Approach to patient with MDR-TB - by Dawit.pptx

Mdr Tb

1. Management of drug resistant TB By Dr. Dawit H (IMR3) Moderator Dr. Anteneh , MD, Internist, ID subspecialist

2. Outline Introduction Epidemiology Pathophysiology and risk factors for MDR TB Diagnosis Treatment, Surgical management Monitoring 12/4/2023 2

3. Introduction Approximately 500,000 cases of MDR-TB occur in the world annually, representing nearly 5% of the world’s annual TB burden

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10. Resistance associated with mutations genes Strains of M. tuberculosis resistant to individual drugs arise by spontaneous point mutations in the mycobacterial genome that occur at low but predictable rates ( 10 ᶺ 7 to10 ᶺ 10 for the key drugs). R ifampin ; rpoB gene in 95% of cases , isoniazid; katG gene (50–95% of cases) and the inhA gene promoter region (up to 45%), Pyrazinamide; pncA gene (up to 98%), Ethambutol : embB gene (50–65%), T he fluoroquinolones ; gyrA – gyrB genes (75–95%), and The aminoglycosides mainly in the rrs gene (up to 80%); 12/4/2023 10

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14. The most important predictors of drug-resistant TB are; A previous episode of TB treatment Persistent or progressive clinical and/or radiographic findings while on first-line TB therapy Residence in or travel to a region with high prevalence of drug-resistant TB Exposure to an individual with known or suspected infectious drug-resistant TB 12/4/2023 14

15. The clinical manifestations and radiographic features of drug-resistant TB are comparable with those of drug-susceptible TB 12/4/2023 15

16. EMPIRIC TREATMENT FOR DRUG-RESISTANT TB The decision to treat empirically for drug-resistant TB , pending conventional, culture-based drug susceptibility data depends on the severity of ; clinical illness (smear positivity, presence of cavitary disease, extrapulmonary disease) and the degree of suspicion for drug-resistant TB 12/4/2023 16

17. When to pursue empiric treatment for drug-resistant TB   Patients for whom an empiric treatment regimen for drug-resistant disease may be warranted include: Patients with treatment failure (acid-fast bacilli sputum culture positive after four months of therapy) Patients with relapse (recurrent TB after apparent cure) Patients with exposure to an individual with infectious drug-resistant pulmonary TB Patients with residence in or travel to a region with high prevalence of drug-resistant TB 12/4/2023 17

18. Isoniazid only resistant tuberculosis 11% (range, 6.5–15%) of all incident cases of TB had isoniazid-resistant and rifampicin-susceptible TB 12/4/2023 18

19. Isoniazid monoresistance Option 1 : Daily  rifampin ,  ethambutol ,  pyrazinamide , and  levofloxacin  for six months Option 2 : If the patient does not tolerate  pyrazinamide , a regimen consisting of  rifampin ,  ethambutol , and a FQ for 9 to 12 months may be used fluoroquinolone susceptibility should be confirmed The addition of an FQ to a 6-month RIF-EMB-PZA regimen tended to reduce the number of death and the acquisition of RIF resistance 12/4/2023 19

20. Rifampicin-resistant TB Any patient with RR-TB in whom HrTB is absent or unknown, needs to be treated with a recommended MDR-TB regimen The regimen could be a shorter/longer all-oral bedaquiline MDR-TB regimen RRTB is considered a marker for other drug resistances TB Rifampin resistance is considered a surrogate for MDR-TB because rifampin monoresistance is rare 12/4/2023 20

21. Monoresistance to other agents Pyrazinamide  – Patients with pyrazinamide monoresistance should be treated with INH and  rifampin  for nine months. This combination has a success rate >96 percent in large trials Many isolates with pyrazinamide monoresistance reflect  M. bovis   disease Monoresistance to  ethambutol ,  streptomycin , or second-line agents is of little clinical significance; patients with disease caused by these isolates may be treated as for drug-susceptible TB 12/4/2023 21

22. TREATMENT OF POLYRESISTANT TB The Patients with TB resistant to INH and  ethambutol  should be treated with  rifampin ,  pyrazinamide , and a fluoroquinolone ( levofloxacin  or  moxifloxacin ) for six to nine months. Patients with TB resistant to INH and  pyrazinamide  should be treated with  rifampin ,  ethambutol , and a fluoroquinolone ( levofloxacin  or  moxifloxacin ) for 9 to 12 months. Patients with TB resistant to INH,  ethambutol , and  pyrazinamide  should be treated with  rifampin , a fluoroquinolone , and one or two additional oral agents to which the isolate is susceptible (possible additional agents include ethambutol ,  linezolid , or  clofazimine ; use of  bedaquiline  with a rifamycin is contraindicated) for 9 to 12 months. 12/4/2023 22

