Treatment of tuberculosis

Treatment of TB

1. Treatment of Tuberculosis Shyala Chand Year 4

2. M. tuberculosis Gram + ve , aerobic acid fast bacilli. Resistant to disinfectant ,detergent & common antibiotics. Capable of intracellular growth. Person to person spread is by aerosol. Human are the only natural reservoir. Disease is most common in south east A sia , sub S aharan region, eastern E urope .

3. Treatment The two aims of TB treatment are (1) to prevent morbidity and death by curing TB while preventing the emergence of drug resistance. (2) to interrupt transmission by rendering patients non-infectious.

4. Uses of First Line Drugs Bactericidal activity ( i.e , their ability to rapidly reduce the number of viable organisms and render patients non-infectious) S terilizing activity ( i.e , their ability to kill all bacilli and thus sterilize the affected tissues, measured in terms of the ability to prevent relapses) Low rate of induction of drug resistance by selection of mutant bacilli.

5. Isoniazid (INH) Mechanism : Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls. Indications : Active & Latent TB. Effects : Bactericidal against actively diving M. tuberculosis and Bacteriostatic against resting bacteria. Contraindications : Hypersensitive reactions, Acute Liver Disease

6. Precautions : Renal impairment, Hepatic impairment, Alcoholism, Severe malnutrition, Diabetes, HIV (Pyridoxine is used as prophylaxis ) Adverse Effects : Peripheral Neuropathy, Hepatotoxicity, CNS toxicity, Rash, Haemolytic anemia, Thrombocytopenia, Lupus like Syndrome, Gynecomastia . Biological half-life : 0.5-1.6h (fast acetylators ), 2-5h (slow acetylators )

7. Rifampin Mechanism : Inhibits RNA synthesis in bacteria. Indications : TB, MRSA, Mycobacterial infections, Prophylaxics of meningitis & epiglottitis Effects : Bactericidal, Sterilizing agent Contraindications : Allergy, Concomitant administration of live bacterial vaccines, patients receiving ritonavir-boosted saquinavir , because of increased risk of severe hepatocellular toxicity, Jaundice, Renal Failure, Hemolytic anemia , Thrombocytopenic purpura

8. Precaution s: May decrease the effectiveness of oral contraceptive pills (OCPs ), Type 2 Diabetes, Discontinue therapy if patient develops any signs of hepatocellular damage, including hyperbilirubinemia , Alcoholism Adverse Effects : Increased Hepatic Enzymes (CYP450), GI symptoms, Rash, Orange-Red discoloration of body fluids, Flu like syndrome (with irregular dosing) Biological Half life : 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease, 1.8-11 hr

9. Pryazinamide Mechanism : Requires acid pH for activity. Active both intra/extracellular (Very active in first 2 months of therapy) Indication : TB Effect : bactericidal, Sterilizing action (reduces risk of relapse). Allows for shorter duration of treatment (6 months) Contraindications : Acute Gout, Hepatic Impairement , Renal Impairment ( Crcl <25ml/min) Precaution s: Alcoholism (perform routine liver function tests)

10. Adverse Effects : Hyperuricaemia , polyarthralgia , Hepatotoxicity, photosensitivity, Thrombocytopenia Biological Half life : 9- 10 hrs

11. Ethambutol Mechanism : inhibit incorporation of mycolic acid in to the mycobacterial wall. Indications : TB, Atypical mycobacterial infections Effects : Bacteriostatic Contraindications : Gout, Optic Neuritis, Hypersensitivity. Precautions : Diabetic retinopathy, Cataract

12. Adverse Effects : Optic Neuritis ( decreased visual acuity, colorblindness) , Gout, Abdominal Pain, Headache, Jaundice, Malaise, Nausea Biological Half life : 4 hours

13. Streptomycin Effects : Bactericidal Indications : used in strains resistant to other anti-tubercular drugs or when other drugs are contraindicated Contraindications : Hypersentivity Precautions : Vestibular disturbances, Myasthenia gravis, Renal impairment, Elderly Adverse effects : Fever, Rash, Sterile abscess at injection site, tinnitus, vestibular toxicity, albuminuria, aplastic anemia (rare)

14. Directly Observed Treatment (DOT)  T uberculosis control strategy recommended by the World Health Organization . DOT involves TB nurses, outreach volunteers or trained volunteers meeting regularly with patients to watch them take their medication. Standard short course regimen (up to 6 months)

