Tuberculosis is a chronic infectious disease caused primarily by Mycobacterium tuberculosis or sometimes M.bovis; the closely related form M. africanum has occasionally been implicated as a cause of human tuberculosis. Infection is usually due to inhalation of infected droplet nuclei, and the lung is generally the first organ affected, but the primary infection is usually asymptomatic.

Drug treatment for clinical infection always involves multi drug regimens, chosen to provide early bactericidal activity (activity against actively dividing mycobacteria), and sterilizing activity (activity against non-dividing, semi-dormant organisms), and to prevent resistance. Treatment is divided into 2 phases, an initial intense phase involving daily administration of 3 or more drugs for 8 weeks, followed by a continuation phase for 4 or more months usually 2 drugs are used in the continuation phase and they may be administered daily or 2 or 3 times per week. The continuation phase may be extended beyond 4 months when treating extrapulmonary tuberculosis or AIDS - associated tuberculosis.

Direct observation of therapy (DOT) is considered essential to ensure compliance in the initial phase and also useful in the continuation phase if patients are receiving rifampicin. The six antituberculosis drugs, isoniazid, rifampicin, pyrazinamide, streptomycin, (which are bactericidal) ethambutol and thioacetazone (which are bacteriostatic) are used in various combinations as part of WHO recommended treatment regimens

In supervised regimens change of drug regimen should be considered only if the patient fails to respond after 5 months of DOTs.

Isoniazid, Rifampicin, and Pyrazinamide are components of all antituberculosis drug regimens currently recommended by WHO. Unsupervised and alternative regimens as set out in the following tables may be administer as specified.

^a Unless otherwise indicated, doses are suitable for both adults and children
^b 15mg/kg for children
^c Not suitable for children

World wide, an important predisposing cause of immuno suppression leading to tuberculosis is human immunodeficiency virus (HIV) infection. It increases susceptibility to primary infection and increases the reactivation rate of tuberculosis. Preventative antituberculosis therapy for such persons is recommended.

Chemoprophylaxis with isoniazid can prevent the development or clinically apparent disease in persons in close contact with infectious patients, and in other persons at high risk particularly those who are immuno deficient.

Monitoring: since isoniazid, rifampicin and pyrazinamide are associated with liver toxicity, hepatic function should be checked before treatment with these drugs. Those with preexisting liver disease or alcohol dependence should have frequent checks particularly in the first 2 months. If there is no evidence of liver disease (and pre-treatment liver function is normal), further checks are only necessary if the patient develops fever, malaise, vomiting, jaundice or unexplained deterioration during treatment.

Renal function should be checked before treatment with antituberculous drugs and appropriate dosage adjustments made. Streptomycin or Ethambutol should preferably be avoided in patients with renal impairment, but if used, the dose should be reduced and the plasma - drug concentration monitored. Visual acuity should be tested before Ethambutol is used.

Isoniazid is cheap and highly effective. It should always be indicated in any antituberculous regimen unless there is a specific contraindication. Its only common side effect is peripheral neuropathy which is more likely to occur where there are pre-existing risk factors such as diabetes, alcohol dependence, chronic renal failure, malnutrition and HIV infection. In these circumstances pyridoxine 10 mg daily (or 20 mg daily if suitable product not available) should be given prophylactically from the start of treatment. Other side effects such as hepatitis and psychosis are rare.

Rifampicin, a rifamycin, is a key component of any antituberculous regimen. Like isoniazid it should always be included unless there is a specific contraindication. During the first two months (initial phase) of rifampicin administration transient disturbance of liver function with elevated serum transaminases is common but generally does not require interruption of treatment. Occasionally more serious liver toxicity requires a change of treatment particularly in those with preexisting liver disease (important: see monitoring above). Rifampicin induces hepatic enzymes which accelerate the metabolism of several drugs including oestrogens, corticosteroids, phenytoin, sulphonylureas, and anti-coagulants. The effectiveness of oral contraceptives is reduced and alternative family planning advice should be offered.

Pyrazinamide is a bactericidal drug only active against intracellular dividing forms of Mycobactrium tuberculosis; it exerts its main effect only in the first two or three months. It is particularly useful in tuberculoses meningitis because of good meningeal penetration. It is not active against M.Bovis. Serious liver toxicity may occasionally occur.

Ethambutol is included in a treatment regimen if isoniazid resistance is suspected, it can be omitted if the risk of resistance is low.

Side effects of Ethambutol are largely confined to visual disturbances in the form of loss of acuity, colour blindness, and restriction of visual fields. These toxic effects are more common where excessive dosage is used or if the patients renal function is impaired. Early discontinuation of the drug is almost always followed by recovery of eyesight. Patients who cannot understand warnings about visual side effects should, if possible, be given an alternative drug. In particular, Ethambutol should be used with caution in children until they are at least 5 years old and capable of reporting symptomatic visual changes accurately.

