Treatment of Tuberculosis

Name: Razvi Janny

Roll no. 19

Aims of TB treatment

1) To interrupt transmission by rendering patients noninfectious.

2) Prevent morbidity and death by curing patients with TB while preventing emergence of drug resistance.

Drugs

First line drugs Second line drugs

Well absorbed after oral administration

Peak levels at 2 – 4 h.

Lower degree of efficacy.

Higher degree of intolerabilityand toxicity.

4 major drugs are considered the first-line agents for treatment:

1) Isoniazid

2) Rifampin

3) Pyrazinamide

4) Ethambutol

Second-line drugs:

1)Injectable aminoglycosides: streptomycin,

Kanamycin

amikacin

2)Oral agents: ethionamide

cycloserine

PAS

Third gen. fluoroquinolones

Isoniazid Has bactericidal activity against actively

dividing intracellular and extracellular organisms.

Has bacteriostatic activity against slowly dividing organisms.

Often given together with 25-50mg pyridoxine daily to prevent drug-related peripheral neuropathy.

Mechanism of action

INH

INH+

Nicotinic acyl-NADHcomplex

Blocks InhA

Inhibit fatty acid synthesis and mycolic

acid synthesis which is essential

for the bacterial cellwall.

KatG

NADH

Adverse effects Drug-induced liver injury Peripheral neuropathy Fever Anemia Acne Arthritic syndrome SLE-like syndrome Optic atrophy seizures

Rifampin Has bactericidal activity against both dividing

and non-dividing M.tuberculosis with sterilizing activity.

Mechanism of action Exerts both intracellular and extracellular

bactericidal activity. Binds to and inhibits mycobacterial DNA-

dependent RNA polymerase, blocking RNA synthesis.

Adverse effects Hepatotoxicity in case of preexisting liver

disease. Pruritus Rash Gastrointestinal symptoms Pancytopenia Hypersensitivity reactions.

Ethambutol It is a bacteriostatic antimycobacterial agent. Provides synergy with other drugs. Among the first-line drugs, it is the least potent.

Mechanism of action Inhibition of the arabinosyltransferases involved

in cell wall synthesis.

Adverse effects Optic neuritis Peripheral sensory neuropathy.

Pyrazinamide

• Bactericidal drug used in the initial phase of TB treatment.

• Shortens duration of treatment.

• Decreases rates of relapse.

Mechanism of action:

• More active against slowly replicating organisms than against actively replicating organisms.

• It is a prodrug that is converted by mycobacterial pyrimidase to the active form, pyrazinoic acid.

• It is active only in acidic environments as in phagocytes or granulomas.

• Fatty acid synthetase 1 is the primary target.

Adverse effects

• Hepatotoxicity

• Hyperuricemia

• Teratogenicity if given during pregnancy.

Streptomycin

• First antimycobacterial agent used for the treatment of TB.

• Bactericidal against dividing M.tuberculosis organisms.

Mechanism of action:

• Inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome.

Adverse effects:

• Ototoxicity (primarily vestibulotoxicity)

• Neuropathy

• Renal toxicity

Second-line drugs

FluoroquinolonesMechanism of action

• Inhibit mycobacterial DNA gyrase and topoisomerase IV, preventing cell replication and protein synthesis.

• Bactericidal.

Adverse effects:

• Gastrointestinal intolerance

• Rashes

• Dizziness

• Headache

• Cardiac arrhythmias

Capreomycin

Mechanism of action:

• Involves interference with the mycobacterial ribosome and inhibition of protein synthesis.

Adverse effects:

• Hypokalemia

• Hypomagnesemia

• Ototoxicity

• Renal toxicity

Amikacin and kanamycin

• Exert mycobactericidal activity

• Given by IM or IV route.

Adverse effects

• Ototoxicity

• Nephrotoxicity

• Neurotoxicity

Ethionamide

Mechanism of action:

• Bacteriostatic against metabolically active M.tuberculosis.

• Inhibits InhA gene product enoyl-acyl carrier protein reductase which is involved in mycolic acid synthesis.

Adverse effects:

• Gastrointestinal reactions (abdominal pain, nausea and vomiting)

• Central and peripheral neurologic side effects.

• Reversible hepatitis

• Hypersensitivity reactions

• Hypothyroidism

Para-aminosalicylic acid

• Oral agent.

• Used in multiple drug resistant TB.

Mechanism of action:

• Bacteriostatic.

• Inhibition of folate synthesis and of iron uptake.

Adverse effects:

• Nausea, vomiting and diarrhea.

• PAS may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

Management Chemotherapy

Initial phase Continuation phase

Reduce bacterial population rapidly. Destroy any remaining

bacteria.

• Standard treatment involves 6 months treatment with isoniazid, rifampicin, pyrazinamide and ethambutol.

• Fixed-dose tablets combining two or three drugs are preferred.

