Chemotherapy of Tuberculosis

Tuberculosis Chronic granulomatous disease. Usually affects the lungs, up to one third of cases, other organs are involved.

Etiologic agent Mycobacterium causes: Tuberculosis Mycobacterium avium complex disease Leprosy

Mycobacterium tuberculosis complex: Rod shaped, non- pore-forming, thin aerobic bacterium. Important agent for human disease. M. bovis Important cause of tuberculosis for transmitted by unpasteurised milk. M . africanum West, central & east africa. M .microti Less virulent, rarely encountered organism.

As many as 3000 infectious nuclei per cough. M.tuberculosis transmitted from patient with infectious pulmonary Tb to other persons By droplet nuclei, Aerosolised by coughing, sneezing or speaking. As many as 3000 infectious nuclei per cough.

Tiny droplets dry rapidly. Smallest droplets (<10 um in diameter) Suspended in the air for several hours , May gain direct access to the terminal air passages when inhaled.

Risk factors for acquiring infection with M.Tuberculosis: Probability of contact with the case of Tb. Intimacy and duration of that contact. Degree of infectiousness of the case. Shared environment of the contact.

Risk factor for developing disease after being infected : Individuals innate susceptibility to disease. Level of function of cell mediated immunity.

Clinical manifestations Pulmonary Tb Primary Secondary Extra pulmonary Tb Lymph node Tb Pleural Tb Tb of upper airways Genitourinary Tb Skeletal Tb Tuberculous meningitis Gastrointestinal Tb Pericardial Tb Miliary / disseminated Tb

Primary Tuberculosis Results from initial infection with tubercle bacilli. Children up to 4 yrs of age. Middle, lower lung zone affected mainly. Rapid progression to illness in HIV patients.

Obstruction & subsequent segmental collapse: Obstructive emphysema: Pleural effusion: due to penetration of bacilli into pleural space from subsequent subpleural area. Lymphadenopathy: due to spread of bacilli from lung parenchyma through lymphatic vessel. Obstruction & subsequent segmental collapse: as enlarged lymph node compress bronchi. Obstructive emphysema: due to partial obstruction. Granulomatous lesions: seen in severe cases as bacilli reach blood stream from pulmonary lesion/lymph nodes

Secondary Tuberculosis Adult type. Dormant bacilli, may persist for years before reactivating to produce Secondary Tuberculosis- often infectious. Localised to the apical & posterior segments of the upper lobes , where high oxygen concentration favours mycobacterial growth.

Early symptoms: fever, night sweats, weight loss, malaise, weakness. Secondary Tb..... Early symptoms: fever, night sweats, weight loss, malaise, weakness. Development of Cough : non productive initially, production of purulent sputum.

Diagnosis of Tuberculosis AFB (Acid Fast Bacilli) microscopy Presumptive diagnosis. Mycobacterial culture Definitive diagnosis Nucleic acid amplification Use limited due to low sensitivity. Drug susceptibility testing To find out drug resistance. Radiographic procedure Based on abnormal chest radiographic findings Tuberculin skin testing Lack of mycobacterial specificity limits use Cytokine release assay Diagnosis of latent tuberculosis infection.

Treatment Aim of treating Tuberculosis: To interrupt tuberculosis transmission by rendering patients non-infectious. To prevent morbidity & mortality by curing patients with tuberculosis disease.

Antitubercular drugs First line drugs : High efficacy & low toxicity. Isoniazid 5mg / kg /d , max of 300 mg / d Rifampin 10 mg/kg/d, max of 600 mg / d Pyrazinamide 20-25 mg/kg/d, max of 2g / d Ethambutol 15 -20 mg / kg / d Streptomycin 15 mg / kg / d

Second line agents Either low efficacy or high toxicity or both Slide 76 Drugs Doses Amikacin 15 mg/kg/d Aminosalicylic acid 8-12 g/d Capreomycin Ciprofloxacin 1500 mg/kg/d Clofazimine 200 mg/d Cycloserine 500-1000 mg/d Ethionamide 500-750 mg/d Levofloxacin 500 mg/d Rifabutin 300 mg/d Rifapentine 600 mg o.d weekly

Isoniazid Bacteriostatic for resting bacilli but bactericidal for rapidly dividing micro- organisms. Minimal effective conc.: 0.025-0.05 ug/ml. Peak plasma conc. : 1-2 hrs. Good oral & parenteral absorption.

