Second Line TB Drugs.pptx

Clinical situations when to use 2nd line agents
In case of resistance to first-line agents
In case of failure of clinical response to conventional therapy
In case of serious Rx-limiting adverse drug reactions
When expert guidance is available to deal with the toxic effects
Many of 2nd -line drugs , their dosage, emergence of resistance & long-term toxicity have not been fully established.
Ethionamide
Chemically related to isoniazid
Mechanism of action
Blocks synthesis of mycolic acids.
Anti-mycobacterial activity
M. tuberculosis & some other Spp of mycobacteria

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

2. A lternative 2 nd -line drugs for tb RX E xamples Aminosalicylic Acid (PAS) Rifapentine Ethionamide Capreomycin Kanamycin & Amikacin Fluoroquinolones Linezolid Rifabutin (Ansamycin) Dr Ndayisaba Corneille

3. Clinical situations when to use 2 nd line agents In case of resistance to first-line agents In case of failure of clinical response to conventional therapy In case of serious Rx -limiting adverse drug reactions When expert guidance is available to deal with the toxic effects Dr Ndayisaba Corneille

4. Many of 2 nd -line drugs , their dosage, emergence of resistance & long-term toxicity have not been fully established. Ethionamide Chemically related to isoniazid Mechanism of action Blocks synthesis of mycolic acids. Anti-mycobacterial activity M. tuberculosis & some other Spp of mycobacteria Dr Ndayisaba Corneille

5. Pharmacokinetics It is poorly water-soluble & thus available only in oral form. Initial dose of 250 mg o.d daily, is increased in 250-mg increments to max of 1 g/d (15 mg/kg/d), if possible. 1 g/d dosage is poorly tolerated bc oz of intense gastric irritation & neurologic Sx s that commonly occur Dr Ndayisaba Corneille

6. Thus one often must settle for a total daily dose of 500–750 mg. [ C SF] s are equal to those in serum It is metabolized by the liver. Resistance develops rapidly when its used as a lone . There can be low-level cross-resistance btn isoniazid & ethionamide. Dr Ndayisaba Corneille

7. Side effects Neurologic Sx s Hepatotoxi city Intense GI irritation . Neurologic Sx s may be alleviated by pyridoxine. Dr Ndayisaba Corneille

8. Capreomycin Antibiotic obtained from Streptomyces capreolus. Mechanism of action A peptide protein synthesis inhibitor Pharmacokinetics Given IM Dosage 1 g/d ( 15 mg/kg/d ) Dr Ndayisaba Corneille

9. Anti-mycobacterial activity Many mycobacteria Spp Multidrug-resistant strains of M tuberculosis. Strains of M tuberculosis that are resistant to streptomycin or amikacin are usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation. Dr Ndayisaba Corneille

10. Side effects Nephrotoxic ity Ototoxic ity Thus tinnitus, deafness & vestibular disturbances occur. Injection c ozes significant local pain Sterile abscesses may occur. Toxicity is reduced if 1 g is given 2-3 times wkly after an initial response has been achieved with a daily dosing schedule. Dr Ndayisaba Corneille

11. Cycloserine Mechanism of action An inhibitor of cell wall synthesis Inhibit s many strains of M tuberculosis. Pharmacokinetics Dosage in TB is 0.5–1 g/d in two divided doses. Is cleared renally Th us dose shld be reduced in renal insufficiency Dr Ndayisaba Corneille

12. Serious toxic effects ; esp at higher doses Peripheral neuropathy CNS dysfunction ; depression & psychotic reactions. Pyridoxine 150 mg/d shld be giv en b coz this ameliorates neurologic toxicity. S /E can be minimized by monitoring peak [ serum ]s . Dr Ndayisaba Corneille

13. Aminosalicylic Acid (PAS) Structurally similar to p- aminobenzoic aid (PABA) & to the sulfonamides Pharmacodynamics A folate synthesis antagonist that is active almost exclusively against M tuberculosis. Dr Ndayisaba Corneille

14. Pharmacokinetics Given PO & readily absorbed frm GIT . Dosage is 8–12 g/d for adults & 300 mg/kg/d for children. Widely distributed in tissues & body fluids except CSF . Dr Ndayisaba Corneille

15. Rapidly excreted in urine, in part as active PAS & in part as the acetylated compound + other metabolic products. Very high [PAS] are reached in the urine, which can result in crystalluria. Used infrequently now bec oz other oral drugs are better tolerated. Dr Ndayisaba Corneille

16. G I Sx s are common & may be diminished by giving the drug with meals & antacids. Side effects Peptic ulceration + hemorrhage may occur. Hypersensitivity reactions manifested by ; Fever, Joint pains, Skin rashes Dr Ndayisaba Corneille

17. H epatosplenomegaly Hepatitis A denopathy & granulocytopenia These often occur after 3–8 wks of PAS therapy, making it necessary to stop Rx temporarily or permanently. Dr Ndayisaba Corneille

