First Line TB Drugs.pptx

Introduction
Mycobacteria are intrinsically resistant to most antibiotics & they grow slowly compared with other bacteria.
Thus antibiotics that are most active against growing cells are relatively ineffective.
Mycobacterial cells can also be dormant & thus completely resistant to many drugs or killed only very slowly.

1. Dr. NDAYISABA CORNEILLE CEO of CHG MBChB,DCM,BCSIT,CCNA Supported BY FIRST LINE TB DRUGS

2. Antituberculosis First line anti-TB agents Isoniazid Rifampicin Ethambutol Pyrazinamide Second line agents Cycloserine Streptomycin Rifabutin Ethionamide Prothionamide Capreomycin Dr Ndayisaba Corneille

3. Introduction Mycobacteria are intrinsically resistant to most antibiotics & they grow slowly compared with other bacteria . Thus antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant & thus completely resistant to many drugs or killed only very slowly. Dr Ndayisaba Corneille

4. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens & organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Dr Ndayisaba Corneille

5. Mycobacteria have ability to develop resistance. Combinations of 2 or more drugs is required to overcome emergence of resistance during course of therapy. The response to chemotherapy is slow & Rx must be administered for months to years, depending on which drugs are used. Dr Ndayisaba Corneille

6. First line Drugs Used in TB RX 1 st line agents Isoniazid ( H ) Rifampin ( R ) P yrazinamide (P) E thambutol (E) Streptomycin (S) Thiacetazone (T) Dr Ndayisaba Corneille

7. Isoniazid & rifampin are the most active drugs. In practice, therapy is initiated with a four-drug regimen of 2HERZ/6EH OR 2HERZ/4RH after pts are diagnosed of TB . Prevalence of isoniazid resistance among US clinical isolates is approx 10%. Prevalence of resistance to both H&R (multiple drug resistance) is about 3%. Dr Ndayisaba Corneille

8. I soniazid (H) or (INH) Most active drug for Rx of TB c ozed by susceptible strains. Has structural similarity to pyridoxine Its bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. It penetrates into macrophages & is active against both extracellular & intracellular organisms. Dr Ndayisaba Corneille

9. Mechanism of Action Inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Blocks mycolic acid synthesis & kills the cell. Basis of Resistance Mutations in certain genes controlling synthesis of mycolic acids Dr Ndayisaba Corneille

10. Mutants are readily selected out if isoniazid or any other drug is given as a single agent. The use of two or more independently acting drugs in combination is much more effective. Probability that a bacillus is resistant to both drugs is usually less Dr Ndayisaba Corneille

11. Thus, at least two or more active agents shld always be used to Rx active TB to prevent emergence of resistance during therapy. Pharmacokinetics Typical adult dose is 300 m g o.d . ( 5 mg/kg/d ) Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. Dr Ndayisaba Corneille

12. 5 mg/kg /d , or 900 mg, may be used in some situations Given IV or PO & is readily absorbed frm GIT . I t diffuses readily into all body fluids & tissues. The [CNS & CSF]s ranges btn 20% & 100% of simultaneous [ serum ] s. Metabolism is esp by acetylation by liver N- acetyltransferase & this is genetically determined . Dr Ndayisaba Corneille

13. Rapid clearance of drug occurs in rapid acetylators but its usually of no therapeutic consequence whn appropriate doses are administered daily . [ subtherapeutic ] s may occur if drug is administered as a once-weekly dose or if there is malabsorption. Drug metabolites & a small amount of unchanged drug are excreted mainly in urine. Dr Ndayisaba Corneille

14. The dose need not be adjusted in renal failure. Is contraindicated if it is the c oz of hepatitis Clinical Uses Rx of active TB in combination with other agents Rx of Latent tuberculosis with 300 mg/d Dr Ndayisaba Corneille

15. Adverse Reactions The incidence & severity of un wanted effects to isoniazid are related to dosage & duration of administration. I mmunologic reactions Fever skin rashes. Drug-induced systemic lupus erythematosus has been reported. Dr Ndayisaba Corneille

16. D irect toxicity Isoniazid-induced hepatitis Most common major toxic effect. Liver aminotransferases increase 3- 4 times normal . This does not require cessation of drug if pt is asymptomatic This is seen in 10–20% of p ts. Dr Ndayisaba Corneille

17. Clinical hepatitis with ; loss of appetite, nausea, vomiting, jaundice & right upper quadrant pain occurs in 1% of (H) recipients & can be fatal, particularly if drug is not discontinued promptly. There is histologic evidence of hepatocellular damage & necrosis is present Dr Ndayisaba Corneille

18. Pts at high risk of Isoniazid hepatitis ; Age >50 years A lcoholic s Pregnan t women Postpartum mothers Dev ’ t of (H) hepatitis contraindicates its further use . Dr Ndayisaba Corneille

19. Peripheral neuropathy Observed in 10–20% of pts given dosages > 5 mg/kg/d Infrequently seen with standard 300 mg adult dose. Patients at risk of neuropathy Slow acetylators Those with predisposing conditions like AIDS , malnutrition, alcoholism, DM , & uremia. Dr Ndayisaba Corneille