Ethambutol

Tablet, 100mg, 400mg

Indications: - tuberculosis, in combination with other drugs (see notes and tables above)

Cautions: - visual disturbances - ocular examination recommended before and during treatment; reduce dose in renal impairment and monitor plasma concentration: elderly; pregnancy; breastfeeding.

Contraindications: - optic neuritis, poor vision, children under at least 6 years of age.

Side effects: - optic neuritis, red/green colour blindness, peripheral neuritis, rarely rash, pruritus, uriticaria, and thrombocytopenia.

Dose and Administration

Tuberculosis (initial phase of combination therapy; see notes and tables above), by mouth, Adult 15mg/kg daily or 30 mg/kg 3 times a week; child 15mg/kg daily.

Storage: - at room temperature, in a well-closed containers. Protect from light, moisture, and excessive heat.

Isoniazid

Tablet, 100mg, 300mg
Injection, 100mg/ml in 10ml ampoule

Indications: - tuberculosis treatment, in combination with other drugs (see notes and tables above); tuberculosis prophylaxis.

Cautions: - hepatic impairment; renal impairment; slow acetylator status (increased risk of side effects); epilepsy; history of psychosis; alcohol dependence, malnutrition, diabetes mellitus, HIV infection (risk of peripheral neuritis); pregnancy and breast-feeding; porphyria

Drug interactions: - carbamazepine, ethosuximide, phenytoin.

Side effects: - nausea, vomiting, constipation, dry mouth; peripheral neuritis with high doses (pyridoxine prophylaxis, see notes above), optic neuritis, convulsions, psychotic episodes, vertigo; hypersensitivity reactions including fever, erythemamultiforme, purpura; blood disorders including agranulocytosis, haemolytic anaemia, aplastic anaemia; hepatitis (especially over age of 35 years); systemic lupus erythematosus- like syndrome, pellagra, hyperreflexia, difficulty with micturation, hyperglycaemia, and gynaecomastia reported.

Contraindications: - drug induced hepatic disease.

Dose and Administration

Tuberculosis, treatment (combination therapy; see also notes and tables), by mouth, Adult and Child 5mg/kg (4-6 mg/kg) daily (maximum, 300 mg daily), or 10mg/kg 3 times weekly.

Tuberculosis, treatment in critically ill patients unable to take oral therapy (combination therapy), by intramuscular injection, Adult 200 - 300 mg as single daily dose; Child 10 - 20 mg/kg daily.

Tuberculosis, prophylaxis, by mouth, Adult 300mg daily for at least 6 months; child 5mg/kg daily for at least 6 months.

Note: - isoniazid should be taken on an empty stomach; if taken with food to reduce gastrointestinal irritation, oral absorption and bioavailability may be impaired.

Storage: - at room temperature, in a well closed, light resistant containers.

Ethambutol + Isoniazid

Tablet, 400mg + 150mg

Indications: - tuberculosis, in combination with other drugs (see notes and tables above)

Cautions: - see ethambutol, and isoniazid

Drug interactions: - see ethambutol, and isoniazid

Side effects: - see ethambutol, and isoniazid

Contraindications: - preparation not suitable for use in children; see ethambutol, and isoniazid.

Dose and Administration

Tuberculosis, continuation phase of 8-month regimen in place of thioacetazone with isoniazid (see notes and tables), by mouth, Adult ethambutol hydrochloride 800mg and isoniazide 300 mg daily.

Storage: - at room temperature, in a well closed, light resistant container.

Pyrazinamide

Tablet, 500mg

Indication: - tuberculosis, in combination with other drugs (see notes and tables above)

Cautions: - hepatic impairment (monitor hepatic function); renal impairment; diabetes mellitus (monitor blood glucose - may change suddenly); increased uric acid level in urine; breast-feeding.

Note: - Patients or their carers should be told how to recognize signs of liver disorders and advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop.

Drug interactions: - uricosurics (probenecid, sulfinpyrazone)

Side effects: - hepatotoxicity including fever, anorexia, hepatomegaly, jaundice, liver failure; nausea, vomiting; arthralgia; gout; sideroblastic anaemia; urticaria; skin flushing.

Contraindications: - severe hepatic impairment; porphyria.

Dose and Administration

Tuberculosis (initial phase of combination therapy; see notes and tables above), by mouth, Adult and child 25-mg/kg daily or 35 mg/kg 3 times weekly.

Storage: - at room temperature, in a well closed container.

Rifampicin

Capsule, 150mg, 300mg, 600mg
Syrup, 20mg/5ml
Powder for injection (sodium) 300mg, 600mg in vial

Indications: - tuberculosis, in combination with other drugs (see notes and tables above); leprosy, see section 7.1.4

Cautions: - reduce dose in hepatic impairment, liver function tests and blood counts required in liver disorders, elderly, and on prolonged therapy; renal impairment (if dose above 600 mg daily); pregnancy; breastfeeding; porphyria; discolour soft contact lenses.

Note: Advise patients on oral contraceptives to use additional means.

Resumption of rifampicin treatment after a long interval may cause serious immonulogical reactions, resulting in renal impairment, haemolysis, or thrombocytopenia. Discontinue permanently if serious adverse effects occur.

