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Tuberculosis pharmacotherapy
- 1. PHARMACOTHERAPY OF TB, MDRTB & XDR TB Dr. Sachin Panwar Jr-2 Department of Pharmacology KGMU, Lucknow
- 2. INTRODUCTION • Tuberculosis(Tb )is one of the oldest diseases known to affect humans • Tb is a chronic granulomatous disease and is a major cause of death worldwide. • 3 death per 2 minutes worldwide • Important agent of human disease is M. tuberculosis • 95% of cases were reported from developing countries Cusabio.com
- 3. • Tb ismost commonly transmitted from a person with infectious pulmonary TB to others by droplet nuclei, which are aerosolized by coughing, sneezing, or speaking Indianexpress.com
- 4. • Risk factorsfor development of active disease after M. tuberculosis infection include: comorbidity (e.g., HIV disease, diabetes, silicosis, immunosuppression), malnutrition, tobacco smoking, and presence of fibrotic lesions.
- 5. • Globally, thebest estimate is that 10.0 million people developed TB disease in 2017 of which India accounts for 27% • TB-related deaths—almost entirely in low-income countries.
- 6. CLINICAL MANIFESTATIONS • TBis classified as pulmonary, extrapulmonary, or both. • Extrapulmonary TB may occur in 10–40% of pts, with even higher rates among HIV-infected pts.
- 7. • Adult-type diseasepresents initially with nonspecific signs and symptoms, such evening fever, night sweats, weight loss, anorexia, malaise, and weakness Cityhealth.com
- 8. • As thedisease progresses, pts develop cough and purulent sputum production, often with blood streaking. • Extensive cavitation may develop, with occasional massive hemoptysis following erosion of a vessel located in the wall of a cavity. • Disease is usually localized to the apical and posterior segments of the upper lobes and the superior segments of the lower lobes.
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- 10. EXTRAPULMONARY TB • Anysite in the body can be involved, but the most commonly affected sites are (in order of frequency) the lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum, and pericardium. • Up to two-thirds of HIV-infected pts with TB have extrapulmonary disease.
- 11. DIAGNOSIS • The keyto diagnosis is a high index of suspicion based on clinical symptoms • Sputum microscopy • Mantoux test • Interferon γ release assays (IGRAs) • Sputum culture • The Xpert MTB (CBNAAT) detects DNA sequences specific for Mycobacterium tuberculosis and rifampicin resistance by polymerase chain reaction
- 12. • Definitive diagnosisrequires growth of M.tuberculosis in culture or identification of the organism’s DNA in clinical samples. • In suspected pulmonary TB, two or three sputum samples should be examined.
- 13. TREATMENT TUBERCULOSIS First linedrugs: 1. Isoniazid (H) 2. Rifampin (R) 3. Pyrazinamide (Z) 4. Ethambutol (E) 5. Streptomycin (S)
- 14. TREATMENT TUBERCULOSIS Second linedrugs • Ethionamide (Eto) Fluoroquinolones • Prothionamide (Pto) Ofloxacin (Ofx) • Cycloserine (Cs) Levofloxacin (Lvx/Lfx) • Terizidone (Trd) Moxifloxacin (Mfx) • Para-aminosalicylic Ciprofloxacin (Cfx) acid (PAS) Injectable drugs • Kanamycin (Km) , Amikacin (Am) ,Capreomycin (Cm)
- 15. TREATMENT TUBERCULOSIS Isoniazid: • Isoniazidis a critical drug for active and latent TB disease. The usual adult dosage is 300 mg/d or 5mg/kg • Isoniazid is distributed well throughout the body and infected tissues, including CSF and body cavities.
- 16. • The primarymechanism of action of INH is inhibition of synthesis of mycolic acids which are unique component of mycobacterial cell wall. • This is achieved by Kat G and Inh A genes whose mutation is also the primary cause of resistance.
- 17. • The mostimportant toxicities are hepatotoxicity and peripheral neuropathy. • Pyridoxine (25–50 mg/d) should be given to pts with other risk factors for peripheral neuropathy, such as diabetes, alcohol abuse, or malnutrition. • INH neurotoxicity is treated by pyridoxine 100 mg/day.