20. Pyridoxine, 25–50 mg/d, is recommended for those with conditions predisposing to neuropathy Neuropathy is due to a relative pyridoxine deficiency as (H) promotes excretion of pyridoxine Dr Ndayisaba Corneille

21. C NS toxicity ; less common Memory loss, Psychosis & Seizures. These may also respond to pyridoxine. Dr Ndayisaba Corneille

22. Miscellaneous adverse effects Hematologic abnormalities Provocation of pyridoxine deficiency anemia . Tinnitus G I discomfort Reduce d metabolism of phenytoin, increasing its blood level & toxicity Dr Ndayisaba Corneille

23. R ifampin A semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. Antibacterial activity . Active against; Gram-positive & gram-negative cocci, Some enteric bacteria, Mycobacteria, Chlamydia. Dr Ndayisaba Corneille

24. Resistant mutants are present in all microbial popns at approx 1 in 10 6 & are rapidly selected out if rifampin is used as a single drug during active infection. No cross-resistance to other classes of antimicrobial drugs but cross-resistance occur to other rifamycin derivatives, eg, rifabutin & rifapentine. Dr Ndayisaba Corneille

25. Mechanism of action Thus inhibits DNA synthesis Bactericidal Binds to the subunit of bacterial DNA-dependent RNA polymerase & thereby inhibits RNA synthesis. Dr Ndayisaba Corneille

26. Pharmaco kinetics Dosage is usually 600 mg/d (10 mg/kg/d) Given PO & well absorbed frm GIT with wide distribut ion in body fluids & tissues. Relatively highly protein-bound & adequate [CSF] s are achieved only in presence of meningeal inflammation. Dr Ndayisaba Corneille

27. Readily penetrates most tissues & phagocytic cells. Kill s organisms that are in accessible to many drugs, such as intracellular organisms & those sequestered in abscesses + lung cavities. Excreted mainly thr u liver into bile. Then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces & a small amount in urine. Dr Ndayisaba Corneille

28. Dose reduction in liver & renal insufficiency are not required Resistance Results frm any one of several possible point mutations in rpoB, the gene for the subunit of RNA polymerase. Th is result in reduced binding of rifampin to RNA polymerase. Dr Ndayisaba Corneille

29. Clinical uses M ycobacterial infections like TB Atypical mycobacterial infections Leprosy. Alternative to (H) prophylaxis for pts with latent TB only who are unable to take isoniazid . Dr Ndayisaba Corneille

30. 2) O ther indications Eliminat ion of meningococcal carriage Prophylaxis for haemophilus influenzae type b disease in contacts of children. Eradicat ion of staphylococcal carriage whn combined with a 2 nd agent . Rx of serious staphylococcal infections such as osteomyelitis & prosthetic valve endocarditis whn used in combination therapy Dr Ndayisaba Corneille

31. Adverse Reactions I mpart s a harmless orange color to urine , sweat, tears & contact lenses (soft lenses may be permanently stained). Occasional adverse effects Rashes T hrombocytopenia Nephritis or ATN Dr Ndayisaba Corneille

32. Cholestatic jaundice Hepatitis . Light-chain proteinuria. If administered less often than twice weekly it c ozes a flu-like syndrome with; F ever c hills, m yalgias, a nemia, & thrombocytopenia Dr Ndayisaba Corneille

33. Drug interactions Strongly induces most P450 enzymes thus increase d elimination of drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, PI s, NNRTI s esp neverapine , oral contraceptives & a host of others. Dr Ndayisaba Corneille

34. Ethambutol Synthetic, water-soluble, heat-stable compound Mechanism of action Inhibit mycobacterial cell wall synthesis Inhibits mycobacterial arabinosyl transferases, which are encoded by embCAB operon. Dr Ndayisaba Corneille

35. Arabinosyl transferases are involved in polymerization reaction of arabinoglycan, an essential component of mycobacterial cell wall. Resistance Resistance to ethambutol is due to mutations resulting in overexpression of emb gene p d ts or within the embB structural gene. Dr Ndayisaba Corneille

36. As with all other anti cocks , resistance to emerges rapidly whn drug is used alone . Pharmacokinetics Given PO & well absorbed frm the gut Dosage is 15–25 mg/kg /d , usually given as a single daily dose in combination with other drugs . Dr Ndayisaba Corneille

37. It crosses BBB only if meninges are inflamed with highly variable [CSF]s of drug, ( 4% to 64% ) of serum levels in the setting of meningeal inflammation. About 20% of drug is excreted in feces & 50% in urine in unchanged form. It accumulates in renal failure . Dose shld be reduced by half if creatinine clearance is < 10 mL/min. Dr Ndayisaba Corneille

38. Clinical Use Rx of active TB *A higher dose is recommended for Rx of TBM Dr Ndayisaba Corneille

39. Adverse Reactions Hypersensitivity ; Is rare. Retrobulbar neuritis , resulting in loss of visual acuity & red-green color blindness. Most common serious adverse event This dose-related S/E, more likely to occur at doses of 25 mg/kg/d continued for several months. Dr Ndayisaba Corneille

