Recent update in MANAGEMENT OF TUBERCULOSIS.pptx

recent updates of tb

1. Recent Updates in T uberculosis Presented by : Dr . Malhar Pandya First Year Resident Pharmacology Department GMC, Bhavnagar U nder guidance by : Dr . Nutanbala Goswami 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 1

2. Outline Current scenario of TB First line Anti TB drugs Second line Anti TB drugs New drugs NTEP regimens BPaLM regimen 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 2

3. Current scenario of TB 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 3 The estimated 10.6 million people who fell ill with TB worldwide in 2022. An estimated 4,40,000 new cases of MDR TB occurs annually around the world.

4. Terminology Presumptive TB case : person with fever/cough/night sweats/weight loss for more than 2 weeks Drug sensitive TB(DSTB) : sensitive to all 1 st line Anti TB drugs Drug resistant TB (DRTB) : resistant to any of Anti TB drugs H – Mono resistant TB : only isoniazid (H) resistant Multi Drug resistant TB(MDR TB) : resistant to both isoniazid(H) AND rifampin(R) Extensively Drug resistant TB (XDR TB): (H + R resistant) + any FQ + any Group A drug (at least one of bedaquiline or linezolid) Pre XDR TB : (H + R resistant) + any FQ 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 4

5. Rifampin(Rifampicin) Mechanism of Action : Rifampin enters bacilli and binds to the β subunit of DNA-dependent RNA polymerase ( rpoB ).  suppresses in RNA synthesis. Mechanism of Resistance : Alteration of the target of this drug, rpoB , with resistance in 86% of cases due to mutations at codons 526 and 531 of the rpoB gene. Efflux pump induction and mutations in efflux pumps 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 5

6. Rifampin ADR : Harmless red-orange discoloration of skin, urine, feces, saliva, tears, and contact lenses Hypersensitivity reactions which present with a flu-like syndrome of fever, chills, and myalgias Hypersensitivity reaction is more common with intermittent dosing and among female 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 6

7. Pyrazinamide Mechanism of Action : Pyrazinamide is well known to be active only in acidic conditions D rug passively diffuses into mycobacterial cells, where M. tuberculosis pyrazinamidase (encoded by the pncA gene) deaminates pyrazinamide to pyrazinoic acid . P yrazinoic acid inhibits fatty acid synthesis . 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 7

8. Pyrazinamide Mechanisms of Resistance : mutations in pncA gene lead to expression of pyrazinamidase with reduced affinity for pyrazinamide, leading to decreased conversion of pyrazinamide to its active form. M. tuberculosis efflux pumps can cause resistance to pyrazinamid e ADR : Injury to the liver is the most serious side effect of pyrazinamide. Hepatotoxicity appears to be idiosyncratic, up to doses of at least 40 mg/kg . pyrazinamide inhibits excretion of urate, resulting in hyperuricemia, which may cause acute episodes of gout 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 8

9. Isoniazid ( isonicotinic acid hydrazide ) Mechanism of Action : Isoniazid enters bacilli by passive diffusion It must be activated by KatG , a multifunctional catalase-peroxidase produces 2 adducts : a nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl carrier protein reductase ( InhA ) and β- ketoacyl-acyl carrier protein synthase ( KasA ) , blocking synthesis of mycolic acid, an essential component of the mycobacterial cell wall, leading to bacterial cell death . 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 9

10. Isoniazid Mechanisms of Resistance: mutation or deletion of KatG which leads to high-level resistance overexpression of the genes for InhA which leads to g low-level resistance to INH and cross-resistance to ethionamide. ADR: Hepatitis, a major adverse effect of INH, is rare in children, but more common in older people and in alcoholics (chronic alcoholism induces CYP2E1 which generates the hepato toxic metabolite). If pyridoxine is not given concurrently, peripheral neuritis (most commonly paresthesias of feet and hands) Neuropathy is more frequent in slow acetylators and in individuals with diabetes mellitus, poor nutrition, or anemia. Other side effects are lethargy, rashes, mild anaemia and arthralgia 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 10

11. Ethambutol Mechanism of Action: Ethambutol inhibits arabinosyl transferase III, thereby disrupting the transfer of arabinose into arabinogalactan biosynthesis, which in turn disrupts assembly of the mycobacterial cell wall A rabinosyl transferases are encoded by embB genes Mechanisms of Resistance: In 30% to 70% of clinical isolates that are resistant to ethambutol, mutations are encountered in the ethambutol resistance–determining region of the embB gene Enhanced efflux pump activity may induce resistance to both INH and ethambutol 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 11