Metabolism via acetylation (acetylisoniazid) & via hydrolysis (isonicotinic acid).

N-acetyltransferase type 2 (NAT 2) Fast acetylators Slow acetylators t½ of INH =1hr t½ of INH =2-5 hrs Hepatic insufficiency In case of renal impairment, may accumulate to toxic concentration. Dosage reduction recommended

Mechanism of action….inh

Resistance Mutation in catalase peroxidase Decreases its activity Prevent conversion of prodrug to active metabolite. Mutation in inh A gene involved in mycolic acid biosynthesis. Resulting in over expression of inh A.

Tuberculous cavity contains 109 micro- organism. 1 in 106 bacilli genetically resistant to INH. So, resistant mutants selected out in INH monotherapy.

Adverse effects INH induced hepatotoxicity. Peripheral neuropathy. Neurotoxicity. Hematological reactions. Hypersensitivity reactions.

INH induced hepatotoxicity. Multilobular necrosis – by liver biopsy. Risk factor : Older age & excessive alcohol intake. <20 years: Rare 35-49 years & >50 years: elevated serum transaminase level. > 5 times serum transaminase level: DISCONTINUE Drug.

Peripheral neuropathy: Due to interference with utilization of pyridoxine and its increased excretion in urine. Paresthesia of feet & hands. Pyridoxine 10 mg/d for treatment.

Neurotoxicity: Convulsion , in patients with seizure disorder. Optic neuropathy. Muscle twitching, stupor.

Hematological reaction: Agranulocytosis, eosinophilia, thrombocytopenia. Sideroblastic anemia (presence of ring sideroblasts in the bone marrow) Reversible . INH deprives ALAS2 (delta-aminolaevulinic acid synthase 2) of pyridoxal phosphate therefore inhibits haem synthesis. Overcome by concomitant administration of pyridoxine(25 to 50 mg/d).

Hypersensitivity reaction: Fever, rashes, hepatitis , SLE. INH overdose: Tonic - clonic seizure, metabolic acidosis, coma in pregnant women. Pyridoxine – specific antidote.

Pyridoxine – a necessary co-factor for production of neurotransmitter GABA. In isoniazid overdose, the susceptibility to seizures is induced by isoniazid binding to endogenous pyridoxine, make it inactive and resulting in a depletion of GABA in the brain. Therefore, the administration of exogenous pyridoxine directly counteracts this neurotoxic effect.

Increase in the generation of lactic acid as a result of muscular activity and recurrent seizures. Generation of acidic INH metabolites. Increase in ketoacids due to enhanced fatty acid oxidation.

COMA due to CNS catecholamine depletion.

Management : GI decontamination with gastric lavage, Stabilization of vital signs with provision of patent airway and IV sodium bicarbonate, Cardiovascular support with IV fluids and vasopressors. IV pyridoxine – highly effective for INH intoxication and should be administered to all symptomatic patients.

Uses of INH Latent Tb Recent converters: who test positive within 2 years after a documented negative skin test. Immunocompromised patients. Prevention, in close contacts of active cases of pulmonary Tb.

Effect : Mode : Monitoring: Increased serum phenytoin level. INH ᵡ Phenytoin Effect : Increased serum phenytoin level. Slow acetylators – Phenytoin toxicity. Mode : INH – hepatic microsomal enzyme inhibitor. Monitoring: Need to monitor serum phenytoin level.

INH ᵡ Rifampin Effect: Mode: Monitoring: Hepatotoxicity. Altered INH metabolism by rifampin. Monitoring: If LFT alter, discontinue one or both agents.

Rifamycins Rifampin Rifabutin Rifapentine

Mechanism of action: Bactericidal at 3-12 ng/ml for both intracellular & extracellular microorganisms. Kills organisms at poorly accessible sites like abscess, lung cavities.

