Antituberculosis Drugs Notes 2022 PDF

Department of Pharmacology FAR 381 TUBERCULOSIS Keith Ncube Office 7-16, Department of Pharmacology Basic Medical Sciences building, Prinshof campus [email protected]  Tuberculosis Definitions TB is the leading infectious cause of de...

Department of Pharmacology FAR 381 TUBERCULOSIS Keith Ncube Office 7-16, Department of Pharmacology Basic Medical Sciences building, Prinshof campus [email protected]  Tuberculosis Definitions TB is the leading infectious cause of death worldwide Over 2 billion people already have been infected Caused by Mycobacterium tuberculosis Mtb Slow growing rod-shaped aerobic bacilli Cell walls contain mycolic acids Very long chain, β hydroxylated fatty acids Result in the formation of slow growing, granulomatous lesions that cause tissue destruction anywhere in the body Slide 2  Tuberculosis Transmssion M tuberculosis is only transmitted between humans Spread through air in water droplets Normal breathing 1 m Respiratory exhalation 2 m Sneezing 6 m Slide 3 Tuberculosis Slide 4  Tuberculosis Pathogenesis Mycobacterium tuberculosis (M. tuberculosis) Transmitted in airborne droplets (live bacteria) Primary infection: asymptomatic Bacilli proliferate in macrophages Clinical manifestations/symptoms Central: loss of appetite, fatigue Lungs: productive prolonged cough Skin: night sweat, pallor Slide 5  Tuberculosis Incidence and risk factors Global incidence One third of the word’s population infected with M. tuberculosis 50 -60% of those with HIV will develop active TB 10% of healthy individuals will develop active TB Mortality rate of approximately 50% Risk factors Immunosuppressive conditions (HIV/AIDS, cancer) Silicosis Diabetes mellitus Prolonged corticosteroid use Slide 6  Tuberculosis Latent vs active TB Infection can either cause latent TB or progress to active TB Active TB TB Bacilli progressively invade and damage parts of the body Can be pulmonary (attacks lung) or extrapulmonary (affects other organs) Signs and symptoms are present Infectious Latent TB TB Bacilli live dormant in the lungs Do not cause destruction of organs No signs and symptoms of disease Not infectious Slide 7  Tuberculosis Pulmonary vs extra-pulmonary TB Pulmonary TB (PTB) Disease involves the lung tissue Smear positive: visible TB bacilli in sputum – extremely infectious Smear negative: no visible TB bacilli in sputum – less infectious Slide 8  Tuberculosis Pulmonary vs extra-pulmonary TB Extra-pulmonary TB (EPTB) Disease involving organ other than the lung Pleura of lungs, lymph nodes, abdomen, genitourinary tract, skin, joints bones, meninges Not infectious unless also have pulmonary TB Slide 9  Tuberculosis Signs and symptoms Classic symptoms of active TB infection Chronic cough with/without blood-tinged sputum (>2 weeks) Fever Night sweats Weight loss Slide 10  Tuberculosis Detection methods Serological tests (test for antibodies (many false positives observed) Skin test tuberculin injected in skin, return after 48 hours t measure skin surface reaction latent vs active not distinguished Sputum test microscope analysis (sensitivity 50% - 60%) Chest X-ray pulmonary inflammation visible (not specific) Slide 11  Tuberculosis Diagnosis of TB Diagnosis of active TB relies on Radiology (chest x-rays) Microscopic examination and microbiological culture of body fluids PCR to detect drug resistance Diagnosis of latent TB relies on Tuberculin skin test Blood tests Slide 12  Tuberculosis Morbidity and mortality Leading cause of death due to: Inadequate programs for disease control Multiple drug resistance Co-infection with HIV Decreased socio economic conditions such as poverty, overcrowding and poor sanitation Slide 13  Tuberculosis Treatment goals Cure the patient Prevent death from active TB, or its late effects Prevent relapse Decrease transmission to others Prevent development of acquired drug resistance Slide 14  Tuberculosis Treatment goals Treatment affected by: Bacilli only vulnerable when metabolically active Small subpopulation of bacilli remain semi dormant Transient activity for short periods Drug resistant mutants Require treatment beyond disappearance of clinical symptoms Slide 15  Tuberculosis Treatment of TB In South Africa, there are different regimes of treatment and treatment guidelines are reviewed continuously Standardized treatment protocols with fixed dose combination medications Standard treatment regimen for new and previously treated patients Correct drugs for an adequate duration of time Directly observed therapy (DOT) Achieve treatment completion and compliance Slide 16  Tuberculosis Combination therapy Multidrug therapy intensive and continuous phases Intensive phase Bacilli rapidly eradicated from the sputum Kill dividing bacilli Kill persistent bacilli Clinical improvement in illness Infectious patient become less infectious (after 10 - 14 days) Majority will become smear negative after 2 months Slide 17  Tuberculosis Combination therapy Continuation phase Sterilizing effects of treatment Elimination of the remaining viable bacilli Prevention of relapse Slide 18  Tuberculosis Regimens For new and previously treated adults