Multi drug resistant Tuberculosis managemnt

This is a very important document for recent and updated knowledge on mdr tb management

1. Seminar on MDR TB management Presenter - Dr.Amdemeskel M. (IMR2 ) Moderator - Dr. Amsalu (MD, Internist, consultant PCCM) Sept 25, 2023

2. Outline Introduction Definitions Epidemiology Management Monitoring References

3. Introduction Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of MDR strains of M.tuberculosis , Drug-resistant tuberculosis was recognized shortly after the introduction of effective chemotherapy in the late 1940. 4/6/2024 3

4. Cont … Strains of M. tuberculosis resistant to individual drugs arise by spontaneous point mutations in mycobacterial genome, that occur at low but predictable rates ( 10–7–10–10 for the key drugs) Resistance to rifampin is associated with mutations in the rpoB gene in 95% of cases . 4/6/2024 4

5. Cont … That to isoniazid with mutations mainly in the katG gene (50–95% of cases) and the inhA gene promoter region up to 45 %. That to pyrazinamide in the pncA gene (up to 98 %) ,that to ethambutol in the embB gene (50–65 %) That to the fluoroquinolones in the gyrA – gyrB genes (75–95 %) and that to the aminoglycosides mainly in the rrs gene (up to 80 %). 4/6/2024 5

6. Cont … Since resistance to various TB drugs is not genetically linked, it is uncommon for a bacillus to be resistant to more than one TB drug. For instance, one would require bacillary load of 2.56*108 x 2.25*1010 = 5.76*1018 to find one bacillus that is resistant to the combination of INH and RIF. 4/6/2024 6

7. Definitions Drug-resistant TB refers to TB caused by an isolate of Mycobacterium tuberculosis that is resistant to one or more antituberculous drugs. ● Monoresistant - single antituberculous agent. ●Poly-resistant- more than one antituberculous agent; either isoniazid or rifampin but not both. ●Pre-extensively drug-resistant TB (pre-XDR-TB)- INH and rifampin as well as fluoroquinolones . 4/6/2024 7

8. Cont … ● Extensively drug-resistant TB (XDR-TB)- resistant to at least INH, rifampin, and fluoroquinolones as well as at least one additional group A drug( bedaquiline and linezolid). ●Totally drug-resistant TB (TDR-TB)- all locally tested medications, did not include less frequently used agents ( cycloserine , terizidone , clofazimine , linezolid, or carbapenems ) or more recently introduced agents ( bedaquiline , pretomanid , and delamanid ). 4/6/2024 8

9. Cont … Multidrug-resistant TB (MDR-TB) refers to TB caused by an isolate of M. tuberculosis that is resistant to both INH and rifampin and possibly additional agents. ● Primary drug resistance- in a patient who has not previously received antituberculous therapy. ● Secondary drug resistance- during or following antituberculous therapy in patients who had previously had drug-susceptible TB. 4/6/2024 9

10. Case definitions Presumptive DR-TB : refers to a person who presents with clinical features suggestive of TB or diagnosis of active TB and with known risk to harbor Drug resistant TB. Bacteriologically confirmed DR-TB : refers to those cases with documented laboratory DST results for DR-TB or Rifampicin Resistant TB. Clinically diagnosed DR-TB case : refers to a person who is diagnosed to have DR-TB without documented DST result . 4/6/2024 10

11. Epidemiology Drug-resistant TB threatens global TB care and prevention and remains a major public health concern in many countries. According to the Global TB Report 2022, 10.6 million people are estimated to have fallen ill with TB in 2021. Globally, an estimated 3.6% of new TB cases and 18% of previously treated TB cases were having MDR/RR-TB in 2021 . Overall, total of 450,000 incident MDR/RR TB cases were estimated to be have emerged in 2021. 4/6/2024 11