12. Ethambutol ADR : most important side effect is optic neuritis, resulting in decreased visual acuity and loss of red-green discrimination , incidence of this reaction is proportional to the dose and duration of ethambutol. Tests of visual acuity and Red green discrimination prior to the start of therapy and periodically thereafter are thus recommended. Recovery usually occurs when ethambutol is withdrawn but in some cases can be permanent. Pruritus, joint pain, GI upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucination. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 12

13. Second line drugs 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 13

14. Clofazimine Mechanism of Action : membrane disruption, inhibition of mycobacterial phospholipase A2 , inhibition of microbial K+ transport, generation of hydrogen peroxide, interference with the bacterial electron transport chain, and efflux pump inhibition. Clofazimine has both antibacterial activity and anti-inflammatory effects via inhibition of macrophages, T cells, neutrophils, and complement. Mechanisms of Resistance: Resistance has been associated with mutations in Rv0678, a repressor gene that affects the mmpS5-mmpL5 efflux pump; this is associated with cross-resistance to bedaquiline . 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 14

15. Clofazimine ADR: Abdominal pain, crystal deposition throughout the intestinal mucosa, liver, spleen, and abdominal lymph nodes was found Ichthyosis and discoloration of skin, eyes, and bodily secretions can be distressing or stigmatizing to patients. Clofazimine is also associated with prolongation of the QT interval on electrocardiogram (ECG). 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 15

16. Ethionamide Mechanism of Action: Ethionamide inhibits mycobacterial growth by inhibiting the activity of the inhA gene product, the enoyl-ACP (acyl carrier protein) reductase of fatty acid synthase II ,This is the same enzyme that activated INH inhibits. inhibition of mycolic acid biosynthesis and consequent impairment of cell wall synthesis. Mechanisms of Resistance: Mainly via changes in the enzyme EthA that activates ethionamide Mutations in the inhA gene or in its promoter lead to resistance to both ethionamide and INH 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 16

17. Ethionamide ADR: The most common reactions are anorexia, nausea and vomiting, gastric irritation, and a variety of neurological symptoms. Severe postural hypotension, mental depression, drowsiness, and asthenia are common. olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias , headache, restlessness, and tremors Pyridoxine (vitamin B6 ) may relieve or prevent the neurological symptoms, and its concomitant administration is recommended. Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence, menorrhagia, acne, metallic taste, and alopecia have also been observed. Hepatitis has been associated with the use of the ethionamide in about 5% of cases. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 17

18. Cycloserine and Terizidone Terizidone is a structural analogue of cycloserine , and the two drugs are used interchangeably. Mechanism of Action: Cycloserine and d-alanine are structural analogues; thus, cycloserine inhibits alanine racemase, which converts l-alanine to d-alanine, and d-alanine–d-alanine ligase, thereby stopping reactions in which d-alanine is incorporated into bacterial cell wall synthesis. Mechanisms of Resistance: mutations in alr , which encodes alanine racemase. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 18

19. Cycloserine and Terizidone ADR: Neuropsychiatric symptoms are common and occur in 50% of patients on 1 g/day , Because of the prevalence of these occurrences, the drug is sometimes referred to as “psycho-serine”. headache and somnolence to severe psychosis, seizures, and suicidal ideations Cycloserine is contraindicated in individuals with a history of epilepsy and should be used with caution in individuals with a history of depression 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 19

20. Bedaquiline Bedaquiline was discovered by Andries and colleagues in 2005 and was registered with the FDA in 2012 for the treatment of DR TB. Mechanism of Action: Bedaquiline acts by targeting subunit c of the ATP synthase of M. tuberculosis, leading to inhibition of the proton pump activity of the ATP synthase, thereby targeting bacillary energy metabolism. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 20

21. Bedaquiline Mechanisms of Resistance: Resistance is associated with mutations in D32V and A63P in the region of the gene encoding the membrane-spanning domain of the ATP synthase c subunit Resistance due to efflux pump mutations and their regulators also occurs and is associated with cross-resistance to clofazimine ADR: The most common side effects include nausea in 26% of patients and diarrhea in 13% of patients. Bedaquiline causes prolongation of the QT interval, driven by its M2 metabolite; thus, serial ECG monitoring is recommended. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 21