and children >18 years/ 30kg NB!! Give all medications in fixed dose combinations 7 days per week for a 6 months Treatment for pulmonary and extra pulmonary disease is the same However, extra pulmonary requires 7 months of continuation of treatment (thus 9 months in total) Slide 19  Tuberculosis First-line drugs Bactericidal against metabolically active bacilli Sterilizing activity against semi dormant bacilli Prevent emergence of resistant strains Slide 20  Tuberculosis Isoniazid Slide 21  Tuberculosis Regimens Isoniazid undergoes metabolism in the liver via N acetylation Genetic control of acetylation Slow acetylators Half life = 3 hours Greater therapeutic response, increased neurotoxicity risk Fast acetylators Half life = 1 hour Require higher dose, increased hepatotoxicity risk Slide 22  Tuberculosis Rifampicin Slide 23  Tuberculosis Pyrazinamide Slide 24  Tuberculosis Ethambutol Slide 25  Tuberculosis Standard treatment regimen New cases in patients younger than 8 years old Intensive phase Isoniazid, rifampicin, pyrazinamide (minimum of 2 months) Continuation phase Isoniazid and rifampicin for minimum of 4 months Isoniazid resistance replace with ethambutol Slide 26  Tuberculosis Standard treatment regimen New cases in patients 8 years and older Intensive phase All 1st line drugs for minimum of 2 months Continuation phase Isoniazid and rifampicin for minimum of 4 months Slide 27  Tuberculosis Dosing of frequency Daily dosing is optimal Alternatively For intensive phase (daily) and continuation (3x per week) For intensive phase and continuation (3x per week) Provided that patient is not living with HIV Slide 28  Tuberculosis Drug resistance Drug resistant TB is caused by: Inadequate or erratic treatment Transmission from one person to another Should only be managed by specialists with regimes individualized according to: Susceptibility results Information about the most appropriate drug combination Resistant TB treatment takes 3 - 4 times longer and cost 100 times more Slide 29  Tuberculosis Drug resistance Mono drug resistant strains A single first line anti-TB drug Multidrug resistant TB (MDR TB) Is defined as TB disease where there is in vitro resistance to both isoniazid and rifampicin with or without resistance to other anti TB drugs Slide 30  Tuberculosis Drug resistance Extensively drug resistant TB (XDR TB) Is defined as MDR TB and in vitro resistance to isoniazid and rifampicin , plus any of the fluoroquinolones and at least one of the injectable second line drugs (i.e. kanamycin, amikacin, or capreomycin) Slide 31  Tuberculosis Retreatment regimens Higher likelihood of drug resistance Intensive phase 3 months All 1st line streptomycin 2 months All 1st line 1 month Continuation phase 5 months Isoniazid, rifampicin, ethambutol Slide 32  Tuberculosis Second line drugs Slide 33  Tuberculosis Streptomycin Slide 34  Tuberculosis Treatment of MDR-TB Intensive phase (6 months) High dose isoniazid or ethambutol Pyrazinamide, moxifloxacin , ethionamide , streptomycin/kanamycin Continuation phase (12 - 18 months) High dose isoniazid or ethambutol Pyrazinamide, moxifloxacin , ethionamide Slide 35  Tuberculosis TB and HIV Risk of active TB infection is increased 100x in HIV+ individuals Do not initiate treatment of both TB and HIV simultaneously due to: Overlapping toxicities (hepatotoxicity) Significant drug interactions (CYP) Adherence requirements Risk of immune reconstitution (IRIS) (11 - 45% within 6 weeks) HAART can lead to paradoxical deterioration of TB Slide 36  Tuberculosis TB and HIV If patient develops TB while on HAART, then HAART must not be discontinued, but modified based on safety aspects If TB develops first: Treat TB first then introduce HAART depending on CD4 count Slide 37  Tuberculosis Isoniazid Preventative Therapy (IPT) People living with HIV, and active TB has been excluded Initiate IPT as soon as possible after initiation of HAART Maximum dose of 300 mg/day Pyridoxine (Vit B6) 25 mg/day Pregnancy is not a contraindication to IPT No evidence that IPT increases isoniazid resistance Contraindicated with alcohol abuse Liver damage is a rare complication Slide 38  Tuberculosis HAART treatment with concomitant TB Slide 39  Summary of mechanisms of action Pyrazinamide Isoniazid MoA: Sterilizing activity inside acidic intracellular compartments MoA: Inhibit mycolic acid synthesis AE: Gout Note: Administer with Vit B6 DDI: probenecid, allopurinol Ethambutol Streptomycin MoA: Inhibit cell wall MoA: Inhibit protein synthesis synthesis CI: pregnancy, renal impairment CI: younger than 8 years old AE: ototoxicity, nephrotoxicity Rifampicin AE: optic neuritis Note: can be used for isoniazid resistance MoA: Inhibits RNA synthesis Note: Body fluid coloration, never use alone Slide 40  Tuberculosis Take home questions Which one of the following drugs should not be given to children younger than 8 years old A –Rifampicin B –Pyrazinamide C –Ethambutol D –Isoniazid Slide 41  Tuberculosis Take home questions Which one of the following drugs is not used for the first line treatment of Mycobacterium tuberculosis? A Rifampicin B –Ethionamide C –Ethambutol D –Isoniazid Slide 42