12. Ethiopia Ethiopia is among the 30 High TB and TB-HIV burden Countries. W ith annual estimated TB incidence of 119/100,000 populations and death rate of 16 per 100,000 populations in 2021. The country has transitioned out of the list of the high burden countries for MDR/RR-TB in 2020. An estimated 1.1% of these new TB cases and 7.5% of previously treated TB cases had drug resistant TB in 2021 and an estimated 1800 MDR/RR-TB cases emerging in 2021. 4/6/2024 12

13. MDR-TB REGIMENS IN ETHIOPIA A. RR/MDR-TB Regimens 1. The 6-month bedaquiline , pretomanid , linezolid and moxifloxacin ( BPaLM ) regimen. 2. The 9-month all-oral Regimens ( Eto or Lzd containing) 3. Individualized Longer Regimens B. Hr -TB Regimen: 6 (H)RZE- Lfx 4/6/2024 13

14. The 6-month BPaL /M Regimen It is the newly recommended regimen in the treatment of RR/MDR-TB patients . It consists of 6-month bedaquiline , pretomanid , linezolid and moxifloxacin ( BPaLM ). DST for fluoroquinolones is strongly encouraged in people with MDR/RR-TB, and, R esults of the test should guide the decision on whether moxifloxacin can be retained or should be dropped from the regimen. 4/6/2024 14

15. TB-PRACTECAL 4/6/2024 15

16. Cont … TB-PRACTECAL was a multicentre , open-label, multi-arm, randomized, controlled, multistage, Phase 2–3 trial evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and repurposed anti-TB drugs (e.g. linezolid and clofazimine ) for the treatment of microbiologically confirmed pulmonary MDR/RR-TB. 4/6/2024 16

17. Zenix 4/6/2024 17

18. Cont … ZeNix was a Phase 3 partially blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid plus bedaquiline and pretomanid in individuals with pulmonary MDR/RR-TB and additional resistance to fluoroquinolones (with or without resistance to injectable agents) or those with treatment intolerant or nonresponsive MDR/RR-TB 4/6/2024 18

19. Cont … Briefly, data from an RCT (stage 2 of TB-PRACTECAL , corresponds to a phase 3 trial) showed much improved treatment success rates with the BPaLM regimen (89%) of 6 months duration compared with the current SoC regimens (52%), lower levels of treatment failure , death and loss to follow-up. Data from two trials ( TB-PRACTECAL and ZeNix ) suggested fewer adverse events with a linezolid dose of 600 mg while maintaining high efficacy. 4/6/2024 19

20. Eligibility Criteria for BPaLM The BPaLM / BPaL regimen is recommended for patients with MDR/RR-TB in the following situations P ulmonary TB or all forms of extrapulmonary TB, except TB involving the CNS, osteoarticular TB and disseminated ( miliary ) TB; Patient is aged 14 years or older; No known allergy to any of the BPaLM component drugs; 4/6/2024 20

21. Cont … N o evidence of resistance to bedaquiline , linezolid, delamanid or pretomanid , or Has not been previously exposed to any of the component drugs for 4 weeks or longer ; All people regardless of HIV status; N o XDR-TB according to the 2021 WHO definitions (21); and Patient is not pregnant or breastfeeding or, if the patient is a premenopausal woman, Willing to use effective contraception. 4/6/2024 21

22. Cont … When exposure to the component drugs is greater than 4 weeks in duration, resistance to the specific medicines with such exposure has to be ruled out to continue with BPaLM . In cases of possible fluoroquinolone resistance it is best to initiate a BPaLM regimen until DST for fluoroquinolones is available. If the result of fluoroquinolone DST is never determined or not done, the BPaLM regimen should be used throughout. 4/6/2024 22

23. Cont … I t is reasonable to omit the moxifloxacin and use the BPaL regimen for treatment A treatment with a fluoroquinolone failed or T he patient is a close contact of a fluoroquinolone -resistant case and was unlikely to get TB from another source, or I f patient is coming from areas with a high prevalence of fluoroquinolone resistance and in the absence of DST 4/6/2024 23

