cfz Electrolyt and ECG/Monthly Hematologic Lzd CBC Neurotoxicity Lzd, Cs, H, FQs, SLIs, Pto/Eto, E. Clinical Ototoxicity Km, Am, Cm Serial audiometry Ophthalmic toxicity Lzd,E,Csf,H Monthly visual acuity test Nephrotoxicity Km, Am, Cm, E, Z, Cs. RFT,ECG,SE/every 2 weeks Musculoskeletal Z, FQs, Bdq Clinical Endocrine Pto/ Eto+PAS , Pto/ Eto , PAS Monthly TSH 2/11/2020 50

51. Start of ART in patients on second-line antituberculosis regimens Antiretroviral therapy is recommended for all patients with HIV and DR-TB requiring secondline antituberculosis drugs, Large beneficial effects and a very high mortality when ART is not employed 2/11/2020 51

52. Surgery for patients on MDR-TB treatment E lective partial lung resection may be used alongside a recommended MDR-TB regimen Prognosis appeared to be better when was performed after culture conversion Partial lung resection for patients with MDR-TB is to be considered only under conditions 2/11/2020 52

53. Care and support for patients with MDR/RR-TB Health education and counseling on the disease and treatment adherence A package of treatment adherence interventions may be offered ambulatory care rather than models of care based principally on hospitalization A decentralized model of care is recommended 2/11/2020 53

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55. XDR-TB Treatment A drug with high bactericidal and high sterilising activity, such as bedaquiline, to be administered throughout treatment duration. A drug with high early bactericidal activity, such as linezolid, to protect Bdq and to prevent resistance amplification. A companion drug with bactericidal activity, such as delamanid, to protect the action of the other drugs and to prevent resistance amplification 2/11/2020 55

56. XDR-TB … A sterilising drug, such as clofazimine, to prevent relapse after treatment cessation. In case of resistance to clofazimine, cycloserine is an option. Pyrazinamide may be added because of its sterilising activity. High-dose isoniazid should also be added in the intensive phase for its bactericidal properties, except in case of confirmed high H resistance 2/11/2020 56

57. Future trends? 2/11/2020 57

58. References: WHO consolidated guidelines on drug-resistant tuberculosis treatment,2019 Field guide for the management of drug resistant tuberculosis,2018 Drug-Resistant Tuberculosis,a survival guide for clinicians,3 rd edition European journal of respiratory medicine WWW.thelancet.com 2/11/2020 58

59. Thank you!!! 2/11/2020 59