40. At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if 25 mg/kg/d dosage is used. Contraindications Relatively contraindicated in children too young to permit assessment of visual acuity & red-green color discrimination. Dr Ndayisaba Corneille

41. Pyrazinamide A relative of nicotinamide . Stable & slightly soluble in water. An important front-line drug used in conjunction with H&R in short-course (ie, 6-month) regimens as a "sterilizing" agent active against residual intracellular organisms that may cause relapse. Dr Ndayisaba Corneille

42. Mechanism of action The drug target & mechanism of action are unknown. Pyrazinamide is converted to pyrazinoic acid the active form of the drug—by mycobacterial pyrazinamidase, which is encoded by pncA. The drug is taken up by macrophages & exerts its activity against mycobacteria residing within acidic environ ’ t of lysosomes. Dr Ndayisaba Corneille

43. Resistance Resistance may be due to impaired uptake of drug Mutations in pncA that impair conversion of pyrazinamide to its active form. Tubercle bacilli develop resistance to it fairly readily . No cross-resistance with other ant i-cocks . Dr Ndayisaba Corneille

44. Pharmacokinetics Given PO Dos e of 25 mg/kg/d. Half-life is 8–11 hours. Well ab s orbed fr m GIT & widely distributed in body tissues, including inflamed meninges. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli & some other mycobacteria Dr Ndayisaba Corneille

45. Parent compound is metabolized by liver, but metabolites are renally cleared . Th us doses shld be lowered in renal insufficiency. In pts with normal renal function, a dose of 40–50 mg/kg is used for thrice-wkly or twice-wkly Rx regimens. Dr Ndayisaba Corneille

46. Adverse Reactions ; Major adverse effects include Hepatotoxicity (1–5% of pts), Nausea Vomiting Drug fever occurs uniformly & is not a reason to halt therapy. Hyperuricemia. May provoke acute gouty arthritis . Dr Ndayisaba Corneille

47. S treptomycin Isolated frm a strain of Streptomyces griseus . The antimicrobial activity is typical of that of other aminoglycosides, as are the mechanisms of resistance. Dr Ndayisaba Corneille

48. Spectrum of activity against in mycobacteria M. tuberculosis sp p Mycobacterium avium complex (MAC) Mycobacterium kansasii Rest of the Spp of mycobacterium are resistant . Resistance All large popns of tubercle bacilli contain some streptomycin-resistant mutants. Dr Ndayisaba Corneille

49. Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or the rrs gene encoding 16S ribosomal rRNA, which alters the ribosomal binding site. Ribosomal resistance develops readily, limiting its role as a single agent. Dr Ndayisaba Corneille

50. Pharmacokinetics Given IM or IV Typical adult dosage is 1g/day ( 15 mg/kg/d ) daily for adults & 7.5–15 mg/kg/d for children It penetrates into cells poorly & is active mainly against extracellular tubercle bacilli. It crosse s BBB & achieves [ therapeutic ]s with inflamed meninges. Dr Ndayisaba Corneille

51. Clinical Uses M ycobacterial infections Used when an injectable drug is needed or desirable 2 nd -line agent for Rx of MDR-TB with other agents. S evere & possibly life-threatening forms of TB eg, TBM & disseminated disease Dr Ndayisaba Corneille

52. Adverse Reactions Hypersensitivity Fever skin rashes & other allergic manifestations. Occurs most frequently with prolonged contact with drug either in pts who receive a prolonged course of Rx or in medical personnel who handle the drug. Dr Ndayisaba Corneille

53. Pain at the injection site Common but usually not severe Disturbance of vestibular function . Most serious toxic effect & manifest by Vertigo & Loss of balance. Toxicity tends to be irreversible. Dr Ndayisaba Corneille

54. Ototoxicity Nephrotoxicity Contraindications Pregnancy, can cause deafness in the newborn Renal failure Vestibular disorders Dr Ndayisaba Corneille

55. Thiacetazone Is bacteriostatic With a low potency Dosage is 2.5mg/day Is the only essential anti-TB drug that can not be given intermittently e.g. 2 timely weekly Dr Ndayisaba Corneille

56. Has a narrow therapeutic range thus margin btn therapeutic & toxic dose is very small Some countries still use it in combination with Isoniazid during continuation phase of Rx Known ISS pts shld not be put on this drug bcoz of its severe skin reactions thus Ethambutol shld replace this drug in areas where HIV is common Dr Ndayisaba Corneille

57. Side effects Common Skin rash often involving mucous membrane & some times blistering Others Agranulocytosis Hepatitis Dr Ndayisaba Corneille

58. END BY DR NDAYISABA CORNEILLE MBChB,DCM,BCSIT,CCNA,Cyber Security contact: [email protected] , [email protected] whatsaps :[phone] / [phone] THANKS FOR LISTENING Dr Ndayisaba Corneille