24. Cont … In Ethiopia, the rate of flouro -quinolone resistance among TB and RR/MDR-TB patients is low. Any FQ resistance among RR/MDR-TB patients was detected in only about 2.7% cases; and among DS-TB cases, no FQ resistance was detected ( Source: DRS 2019). 4/6/2024 24

25. Cont … Considerations in the use of the 6-month BPaL /M Regimen In patients with a known history of cardiac disease. Populations of Concern include those with A baseline corrected QT interval by Fridericia ( QTcF ) of more than 450 ms , History of cardiac disease with syncopal episodes, significant arrythmias , Personal or family history of congenital QTc prolongation, torsade de pointes ( tdP ), Bradyarrhythmia or cardiomyopathy. 4/6/2024 25

26. Cont … Although bedaquiline and moxifloxacin can prolong QTc , reports of serious adverse events and mortality are rare. Linezolid is associated with anaemia and thrombocytopenia , and care should be taken in patients with anaemia . Care should also be taken for patients who have A Hgb level of less than 8 g/ dL or a PLT less than 75 000/mm3. Consideration of a linezolid sparing 9-month or longer regimen may be a safe option. 4/6/2024 26

27. Cont … Patients with liver enzymes at levels>/=3X ULN were excluded from both the ZeNix and TB-PRACTECAL trials because bedaquiline and pretomanid are both associated with increases in liver enzymes . Linezolid is associated with peripheral neuropathy ; therefore, those with pre-existing peripheral neuropathy of Grade 3–4 should be treated with caution when commencing the BPaLM / BPaL regimen . 4/6/2024 27

28. Cont … When initiating the regimen , Ensure that patients have not had previous exposure to bedaquiline , linezolid, pretomanid or delamanid for more than 1-month. When exposure is greater than 1 month , these patients may still receive these regimens if resistance has been ruled out . A standardized treatment duration of BPaLM to 6 months (26 weeks or 180 days) is recommended. For BPaL , the possibility of an extension to a total of 9 months (39 weeks) if sputum cultures are positive between months 4 and 6 is suggested. 4/6/2024 28

29. Cont … Recommended dose for medicines in the BPaLM Regimen 4/6/2024 29

30. Cont … Dose modifications for bedaquiline , moxifloxacin and pretomanid are not allowed. Given the lack of evidence for the use of other fluoroquinolones , the substitution of moxifloxacin with levofloxacin is not recommended. Dose modification of linezolid should be avoided if possible in the first 9 weeks of therapy. If there is significant toxicity associated with linezolid, including optic neuritis, peripheral neuropathy or myelo -suppression. The dose of linezolid can be reduced to 300 mg or can be discontinued. 4/6/2024 30

31. Cont … BPaL regimen The BPaL regimen can be prescribed for those who have proven fluoroquinolone resistance . The BPaL regimen uses the same doses for pretomanid , bedaquiline and linezolid as the BPaLM regimen. If resistance to bedaquiline , linezolid or pretomanid is confirmed or suspected, the treatment is considered to have failed and individuals should be referred to the longer individualized regimen. 4/6/2024 31

32. Linezolid dosing in the BPaLM / BPaL regimen Linezolid is by far the most toxic drug in the BPaLM and BPaL regimens; It requires significant monitoring and at times a mitigation strategy to reduce adverse effects. Action should be taken in the following manner for the common toxicities associated with linezolid: 4/6/2024 32

33. Cont … For optic neuritis diagnosed at any grade, permanent discontinuation of linezolid is indicated. For peripheral neuropathy Grade 2, reduce the dose of linezolid to 300 mg per day with a possible drug holiday for 1–2 weeks before dose reduction; For peripheral neuropathy Grade 3 or 4, in most cases permanent suspension of linezolid will be needed; 4/6/2024 33

34. Cont … Myelosuppression (even of Grade 3 or 4) is often reversible with a short 1-to-2-week drug holiday followed by reducing the dose of linezolid to 300 mg per day; Severe anaemia may need to be treated with transfusions or erythropoietin. 4/6/2024 34