22. Bicyclic Nitroimidazoles: Delamanid and Pretomanid Pretomanid , discovered by Stover and coleagues in 2000 and D elamanid discovered by Matsumoto and colleagues in 2006 . Both are bicyclic nitroimidazo les that are being used in the treatment of XDR- and MDR-TB. Pretomanid is FDA-approved for the treatment of XDR-TB in combination with bedaquiline and linezolid. Delamanid is licensed by the European Medicines Agency for the treatment of MDR-TB. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 22

23. Bicyclic Nitroimidazoles: Delamanid and Pretomanid Mechanisms of Action: Pretomanid has two mechanisms of action First , under aerobic conditions, it inhibits M. tuberculosis mycolic acid and protein synthesis at the step between hydroxymycolate and ketomycolate which kills replicating bacteria . P retomanid requires activation by the bacteria via a nitroreduction step that requires a specific G6PD, FGD1 (NADP-dependent G6PD), and the reduced deazaflavin cofactor F420 encoded by Rv3547. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 23

24. Bicyclic Nitroimidazoles: Delamanid and Pretomanid Second , in nonreplicating persistent bacilli (NRPB), it generates reactive nitrogen species, which then augment the kill of intracellular NRPB by the innate immune system . In addition, direct poisoning of the respiratory complex in the NRPB leads to ATP depletion. Delamanid is also a prodrug that is activated by the same enzyme encoded by Rv3547 , Similarly, it also forms a reactive intermediate metabolite that inhibits mycolic acid production. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 24

25. Bicyclic Nitroimidazoles: Delamanid and Pretomanid Mechanisms of Resistance: Resistance of pretomanid arises from changes in the structure of FGD, which is due to a variety of point mutations in the fgd gene. Resistance of Delamanid has also been shown to be due to fgd1 and fbiA mutations . ADR: Delamanid can cause headaches and insomnia. It has a modest effect on the QT interval on ECG. Pretomanid has been associated with hepatotoxicity 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 25

26. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 26

27. Sutezolid (PUN-100480) Originator : John Hopkins University; Pharmacia Corporation Class : Oxazolidinones Mechanism of Action : I n  M . tb , the functional ribosomes are composed of 50S subunits (including 23S rRNA, 5S rRNA, and 35 proteins) and 30S subunits (including 16S rRNA and 22 proteins) oxazolidinone compounds inhibit bacterial protein synthesis at the initial stage of transformation by binding to the V domain of 23S rRNA  . Highest Development Phases : Phase II/III 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 27

28. Delpazolid (LCB01-0371) Originator : LegoChem Biosciences Class : Oxazolidinones Mechanism of Action : same as sutezolid 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 28

29. Contezolid (MRX-I) Originator : MicuRx Pharmaceutical Class : Oxazolidinones Mechanism of action : same as sutezolid A pproved for Skin and soft tissue infections anti-TB activity of MRX-I is comparable to that of linezolid, while MRX-I is less toxic in inhibiting bone marrow and monoamine oxidase  10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 29

30. Macozinone Originator : A. N. Bach Institute of Biochemistry; Ecole Polytechnique Federale de Lausanne. Inhibits synthesis of arabinogalactan (key component of the cell wall of M.Tuberculosis ) P hase 2 trail No antagonism with other anti-TB drugs 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 30

31. NTEP regimens DSTB : Where H = isonizide , R = rifampin , Z = pyrazinamide , E = ethambutol H – Mono resistant TB: Where O = levofloxacin , R = rifampin , Z = pyrazinamide , E = ethambutol 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 31 INTENSIVE PHASE CONTINUATION PHASE 2 MONTHS HRZE 4 MONTHS HRE For 6 MONTHS ZERO

32. Rifampin Resistant (RR TB) / MDR TB : Shorter MDR regimen 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 32 Start till 4 months 5 and 6 th month 7th till 9th month Bedaquiline ( Bdq ) Bedaquiline ( Bdq ) Levofloxacin ( Lfx ) Levofloxacin ( Lfx ) Levofloxacin ( Lfx ) Clofazamine ( Cfz ) Clofazamine ( Cfz ) Clofazamine ( Cfz ) Pyrazinamide (Z) Pyrazinamide (Z) Pyrazinamide (Z) Ethambutol (E) Ethambutol (E) Ethambutol (E) High dose Isoniazide ( hH ) Ethionamide ( eto ) (4-6) Bdq , Lfx , Cfz , Z, E , hH , eto INTENSIVE PHASE Lfx , Cfz , Z, E CONTINUATION PHASE