- 18. TREATMENT TUBERCULOSIS Rifampin: • Rifampinis the most important and potent antituberculous agent. • The standard dosage in adults is 600 mg/d OR 10mg/kg. • It turns body fluids (e.g., urine, saliva, tears) red- orange(REDMAN) • Resistance by rpoB gene mutation
- 19. • Rifampin interruptsRNA synthesis by binding to RNA polymerase (encoded by rpoB gene) • Rifampin resistance is nearly always due to mutation in the rpoB gene reducing its affinity for the drug
- 20. ADVERSE EFFECTS OFRIFAMPCIN • Cutaneous syndrome: flushing, pruritus + rash (especially on face and scalp) • Flu syndrome: with chills, fever, headache, malaise and bone pain • Abdominal syndrome: nausea, vomiting, abdominal cramps
- 21. ETHAMBUTOL • The leastpotent first-line agent, ethambutol is synergistic with the other drugs in the standard first- line regimen. • Ethambutol is usually given at a dosage of 15 mg/kg daily. • The drug is distributed throughout the body but reaches only low levels in CSF. • This agent can cause optic neuritis, producing central scotoma
- 22. PYRAZINAMIDE • The usualdosage is 25 mg/kg daily (maximum, 2 g/d) • The drug distributes well throughout the body, including the CSF • Hyperuricemia that can be managed conservatively is common • Clinical gout rare
- 23. • Resistance isby mutation in pnc A gene which reduces affinity for bacteria
- 24. OTHER EFFECTIVE AGENTS •Streptomycin: The usual adult dose is 0.75–1.0 g IM daily or 5 times per week. • Streptomycin causes ototoxicity but is less nephrotoxic than other aminoglycosides. • Teretogenic
- 25. SECOND-LINE AGENTS • Fluoroquinolones:Levofloxacin, and moxifloxacin • Ciprofloxacin and ofloxacin are no longer recommended for treatment of TB because of poor efficacy. • Other agents (e.g., capreomycin, clofazimine, linezolid) are used uncommonly but may be needed in disease caused by resistant strains
- 26. REGIMENS • During theinitial stage (IP) patient resolve, and usually the pt becomes noninfectious. • The continuation phase (CP) is required to eliminate persisting mycobacteria and prevent relapse. • Faulty regimen is the most important obstacle to cure. • Directly observed treatment (especially during the initial 2 months) and fixed drug-combination products should be used if possible
- 27. REGIMENS TYPE OF PATIENT INTENSIVE PHASE CONTINUATIO N PHASE TOTAL DURATION NEW2 HRZE 4HRE 6 PREVIOUSLY TREATED 2 HRZES + 1 HRZE 5HRE 8 Based on RNTCP guidelines 2016. In new guidelines frequency of dosing during both IP and CP has been changed from 3 times a week to daily administration Source: KDT 8th
- 28. MONITORING OF TREATMENT •Virtually all pts should have negative sputum cultures after 3 months of treatment. • If the culture remains positive, treatment failure and drug resistance should be suspected. • With extrapulmonary TB, bacteriologic monitoring may not be feasible. In these cases, the response to treatment must be assessed clinically and radiographically.
- 29. MDR TB • MDR-TBis defined as resistance to both H and R • Rapid course with worse outcomes • In India MDR TB accounts for 3% of all new TB cases • The standard RNTCP regimen consists of 6 drugs intensive phase (6-9 months) and 4 drugs continuation phase (18 months)
- 30. MDR TB REGIMEN INTENSIVEPHASE ( 6-9 MONTHS) CONTINUATION PHASE ( 18 MONTHS) KANAMYCIN LEVOFLOXACIN LEVOFLOXACIN ETHIONAMIDE ETHIONAMIDE CYCLOSERINE CYCLOSERINE ETHAMBUTOL PYRAZINAMIDE ETHAMBUTOL PLUS PYRIDOXINE 100 mg/day Source: KDT 8th
- 31. • Few newerdrugs being tried in XDR and MDR TB: • Bedaquilline ---- promising results • Delaminid • Pretomanid
- 32. XDR TB • Theseare MDR-TB cases that are also resistant to FQs as well as one of the injectable 2nd line drugs • WHO estimated that 9.7% of MDR TB patients had XDR TB in 2015 • Rapid course and high mortality • Standard MDR treatment should be immediately stopped when XDR is suspected to prevent spread of resistance
- 33. XDR REGIMEN • TheRNTCP ( 2016) has recommended a treatment regimen for XDR TB consisting of 7 drugs in IP ( 6-12 months) and 6 drugs in CP ( 18 months) • Drugs and daily doses for 46-70 kg body weight are: • Capreomycin 1000mg Linezolid 600mg • Moxifloxazin 400mg Amoxi-Clav (875+125) • High dose isoniazid 900mg (2 tb morning+ 1 tab • PAS 12gm evening) • Clofazimine 200mg
- 34. TREATMENT OF TBIN PREGNANCY • WHO consider H,R, E and Z to be safe to the foetus and recommend the standard 6 month (2HRZE + 4HRE) regimen for pregnant women with TB. • ‘S’ is contraindicated because it is ototoxic to the foetus. • Z is not recommended in the USA (due to lack of adequate teratogenicity data).
- 35. TREATMENT OF TBIN PREGNANCY • In India, it is advised to avoid Z, and to treat pregnant TB patients with 2 HRE + 7HR total 9 months • Treatment of TB should not be withheld or delayed because of pregnancy. • All pregnant women being treated with INH should receive pyridoxine 10–25 mg/day.
- 36. TREATMENT OF BREASTFEEDINGWOMEN • All anti-TB drugs are compatible with breastfeeding • Full course should be given to the mother and breastfeeding should be continued • The infant should receive BCG vaccination and 6 month isoniazid preventive treatment after ruling out active TB followed by BCG vaccination
- 37. • Breast –fed infants whose mother are taking INH and those on INH preventive therapy should be supplemented with pyridoxine 5 mg/ day.
- 38. PREVENTION: Vaccination • BCG:protects infants and young children from serious forms of TB (e.g., meningitis and miliary disease) and is recommended for routine use in countries with high TB prevalence. • BCG-M is used for premature newborns.
- 39. NEW VACCINES UNDERTRIAL • Ag 85 – delete genes • ESAT-6 • HSP-65
- 40. Source: gobal WHOreport 2018
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- 43. SUMMARY • The keyto diagnosis is a high index of suspicion • Fixed dose combinations of HRZE & HRE are available and should be preferred • Full course treatment should be considered to avoid MDR and XDR TB cases • BCG prophylaxis – a must for newborns • “UNITED TO END TB” programme
- 44. References • KD Tripathipharmacology textbook 8th e • Harrison’s text book of medicine 19th e • Goodman and gillman 13e
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