35. Cont … If either bedaquiline or pretomanid needs to be permanently discontinued, the entire BPaLM / BPaL regimen should also be discontinued; If linezolid is permanently discontinued during the initial 9 consecutive weeks of treatment , the entire regimen should be discontinued; If linezolid is withheld in the later weeks of the regimen, with the total remaining duration of the regimen not exceeding 8 weeks , the regimen can be considered to be completed with the remaining component drugs. 4/6/2024 35

36. Cont … The scenario when BPaLM / BPaL regimen should be declared a failure and an individualized longer regimen should be used instead when:- More than 2 weeks of consecutive treatment interruption of all medicines in the regimen occurs; or More than 4 weeks cumulative of nonconsecutive treatment interruption of all medicines in the regimen occurs 4/6/2024 36

37. Cont … Discontinuation of the BPaL /M regimen Treatment failure , Inability to use linezolid for enough time owing to adverse effects Pregnancy that occurs during treatment 4/6/2024 37

38. Cont … Treatment monitoring in BPaLM Regimen Response to treatment should be monitored on the basis of monthly sputum smear microscopy and culture (ideally at the same frequency). Given that the BPaLM / BPaL regimen is a new and shorter regimen that includes novel medications , It is also important to follow up patients after the completion of treatment, to ensure that there is no treatment relapse or unexpected adverse events. 4/6/2024 38

39. Cont … It is advisable to send sputum specimens for culture and DST more frequently (at least every 2 weeks) during the month 4-6 treatment period to improve results availability for early management decisions . The updated definition of treatment failure includes situations where a patient’s treatment regimen has been terminated or permanently changed to a new treatment regimen, due to any of the following: 4/6/2024 39

40. Cont … Adverse drug reactions Poor bacteriological or clinical response to treatment Acquired drug resistance to drugs in the BPaLM / BPaL regimen 4/6/2024 40

41. The 9-month all-oral regimen The use of the 9-month all-oral regimen rather than longer (18-month) regimens is recommended in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. The 9-month regimens can be used in patients not eligible for the shorter . They represent a preferred treatment option over the longer regimens 4/6/2024 41

42. Cont … Bedaquiline (used for 6 months ) + levofloxacin/ moxifloxacin , ethionamide , ethambutol , isoniazid (high dose), pyrazinamide and clofazimine for 4 months Could be extended to 6month if + ve at end of 4month. Levofloxacin or moxifloxacin , clofazimine , ethambutol and pyrazinamide (for 5 months). Ethionamide can be replaced by 2 months of linezolid (600 mg daily). 4/6/2024 42

43. Eligibility Criteria for the 9-month all-oral regimen Those with no documented resistance or suspected ineffectiveness of bedaquiline , clofazimine , or ethionamide or linezolid (whichever is considered for inclusion in the regimen ). Those with no exposure to previous treatment with the drugs or resistance ruled out. Those with no extensive or severe TB disease and no severe extrapulmonary TB. 4/6/2024 43

44. Cont … Women who are pregnant or breastfeeding: these patients may be considered eligible for the linezolid-containing 9-month regimen , but they should not receive the 9-month regimen containing ethionamide . Children and adults without bacteriological confirmation of TB or resistance patterns but who require MDR/RR-TB treatment based on clinical signs and symptoms of TB (including radiological findings) and history of contact with someone with confirmed MDR/RR-TB. 4/6/2024 44

45. Linezolid toxicity Optic neuritis and peripheral neuropathies beyond 2 month. Myelosuppression is significantly dose dependent and occurs within 2 months. 4/6/2024 45

46. Assessment of extent and severity of TB disease The extent of a patient’s TB disease is important in determining appropriate regimen options. Extensive (or advanced) pulmonary TB disease Bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged below 15 years, the presence of cavities or bilateral disease on chest radiography . 4/6/2024 46