Binds to β subunit of bacterial DNA dependent RNA polymerase Binds to β subunit of bacterial DNA dependent RNA polymerase. Suppression of initiation of chain formation but no chain elongation in RNA synthesis. Inhibit RNA synthesis in mammalian mitochondria, viral DNA dependent RNA Polymerase, reverse transcriptase at high concentration.

Mechanism of resistance Mutation between codons 507 & 533 of polymerase rpo B gene “for β subunit of RNA polymerase. Prevent binding of rifampin to RNA polymerase. Alterations in the target of drug: DNA dependent RNA polymerase.

Adverse effects Hepatitis from rifampin rarely occurs in patients with normal hepatic function. Chronic liver disease, alcoholism, and old age increase the risk of severe hepatitis when rifampin is given alone or concurrently with isoniazid. < 5% of patients, serum level of aminotransferase, phosphatase, bilirubin increase slightly, but diminish spontaneously despite continuation of treatment.

Rifampin may potentiate toxic effect of INH, particularly in patients in whom INH is rapidly inactivated. Rifampin induces microsomal enzyme. Facilitate conversion of monoacetylhydrazine, a metabolite of acetylated INH into an acylating agent that could cause hepatic necrosis.

Light chain proteinuria Light chain proteinuria. Imparts a harmless orange colour to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained)

GI disturbances – (epigastric distress, nausea, vomiting, abdominal cramps, diarrhea) occasionally required drug discontinuation. Thrombocytopenia, transient leukopenia, and anaemia have occurred during therapy.

Rifampin × Anticoagulants EFFECT : Decreased anticoagulant effect. MECHANISM: Rifampin induces CYP2C9, CYP2C19, CYP2D6 Increases elimination of other drug. MONITORING: Carefully monitor coagulation parameter. Adjust anticoagulant dose.

Ethambutol Inhibit mycobacterial arabinosyl transferases, which is involved in polymerization reaction of arabinoglycan …….essential component of mycobacterial cell wall.

Adv. : Retrobulbar neuritis causing loss of visual acuity and red-green colour blindness. (Serious). Not recommended for children under 5 years of age because of concern about the ability to test their visual acuity.

Pyrazinamide PRODRUG Pyrazinoic acid pyrazinamidase (ACTIVE FORM) encoded by pnc A BACTERICIDAL Impaired mutation of pnc A RESISTANCE

Hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.

Streptomycin Binds with S12 ribosomal protein. Interfere with initiation of peptide formation. Misreading of mRNA. Breakup of polysomes into nonfunctional monosomes. Irreversible inhibition of mycobacterial protein synthesis.

Ototoxic and nephrotoxic.(8th cranial nerve involves). Vertigo and hearing loss -most common. may be permanent.

Ethionamide Inhibits mycobacterial growth by inhibiting the activity of the enoyl-ACP reductase of fatty acid synthase II. Thus inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.

Neurologic symptoms – depression, drowsiness, and asthenia Neurologic symptoms – depression, drowsiness, and asthenia. olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors. Pyridoxine relieves.

Chemoprophylaxis To prevent development of active TB in patients who are at risk. Tuberculin skin test ȳ interferon test Mantoux test T-Spot.Tb Heaf test QuantiFeron Tb Gold Tine test

Indications for chemoprophylaxis: New born of a mother with active TB. Young children (<6 yrs.) with positive TB. Household contacts of patients with TB. Patients with positive tuberculin test with additional risk factors such as diabetes mellitus, malignancy, AIDS.

Isoniazid prophylaxis, continued for 12 months Isoniazid prophylaxis, continued for 12 months. Pyridoxine co-administered. HIV infected, exposed to MDRTb – rifampin + pyrazinamide (with close monitoring for hepatic toxicity) or high-dose ethambutol +pyrazinamide, with or without a fluoroquinolone.

FOUR drug regimen treatment for whom?

Known to exposed to drug resistant organisms. Recent immigrants. Pts with extrapulmonary TB. Pts with meningitis. HIV pts.

Continued for atleast 6 months after three negative cultures obtained.

MDT Objectives: To make patient non-infectious as early as possible by rapidly killing the dividing bacilli by using 3 to 4 bactericidal drugs. To prevent the development of drug-resistant bacilli. To prevent relapse by killing the persisters (dormant bacilli). To reduce the total duration of effective therapy.

