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:

Mycobacterium tuberculosis : 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.

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.

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.

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 agentsEither low efficacy or high toxicity or both Slide 76

Drugs Drugs Doses Doses

Amikacin 15 mg/kg/d

Aminosalicylic acid 8-12 g/d

Capreomycin 15 mg/kg/d

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

1. Mutation in catalase peroxidase Decreases its activity Prevent conversion of prodrug to active

metabolite.

2. 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.

• 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.

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:

• Hepatotoxicity.

• Mode:

• 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.

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

1. Mutation between codons 507 & 533 of polymerase rpo B gene “for β subunit of RNA polymerase. Prevent binding of rifampin to RNA polymerase.

2. 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.

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.

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:

1. New born of a mother with active TB.

2. Young children (<6 yrs.) with positive TB.

3. Household contacts of patients with TB.

4. Patients with positive tuberculin test with additional risk factors such as diabetes mellitus, malignancy, AIDS.

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?

1. Known to exposed to drug resistant organisms.

2. Recent immigrants.

3. Pts with extrapulmonary TB.

4. Pts with meningitis.

5. HIV pts.

Continued for atleast 6 months after three

negative cultures obtained.

MDTObjectives:

1. To make patient non-infectious as early as possible by rapidly killing the dividing bacilli by using 3 to 4 bactericidal drugs.

2. To prevent the development of drug-resistant bacilli.

3. To prevent relapse by killing the persisters (dormant bacilli).

4. 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 2HRZEThrice weekly 2 (HRZE)3

4HR

4(HR)3

6

6

Category 2 Sputum positive relapse, sputum positive treatment

Daily 2HRZES1HRZE

Thrice weekly2(HRZES)3

1(HRZE)3

5 HRE

5(HRE)3

8

8

H=isoniazid, R=Rifampicin, Z=Pyrazinamide, E=Ethambutol, S=Streptomycin HRZ & E= orally ; S= i.m Prefix= number of months, Subscript= doses per week.

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 weekly2(HRZ)3

4HR

4(HR)3

6

6

Category 4 Chronic or suspected MDR-TB cases

Specially designed standardized or individualized regimen

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 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.