47. Cont … Severe extrapulmonary TB Is defined as the presence of miliary TB or TB meningitis. In children aged below 15 years, extrapulmonary forms of disease other than lymphadenopathy are considered to be severe. 4/6/2024 47

48. Composition and duration of the 9-months regimen 4/6/2024 48

49. Longer MDR/RR-TB treatment regimen Designed based on the new grouping of medicines (Group A, B, C) May be used in MDR/RR-TB patients who are not eligible for treatment with either the 6-month BPaLM regimen or the 9-month all-oral regimens due to resistance , toxicity, contra-indications. Medicines recommended for use in longer (18-20 months) MDR/RR-TB regimen ( LTR) are regrouped differently based on recently available efficacy and safety data. 4/6/2024 49

50. Grouping of Medicines used in longer RR/MDR-TB Regimens 4/6/2024 50

51. LTR 4/6/2024 51

52. Eligibility Criteria for longer MDR/RR-TB Regimen A longer treatment regimen should be proposed mainly when the BPaLM / BPaL or 9-month all-oral regimen cannot be used. Severe extrapulmonary TB . Additional resistance to key medicines of the BPaLM / BPaL regimen ( except moxifloxacin ) or the 9-month all-oral regimen. Lack of response to shorter treatment regimens. 4/6/2024 52

53. Cont … Drug intolerance to the component medicines of the BPaLM / BPaL regimen (except moxifloxacin ) or 9 months shorter all-oral treatment regimen. Pregnant and lactating women who could not benefit from the 9-month shorter all-oral regimen or children aged below 14 years who could not be treated with BpaLM / BpaL or who, for any reason, cannot opt for a 9-month regimen. Longer regimen could also be considered as an option for patients with low BMI (< 17 kg/m2 ), altered hepatic enzymes ( 3X ULN), baseline anaemia ( Hgb <8 g/ dL ), thrombocytopenia (PLT <150 000/mm3) or pre-existing peripheral neuropathy of Grade 3–4. 4/6/2024 53

54. Cont … Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on longer regimens . If 4 Group A and B agents are included and there is confidence in all of them then Group Cagents are not needed. If 3 Group A and B agents are included and there is confidence in all of them then at least one Group C agent is added. If 2 Group A and B agents are included and there is confidence in all of them then at least three Group C agents are added. 4/6/2024 54

55. Cont … Duration of the longer regimen The total length of a long treatment regimen is 18 to 20 months . The duration may be modified according to the patient’s response to therapy. In MDR/RR-TB patients on longer regimens, treatment duration of 15–17 months after culture conversion is suggested for most patients. 4/6/2024 55

56. Cont … 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 all-oral longer MDR-TB regimens have no intensive phase. The duration of use of different medicines will depend on their C linical indication, P atient tolerability ( e.g. linezolid used for as long as no serious adverse event emerges) and I ndividual treatment response (e.g. culture negativity), U ntil completion of the expected total duration of treatment or time after culture conversion. 4/6/2024 56

57. Treatment of Hr -TB In patients with confirmed rifampicin-susceptible, isoniazid resistant tuberculosis,treatment with rifampicin, ethambutol , pyrazinamide and levofloxacin is recommended for a duration of 6 months. In patients with confirmed rifampicin-susceptible, isoniazid resistant tuberculosis, it is not recommended to add streptomycin or other injectable agents to the treatment regimen. Hr -TB Regimen: 6(H)REZ- Lfx 4/6/2024 57

58. Cont … Eligibility Criteria for Hr -TB Regimen The Hr -TB regimen is recommended once isoniazid resistance has been confirmed and rifampicin resistance excluded . It is not advisable to give a regimen for Hr -TB unless isoniazid resistance is confirmed or Highly suspected (e.g. confirmed TB patient who is the close contact of a documented Hr -TB case) The regimen is also likely to be effective in patients with extrapulmonary Hr -TB; however, consultation with appropriate specialists is advised 4/6/2024 58