15. Uses of Second Line Drugs In case of resistance to first-line agents In case of failure of clinical response to conventional therapy I n case of serious treatment-limiting adverse drug reactions

16. Ethionamide Mechanism : Inhibition of mycolic acid biosynthesis and consequent impairment of cell-wall synthesis Indications : TB (when isoniazid, rifampin are resistant) Interactions : Cycloserine , Isoniazid, Magnesium Oxide (cause hepatotoxicity) Contraindications : Hepatic Impairment, Pregnancy, Underactive Thyroid disease, Diabetes, Alcoholism

17. Adverse Effects : Gastrointestinal effects (  nausea, vomiting,  diarrhea , abdominal pain excessive salivation, metallic taste, stomatitis, anorexia, and weight loss), Hypothyroidism, Hypoglycemia , Teratogenicity, Gynecomastia , CNS effects (Headache, Drowsiness, Dizziness, Pscyhosis ) Biological Half life : 2- 3 hrs

18. Cycloserine Mechanism :  acts against enzymes important in the cytosolic stages of peptidoglycan synthesis Contraindications : Epilepsy, Alcoholism, Severe renal impairment, Hypersensitivity Precautions : Psychiatric disorders(depression anxiety, pscyhosis ), Pregnancy Adverse Effects : CNS Dysfunction (Headache, Confusion, Depression, Seizures, Changes in behavior), Sideroblastic Anemia, Hypersensitivity (rash, photosensitivity ) Pyridoxine may be used to reduce CNS effects

19. Terizidone Bacteriostatic Derivative of Cycloserine

20. Para-amino salicylic acid (PAS) Mechanism : Folate synthesis antagonist that is active exclusively against M. tuberculosis. Effects : Bacteriostatic Contraindications : Hypersensitivity Precautions : Renal impairment, May reduce serum levels/ absorption of Digoxin and Rifampin Adverse Effects : Vitamin B12 deficiency, Hypothyroidism, Hepatitis, GI effects, Crystalluria

21. Rifabutin Mechanism : Inhibits RNA polymerase Indications : TB (when rifampicin is unsuitable) Contraindications : Ongoing treatment with ritonavir (may cause uveitis) Precautions : Hypersensitivity to rifamycins , Concomitant live bacterial vaccines, Renal impairment, decrease the effectiveness of oral contraceptive pills ( OCPs) Adverse effects : Eye pain, redness, loss of vision may indicate inflammatory ocular condition, brown-orange colour of urine, faeces, saliva, sputum, perspiration, tears, & skin

22. Thioacetazone   Mechanism : Bacteriostatic Uses : P revent emergence of isoniazid resistance, streptomycin & ethambutol . Adverse effects : Rare - hepatitis, exfoliative dermatitis, SJS, bone marrow depression. Common- Abdominal discomfort, loose motions, rashes, mild anemia , anorexia

23. Fluoroquinolones Mechanism : inhibit bacterial DNA synthesis Indications : Active & Atypical TB Contraindications : Hypersensitivity, Pregnancy (fetal arthropathy ) Precautions : G6PD Deficiency, Recent h istory of corticosteroid use, Athletes in training, Epilepsy, Worsen myasthenia gravis Adverse Effects : GI effects, headache, tendon rupture, SJS, CNS effects(seizures, psychotic reactions) Examples : Ciprofloxacin, Moxifloxacin

24. Injectable Drugs Capreomycin Kanamycin Amikacin

25. Capreomycin (Anti-Mycobacterial) Bacteristatic Indications : Drug intolerance to first line agents Contraindications : Hypersentivity Precautions : Hearing impairment, Renal impairment Adverse effects : Nephrotoxicity, Ototoxicity (hearing loss, tinnitus), proteinuria, Hypokalemia

26. Amikacin (Aminoglycoside) Mechanism : inhibit protein synthesis Contraindications : Hypersensitivity Precautions : Neuromuscular diseases (myasthenia gravis), Dehydration, History of treatment with ototoxic drugs, Renal impairment Adverse effects : Nephrotoxicity, Ototoxicity (risk increases with concurrent loop diuretics), Neuromuscular blockade (respiratory depression), Bronchospasm, Oliguria

27. Kanamycin (Aminoglycoside) Ototoxicity is more common Other Adverse Effects : Agranulocytosis , Anorexia, Diarrhoea, Dyspnea , Elevated BUN, Enterocolitis , Headache, Increased salivation, Muscle cramps, Nausea, Nephrotoxicity, Neurotoxicity, Ototoxicity, Pruritus.