23. Treatment of MDR/Rifampicin-resistant TB Available regimens 6-month treatment regimens: BPaL or BPaLM  composed of bedaquiline , pretomanid , linezolid (600 mg) and moxifloxacin ( BPaLM ) 9-month all-oral regimen : consists of ( i ) intensive phase: bedaquiline in combination with FQ (levofloxacin or moxifloxacin ), ethionamide (or linezolid at the dosage of 600 mg daily), ethambutol, high-dose isoniazid, pyrazinamide and clofazimine (ii) continuation phase: fluoroquinolones, clofazimine , ethambutol, and pyrazinamide longer regimens (18-20 months): based on the WHO drug grouping A, B, and C 12/4/2023 23

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32. shorter all-oral Bedaquiline contacting RR/MDR TB offered to patients ’; with confirmed MDR/RR-TB (at least confirmed resistance to rifampicin), for whom resistance to FQ has been ruled out mutations in either inhA or katG genes (not both ) The presence of both the inhA and katG mutations suggests that INH at high dose and thioamides are not effective ( NO short regimen ) No previous 2 nd line TB drug exposure >1 month( unless DST is done ) No severe extrapulmonary TB disease/extensive disease Not pregnant Children> 6 years 12/4/2023 35

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38. Ethiopian 2021 guidline Reccomendation 12/4/2023 41

39. Shorter regimens in Special populations PLHIV - The shorter all-oral bedaquiline-containing MDR-TB regimen can be used in PLHIV, including those who are receiving ART provided that other eligibility criteria are met drug–drug interactions between moxifloxacin and clofazimine VS efavirenz and bedaquiline (either avoid or use with caution ), because of Efavarenz increases Bedaquiline exposure children -below 6 years, bedaquiline is not recommended by WHO 12/4/2023 42

40. … Pregnant and lactating women - not eligible for treatment with an all-oral Bdq containing shorter RR/MDR-TB regimen The regimen contains ethionamide , which is usually CI in pregnancy because animal studies have shown an adverse effect on the fetus 12/4/2023 43

41. … Rifampicin-resistant TB without MDR-TB : All patients with rifampicin-resistant TB in whom FQ resistance is not confirmed may be treated with the shorter all-oral bedaquiline-containing MDR-TB treatment regimen provided the eligibility criteria are met Extensive TB disease or severe extrapulmonary TB disease is an exclusion criteria 12/4/2023 44

42. Monitoring for all-oral Bedaquiline containing MDR/RR-TB Regimen The shorter all-oral bedaquiline regimen may need to be switched to a longer MDR-TB regimen when : DST results show resistance to key medicines in the shorter regimen lack of response to treatment (e.g. no sputum smear conversion from positive to negative by 6 months of treatment ) treatment interrupted for 2 months or more after being treated for more than 1 month; or another disqualifying criterion emerges Response to treatment is monitored on the basis of monthly sputum smear microscopy&culture , ideally at the same frequency 12/4/2023 45

43. Longer regimens for MDR/RR-TB the longer regimen is preferably given to those MDR/RR-TB patients who are not eligible for shorter all-oral regimens, including those with quinolone resistance and If rifampicin resistance is detected, rapid molecular tests for resistance to isoniazid and fluoroquinolones should be performed 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. ( Conditional recommendation, very low certainty in the estimates of effect ) 12/4/2023 46

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45. where possible, regimens be composed of all three Group A agents and at least one Group B agent At least three agents are continued for the remaining duration of treatment if bedaquiline is stopped after 6 months .

46. MDRTB.. If only one or two Group A agents can be used, both Group B agents are included If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it The all-oral longer MDR-TB regimens do not have intensive phase

47. For patients in whom two agents from Group A are more likely to be stopped before the end of treatment (e.g. pre-existing comorbidities require that both bedaquiline and linezolid be stopped early because of health risks), then starting with five effective agents rather than four may be advisable .

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51. Surgery in treatment of M/XDR-TB Surgery is considered as an adjunct to treatment with effective chemotherapy for patients with indications as it improves quality of life and chance of cure Generally, at least 2 months of therapy should be given before resection surgery, to decrease the bacterial infection in the surrounding lung tissue As an adjunct therapy it improves quality of life and chance of cure should be considered in patients with localized pulmonary disease that cannot be cured by medical treatment alone or when there are life-threatening complications (pulmonary hemorrhage, non-resolving pleural empyema, or extensive necrosis) 12/4/2023 54

52. Monitoring Every MDR/RR-TB patient should undergo regular follow-up during and after treatment including Clinical evaluation Bacteriological Laboratory testing Each MDR-TB patient should be monitored closely for signs of both treatment efficacy and adverse effects of the medications

53. Post treatment monitoring Post treatment monitoring is important to: 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 Once the patient has completed the course of treatment, the post-treatment follow-up assessments should be performed every three months for a period of at least one year

54. References Ethiopian MDRTB 2021 guideline Uptodate online WHO 2022 MDRTB guide line journals Harrison principle of medicine 21 st edition 12/4/2023 59

55. Thank You 12/4/2023 60