59. Adjuvant Therapies in DR TB Corticosteroids MDR-TB patients with severe respiratory insufficiency, or central nervous system or pericardial involvement . Other severe forms of EPTB (pericardium, bone, joints) will need individualized regimen. 4/6/2024 59

60. Cont … Pyridoxine supplementation For the period of the whole treatment duration due to underlying malnutrition and to prevent Isoniazid or cycloserine or linezolid assd neurological side-effects . Surgery for DR TB Surgery as an adjunct to chemotherapy for patients with localized disease with sufficient pulmonary reserve can significantly improve outcomes. 4/6/2024 60

61. Cont … Indications :- Failure to absence of any radiological and/or bacteriological improvements during the initial three to four months of chemotherapy ; Recurrent Persistent positivity of sputum-smear or sputum-culture of positive cultures during MDR-TB treatment. Relapse following completion of MDR-TB treatment. 4/6/2024 61

62. Cont … Irreversible TB progression, despite adequate anti-TB chemotherapy Localized disease amenable to surgery High probability of failure of medical therapy or relapse, Extensive bilateral disease is a contraindication to surgery. 4/6/2024 62

63. Cont … For complications Hemoptysis , tension pneumothorax, Bronchiectasis, Aspergilloma , Pneumothorax, Broncho -pleural fistula, Empyema. Constrictive pericarditis, Abscesses 4/6/2024 63

64. Cont … Contraindications of surgery Extensive cavitary lesion of the both lungs; Impaired pulmonary function test; FEV1 <1.5L in cases of lobectomy and less than 2.0 L where pneumonectomy is planned; Cor pulmonale /pulmonary-heart failure III–IV (functional classification of the New York Hart Association); BMI up to 40–50% of the normal range; Severe comorbidity 4/6/2024 64

65. Treatment Monitoring and Follow Up in MDR/RR-TB Every MDR/RR-TB Patient should undergo appropriate follow-up at baseline, during and after treatment , including clinical evaluation, bacteriological and laboratory testing. Each MDR-TB patient should be monitored closely for signs of both treatment efficacy and adverse effects of the medications. The responsible clinician should assess clinical, microbiologic, and radiologic response to treatment, measure weight, assess possible adverse reactions , and encourage the patient to continue treatment. 4/6/2024 65

66. Cont … Clinical history Resolution or worsening of symptoms of TB Asses for adherence Symptoms for drug adverse events Systematic assessment for co-morbid illness Reproductive age women: Assess for Pregnancy, assess FP need 4/6/2024 66

67. Cont … Physical examination Laboratory monitoring Are important for documenting response and identifying complications earlier Smear, Culture, Culture-based FLD DST, Culture-based SL DST,CBC,RFT,LFT,ECG,Serum electrolyte, Pregnancy test Chest X-Ray 4/6/2024 67

68. Cont … More frequent monitoring Elderly people, P atients infected with HIV, A ffected by HBV- or HCV-related hepatitis, Diabetes mellitus, with moderate to severe hepatic or renal impairment, or Receiving specific drug combinations (i.e. bedaquiline and delamanid ) 4/6/2024 68

69. Cont … Post treatment monitoring Assess for relapse Monitor adverse events like neuropathy, ototoxicity, hypothyroidism and psychosis. Assess and manage sequelae of DR TB like bronchiectasis, pneumothorax, lung fibrosis, cor pulmonale . 4/6/2024 69

70. Cont … Once the patient has completed the course of treatment the patient will be assessed every 6 months for at least 2 years. Clinical history and focused physical examination Body weight and anthropometry Sputum smear examination and culture Chest X-ray DST (if culture result is positive) 4/6/2024 70

71. References Harrison’s Principles of Internal Medicine 21st edition . UpToDate . online WHO consolidated guidelines on TB, module 4: treatment of drug resistant TB 2020 FDRE Ministry of Health National TB Control Program-Clinical and Programmatic Management of Drug Resistant TB in Ethiopia 2023. 4/6/2024 71

72. 4/6/2024 72 Thank you!