18. Kanamycin & Amikacin Kanamycin Has been used for Rx of TB c ozed by streptomycin-resistant strains But the availability of less toxic alternatives ( capreomycin & amikacin) has rendered it obsolete. Dr Ndayisaba Corneille

19. Amikacin its use in Rx of TB has increased with the increasing incidence & prevalence of MDR-TB . Prevalence of amikacin-resistant strains is low ( < 5%) . Most MDR- strains remain amikacin-susceptible. Its also active against atypical mycobacteria. Dosage is 1g/d ( 15 mg/kg /d)IV infusion Dr Ndayisaba Corneille

20. There is no cross-resistance b t n streptomycin & amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Indicat ions Rx of TB suspected or known to be c ozed by streptomycin-resistant MDR- strains. Dr Ndayisaba Corneille

21. It must be used in combination with at least one & preferably 2-3 other drugs to which the isolate is susceptible for Rx of drug-resistant cases. Dr Ndayisaba Corneille

22. Fluoroquinolones Active agents against mycobacteria - Ciprofloxacin - Levofloxacin - Gatifloxacin - Moxifloxacin Antibacterial activity Gram +ve & gram –ve bacteria Mycobacteria Atypical mycobacteria. Dr Ndayisaba Corneille

23. Moxifloxacin ; most active against M tuberculosis by weight in vitro. Levofloxacin ; tends to be slightly more active than ciprofloxacin against M tuberculosis Ciprofloxacin ; slightly more active against atypical mycobacteria. Indications MDR-TB Dr Ndayisaba Corneille

24. Resistance, which may result frm any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used alone. Thus the drug must be used in combination with or more other active agents. Dr Ndayisaba Corneille

25. Dosage Ciprofloxacin is 750 mg orally BD . Levofloxacin is 500–750 mg OD . Moxifloxacin is 400 mg OD . Dr Ndayisaba Corneille

26. Linezolid Inhibits strains of M tuberculosis in vitro It achieves good [ intracellular ] s & it is active in murine models of TB . Used in combination with other 2 nd & 3 rd line drugs to Rx pts with TB c ozed by MDR- strains. Dr Ndayisaba Corneille

27. Adverse effects ;are Significant & at times Rx -limiting Bone marrow suppression Irreversible peripheral & optic neuropathy Dosage 600-mg (adult) o.d in Rx of TB 300 mg o.d in other bacterial infections seems to be sufficient & may limit occurrence of S/E . Dr Ndayisaba Corneille

28. Although linezolid may eventually prove to be an important new agent for Rx of TB. But it shld be considered a drug of last resort for infection c oz ed by MDR- strains that also are resistant to several other 1 st & 2 nd line agents. Dr Ndayisaba Corneille

29. Rifabutin (Ansamycin) Derived frm rifamycin & is related to rifampin. Has significant activity against M tuberculosis M avium-intracellulare M fortuitum . Its activity is similar to that of rifampin & cross-resistance with rifampin is virtually complete. Dr Ndayisaba Corneille

30. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro But a clinical response is unlikely b coz molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate & inducer of cytochrome P450 enzymes. But it is a less potent inducer of cytochrome P450 enzymes. Dr Ndayisaba Corneille

31. Thus indicated in place of (R) for Rx of TB/ HIV co- infected pts who are on HAART with ; NNRTI e . g efavirenz that also are cytochrome P450 substrates. PI or The usual dose is 300 mg/d unless pt is on ART with a PI , in which case , dose is reduced to 150 mg/d. Dr Ndayisaba Corneille

32. If efavirenz (also a P450 inducer) is used, the recommended dose of rifabutin is 450 mg/d. Indications Prophylaxis for mycobacterial infection in AIDS pts with CD4 counts < 50/ mm³ . Rx of disseminated atypical mycobacterial infection in AIDS pts with CD4 counts < 50/ mm³ . Prophylaxis for TB Dr Ndayisaba Corneille

33. Rifapentine Analog of rifampin. Pharmacodynamics Bacterial RNA polymerase inhibitor Cross-resistance b t n rifampin & rifapentine is complete. Dr Ndayisaba Corneille

34. Mycobacterial activity M tuberculosis M avium. Pharmacokinetics Like rifam picin its a potent inducer of cytochrome P450 enzymes & it has the same drug interaction profile. Dr Ndayisaba Corneille

35. Rifapentine & its microbiologically active metabolite, have an elimination half-life of 13 hours. Dosage 600 mg (10 mg/kg) once wkly is indicated for Rx of TB c oz ed by R -susceptible strains during continuation phase only (after 1 st 2 mnths of Rx & ideally after conversion of sputum cultures to - ve). Dr Ndayisaba Corneille

36. It shld not be used to treat HIV-infected pts b coz of an unacceptably high relapse rate with rifampin-resistant organisms. Toxicity is similar to that of rifampin. Dr Ndayisaba Corneille

37. 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