33. NTEP regimens XDR TB Regimen : Drugs : Linezolide (18 – 20 months) Levofloxacine (18 – 20 months) Cycloserine (18 – 20 months) Clofazamine (18 – 20 months) Bedaquiline (6 months) 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 33

34. BPaLM regimen WHO recommended a new 6 months BPaLM regimen for treating MDR TB in 2022. B: Bedaquiline , Pa: Pretomanid , L: Linezolid , M: Moxifloxacin Indication : MDR TB or pre XDR TB Those with confirmed pulmonary TB amd extra pulmonary TB ( except for TB involving CNS, osteoarticular , and miliary TB. Patients > 14 years of age 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 34

35. BPaLM regimen Dosage : Bedaquiline 100 mg tablet : 400 mg OD for 2weeks  200 mg 3 times/week OR 200 mg daily for 8 weeks  100 mg daily Pretomanid 200 mg tablet OD Linezolid 600 mg tablet OD Moxifloxacin 400mg tablet OD 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 35

36. BPaLM regimen Precautions : Linezolid should be continuously monitored due to risk of anemia , thrombocytopenia, optic neuritis, and peripheral neuropathy. Pretomanid has limited safety and hence this regime is contraindicated in pregnant and lactating women. U se cautiously in i ndividuals with CVS disease , elevated liver enzymes , or very low BMI. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 36

37. Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 37

38. M72/AS01E vaccine  M72/AS01E is a subunit candidate vaccine comprised of an immunogenic fusion protein (M72) derived from two  Mycobacterium tuberculosis  ( M.tb ) antigens (MTB32A and MTB39A), and the GlaxoSmithKline (GSK) proprietary adjuvant AS01E. M72/AS0 1E was  found  to be significantly protective against TB disease in a Phase IIb trial conducted in Kenya, South Africa and Zambia , in individuals with evidence of latent tuberculosis infection. The point estimate of vaccine efficacy was 49.7 % over approximately three years of follow-up 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 38

39. References Larkins-Ford J, Aldridge BB. Advances in the design of combination therapies for the treatment of tuberculosis. Expert opinion on drug discovery. 2023 Jan 2;18(1):83-97. Mi J, Gong W, Wu X. Advances in key drug target identification and new drug development for tuberculosis. BioMed Research International. 2022;2022(1):5099312. Ignatius EH, Dooley KE. New drugs for the treatment of tuberculosis. Clinics in chest medicine. 2019 Dec 1;40(4):811-27. Lienhardt C, Raviglione M, Spigelman M, Hafner R, Jaramillo E, Hoelscher M, Zumla A, Gheuens J. New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future. Journal of infectious diseases. 2012 May 15;205(suppl_2):S241-9. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 39

40. References Goswami ND, Ashkin D, Haley CA. Pretomanid in the treatment of patients with tuberculosis in the United States. New England Journal of Medicine. 2022 Sep 1;387(9):850-2. Occhineri S, Matucci T, Rindi L, Tiseo G, Falcone M, Riccardi N, Besozzi G. Pretomanid for tuberculosis treatment: an update for clinical purposes. Current research in pharmacology and drug discovery. 2022 Jan 1;3:100128. Holger DJ, Althubyani A, Morrisette T, Rebold N, Tailor M. Updates in pulmonary drug‐resistant tuberculosis pharmacotherapy: A focus on BPaL and BPaLM . Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2024 Mar;44(3):268-82. James LP, Klaassen F, Sweeney S, Furin J, Franke MF, Yaesoubi R, Chesov D, Ciobanu N, Codreanu A, Crudu V, Cohen T. Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis. Plos Medicine. 2024 May 3;21(5):e1004401. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 40

41. References Broxmeyer L, Sosnowska D, Miltner E, Chacón O, Wagner D, McGarvey J, Barletta RG, Bermudez LE. Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: a model for phage therapy of intracellular bacterial pathogens. The Journal of infectious diseases. 2002 Oct 15;186(8):1155-60. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, Bollaerts A, Demoitié MA. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. New England Journal of Medicine. 2019 Dec 19;381(25):2429-39. Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E, Ayles HM, Henostroza G, Thienemann F, Scriba TJ, Diacon A. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. New England Journal of Medicine. 2018 Oct 25;379(17):1621-34. 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 41

42. T hank you 10/3/2024 Department of Pharmacolgy ,GMC Bhavnagar 42