Recommended by WHO. Choice of treatment regimen based on: Their efficacy, effectiveness, availability of financial recourses.

Long course regimens: INH alone with one or two bacteriostatic drugs for 18 months. Poor patient compliance, high failure rate.

Short course regimen: 6-9 months duration. Highly effective. Less toxic.

Intensive phase: - 3-4 tuberculocidal drugs daily or thrice weekly for a period of 2-3 months. - To render the patient non-contagious. INH 300mg + Rifampicin 600 mg + Pyrazinamide 1500 mg + Ethambutol 1000 mg/Streptomycin 1000 mg + Pyridoxine 10 mg daily for 2 months.

Continuous phase: - 2-3 drugs usually INH & Rifampicin daily or thrice weekly for a period of 4-6 months. - Helps to eliminate persisters & prevents relapse. - INH 300mg +Pyridoxine 10 mg + Rifampicin 600 mg daily for 4 months.

DOTS …. Backbone of RNTCP

RNTCP: Revised National Tuberculosis Control Programme, launched in 1997 DOTS: Directly observed treatment short course.

Patient is administered drugs under the supervision of a health worker to ensure that drugs are actually consumed. Supervised and monitored by bacteriological examinations. Aimed at ensuring patient compliance thus preventing the emergence of drug resistant tuberculosis.

WHO recommended treatment regimen Diagnostic category Type of patient Intensive phase Continuation phase Total duration (months) Category 1 New sputum positive, seriously ill sputum negative, seriously ill extrapulmonary Daily 2HRZE Thrice weekly 2 (HRZE)3 4HR 4(HR)3 6 Category 2 Sputum positive relapse, sputum positive treatment 2HRZES 1HRZE 2(HRZES)3 1(HRZE)3 5 HRE 5(HRE)3 8

Diagnostic category Type of patient Intensive phase Continuation phase Total duration (months) Category 3 Sputum negative, not seriously ill, extrapulmonary, not seriously ill Daily 2 HRT Thrice weekly 2(HRZ)3 4HR 4(HR)3 6 Category 4 Chronic or suspected MDR-TB cases Specially designed standardized or individualized regimen H=isoniazid, R=Rifampicin, Z=Pyrazinamide, E=Ethambutol, S=Streptomycin HRZ & E= orally ; S= i.m Prefix= number of months, Subscript= doses per week.

DOTS plus : - first WHO endorsed DOTS-Plus programmes began in 2000 - To treat MDR-TB using second line anti TB drugs. - Recommended in areas where DOTS is fully in place.

Five components of DOTS Plus

Sustained political and administrative commitment Recording and reporting system Uninterrupted supply of quality assured anti-TB drugs Appropriate treatment strategies Diagnosis of MDR-TB through culture and drug susceptibility testing. Sustained political and administrative commitment

Sustained political and administrative commitment A well functioning DOTS programme. Long term investment of staff and resources. Coordination efforts between community, local governments, and international agencies. Addressing the factors leading to the emergence of MDR-TB

Diagnosis of MDR-TB through quality- assured culture and drug susceptibility testing. Proper triage of patients for Culture & testing and management under DOTS-Plus. Co-ordination with National and Supra-National Reference Laboratories

Appropriate treatment strategies that utilize second-line drugs under proper management conditions Rational standardized treatment design (evidence- based) Directly observed therapy (DOT) ensuring long-term adherence. Monitoring and management of adverse drug reactions. Adequate human resources.

TB treatment in HIV patients: Rifabutin preferred over rifampicin in HIV patients on antiretroviral drugs as it doesn’t interact with PI’s.

Role of glucocorticoids in tuberculosis

Tuberculosis is a relative CI for use of glucocorticoids.

TB of serum membrane like pleura, peritonium, pericardium, meninges, to prevent fibrous tissue formation. To treat hypersensitivity reactions to antiTB drugs. Tuberculosis of eye, larynx, genitourinary tract to prevent fibrosis & scar tissue formation. Once patients general condition improves, steroid is tapered to avoid HPA axis suppression.