Patients or their carers should be told how to recognize signs of liver disorders and advised to discontinue treatment and seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop.

Drug interactions: - azathioprine, ciclosporin, contraceptives, dexamethasone, fluconazole, fludrocortisone, glibenclamide, haloperidol, hydrocortisone, indinavir, saquinavir, lopinavir, nelfinavir, nifedipine, levonorgestrel, medroxyprogesterone, norethisterone, phenytoin, prednisolone, guanidine, verapamil, warfarin.

Contraindications: - hypersensitivity to rifamycins, jaundice.

Side effects: - severe gastrointestinal disturbances including anorexia, nausea, vomiting and diarrhea (antibiotic associated colitis reported); rashes, fever, influenza-like syndrome and respiratory symptoms, collapse, shock, haemolytic anaemia, acute renal failure, and thrombocytopenic purpura-more frequent with intermittent therapy; alterations of liver function jaundice and potentially fatal hepatitis (dose related; do not exceed maximum dose of 600 mg daily); stains body fluid (urine, tears, saliva, and sputum) orange - red.

Dose and Administrations

Tuberculosis (combination therapy; see notes and tables above). By mouth, Adult and child 10mg/kg daily or 3 times weekly (maximum dose, 600mg daily)

Note: - take dose at least 30 minutes before a meal, as absorption is reduced when taken with food.

Storage: - below 40°c, in a tight, light - resistant container.

Rifampicin + Isoniazid

Tablet, 150mg + 100mg, 300mg + 150mg
Capsule, 150mg + 100mg

Indications: - tuberculosis (see notes and tables above)

Cautions: - preparation not suitable for use in children; see under rifampicin, and Isoniazid

Drug interactions, Contraindications, Side effects; see under rifampicin, and isoniazid

Dose and Administration: -

Tuberculosis, 6 - month regimen (combination therapy; see notes and tables), by mouth, Adult 10mg/kg (rifampicin) and 5mg/kg (isoniazid) daily.

Tuberculosis, 6-month regimen (combination therapy; see notes and tables), by mouth, Adult 10mg/kg (rifampicin) and 10mg/kg (isoniazid) 3 times a week.

Rifampicin + Isoniazid + Pyrazinamide

Tablet, 150mg + 75mg + 400mg

Indications: - tuberculosis, in combination with other drugs (see notes and tables above)

Cautions; Side effects, Drug interactions; see Rifampicin, Isoniazid, and Pyrazinamide

Contraindications: - preparations not suitable for use in children; see rifampicin, isoniazid, and pyrazinamide.

Dose and Administrations

Tuberculosis, initial phase of 6 - month treatment regimens (see notes and tables above), by mouth, Adult rifampicin 10mg/kg, isoniazid 5mg/kg, and Pyrazinamide 25 mg/kg daily or rifampicin 10mg/kg, isoniazid 10mg/kg and Pyrazinamide 35mg/kg 3 times a week.

Rifampicin + Isoniazid + Pyrazinamide + Ethambutol

Tablet, 150mg + 75mg + 400mg + 275mg

Indications: - tuberculosis (see notes and tables above)

Cautions, Side effects, Drug interactions, Contraindications; see rifampicin, isoniazid, Pyrazinamide and Ethambutol.

Dose and Administrations

Tuberculosis, induction phase of 6-month regimen (see notes and tables above), by mouth, Adult rifampicin 10mg/kg, isoniazid 5mg/kg, Pyrazinamide 25mg/kg, and Ethambutol hydrochloride 15mg/kg daily.

Streptomycin Sulphate

Powder for injection - 1g, 5g bases in vial

Indications: - tuberculosis, in combination with other drugs (see notes and tables above)

Cautions: -children - painful injection, avoid use if possible, renal impairment, infants, and elderly (dosage adjustment), and monitor renal, auditory, and vestibular function, and plasma streptomycin concentrations.

Drug interactions: - alcuronium, ciclosporin, cisplatin, furosemide, neostigmine, pyridostigmine, suxamethonium, and vecuronium.

Side effects: vestibular and auditory damage; nephrotoxicity; hypersensitivity reactions - withdraw treatment; paraesthesia of mouth, rarely, hypomagnesaemia on prolonged therapy; antibiotic associated colitis; also nausea, vomiting, rash; rarely, haemolytic anaemia, aplastic anaemia, agranulocytosis, thrombocytopenia; pain and abscess at injection site.

Contraindications: hearing disorders; myasthenia gravis, pregnancy.

Dose and Administration

Tuberculosis (initial phase of combination therapy; see notes and table above), by deep intramuscular injection, Adult and child 15mg/kg daily or 3 times a week (patients over 60 years or those weighing less than 50kg may not tolerate doses above 500 - 750mg daily)

Storage: - at room temperature protect from light.

Note: Reconstituted solutions may vary in colour from colourless to yellow and may darken on exposure to light but potency is not affected for 48 hours at room temperature and for up to 14 days when refrigerated.