• Treatment should be started immediately in any patient who is smear-positive or smear-negative but with typical chest x-ray changes and no response to standard antibiotics.

• 6-months therapy is appropriate for new onset pulmonary TB.

• However, a 12-months therapy is recommended for meningeal TB, including involvement of the spinal cord.

• Treatment may be given daily throughout the course or intermittently (either thrice or twice weekly)

• Patients with cavitary pulmonary TB and delayed sputum-culture conversion should have continuation phase extended by 3 months.

Recommended dosage for initial treatment of tuberculosis in adults.

Drug Daily dose Thrice-weekly dose

Isoniazid 5 mg/kg, max 300 mg 10 mg/kg, max 900 mg

Rifampin 10 mg/kg, max 600 mg 10 mg/kg, max 600 mg

Pyrazinamide 25 mg/kg, max 2 g 35 mg/kg, max 3 g

Ethambutol 15 mg/kg 30 mg/kg

Initial phase Continuation phase

Duration, months

Drugs Duration, months

Drugs

New smear or culture positive cases

2 HRZE 4 HR

New culture negative cases

2 HRZE 4 HR

Pregnancy 2 HRE 7 HR

Relapses and default (pending susceptibility testing)

3 HRZES 5 HRE

Resistance to H 6 RZE

Resistance to R 12-18 HZEQ

Resistance to all first-line drugs.

Atleast 20 months

1 injectable agent + 3 of these 4: E, cycloserine,

Q, PAS.

Management guidelines for patients with documented XDR-TB.

1. Use any first-line oral agents that may be effective.

2. Use an injectable agent to which the strain is susceptible, and consider an extended duration of use (12 months).

3. Use a later generation fluoroquinolone (moxifloxacin).

4. Use all second-line oral agents (PAS, cycloserine, ethinamide, prothionamide).

5. Use 2 or more of the following drugs of unclear role: clofazimine, linezolid, thiacetazone.

• Administer high-dose isoniazid if low-level resistance to this drug is documented.

• Adjuvent surgery if there is localized disease.

• Strong infection-control measures implemented.

• Implement DOTs therapy and comprehensive bacteriologic and clinical monitoring.

Treatment of HIV-associated TB• ART is initiated early in TB therapy (within the

first 8 weeks)

• The IRIS may appear as early as 1 week after initiation of ART. This is treated with varying doses of glucocorticoids.

Regimens for the treatment of latent TB infection in adults.

Regimen Schedule Duration

Isoniazid 300 mg daily (5 mg/kg)

9 months

Rifampin 600 mg daily (10 mg/kg)

4 months

Isoniazid plus rifapentine

900 mg weekly + 900 mg weekly (15 mg/kg)

4 months

Monitering treatment response• Patients should have their sputum examined

monthly until cultures become negative.

• Smears that are positive after 3 months of treatment is indicative of treatment failure or drug resistance.

• Drug susceptibility testing must then be done.

Monitering drug toxicityDrug Assessment Management

Isoniazid If ALT is >5 x ULN • Obtain history of alcohol consumption.

• Discontinue H, Z, R.

Rifampin If primary elevation is in bilirubin and ALP, more likely rifampin.

• Discontinue R• Substitute it with Q.

Ethambutol Decrease in visual acuity or color vision.

• Discontinue E and repeat ocular exam.

Pyrazinamide If ALT is >5 x ULN Same as for H.

Fluoroquinolone If QT prolongation is discovered on ECG.

Check audiometry, BUN and creatinine monthly.

Aminoglycoside Abnormal results on audiometry testing, BUN, creatinine, electrolytes at baseline.

• Discontinue aminoglycosides.

• Correct electrolytes• Seek ENT consultation.

Treatment failure and relapse• Patients with treatment failure should receive

an empirical regimen, including second line agents.

• Once drug susceptibility testing results are available, the regimen should be adjusted accordingly.

• Patients who have relapsed are treated with all four first-line drugs plus streptomycin.

Control and preventionDetection of latent TB

•Cases of latent TB are identified using tuberculin skin test.

Tuberculin skin tests

Heaf test Mantoux test

Positive when induration is 5-14 mm.

BCG vaccine• Effective in the protection of infants and young

children from relatively serious forms of TB.

• Given intradermally.

• Recommended for routine use at birth in countries with high TB prevalence.

• Not given to immunocompromised persons.

Directly observed therapy (DOT)• Involves supervised administration of therapy

by trained staff 3 times weekly to improve adherence.

• It is an important control strategy in resource-poor nations.

DOTS approach consists of:

1.Political commitment with increased and sustained financing.

2.Case detection through quality-assured bacteriology (sputum smear, culture and drug susceptibility testing).

3.Administration of standardized short-course chemotherapy, with direct supervision and patient support.

4.Effective drug supply and management system.

5. Monitoring and evaluation of treatment outcomes.

THANK YOU