Tuberculosis is treated in two phases—an initial phase using 4 drugs and a continuation phase using two drugs in fully sensitive cases. Treatment requires specialised knowledge, particularly where the disease involves resistant organisms or non-respiratory organs.

The regimens given below are recommended for the treatment of tuberculosis in the UK; variations occur in other countries. Either the unsupervised regimen or the supervised regimen described below should be used; the two regimens should not be used concurrently. Compliance with therapy is a major determinant of its success. Treatment needs to be carefully monitored in families in whom concordance may be problematic.

Initial phase

The concurrent use of 4 drugs during the initial phase is designed to reduce the bacterial population as rapidly as possible and to prevent the emergence of drug-resistant bacteria.
The drugs are best given as combination preparations, provided the respective dose of each drug is appropriate, unless the child is unable to swallow the tablets or one of the components cannot be given because of resistance or intolerance.

The treatment of choice for the initial phase is the daily use of isoniazid, rifampicin, pyrazinamide and ethambutol. However, care is needed in young children receiving ethambutol because of the difficulty in testing eyesight and in obtaining reports of visual symptoms (see below). Treatment should be started without waiting for culture results if clinical features or histology results are consistent with tuberculosis; treatment should be continued even if initial culture results are negative.

The initial phase drugs should be continued for 2 months. Where a positive culture for M. tuberculosis has been obtained, but susceptibility results are not available after 2 months, treatment with rifampicin, isoniazid, pyrazinamide and ethambutol should be continued until full susceptibility is confirmed, even if this is for longer than 2 months.

Streptomycin is rarely used in the UK although it may be used in the initial phase of treatment if resistance to isoniazid has been established before therapy is commenced and ethambutol is contra-indicated.

Continuation phase

After the initial phase, treatment is continued for a further 4 months with isoniazid and rifampicin (preferably given as a combination preparation). Longer treatment is necessary for meningitis, direct spinal cord involvement, and for resistant organisms which may also require modification of the regimen.

Unsupervised treatment

The following regimen should be used for those who are likely to take antituberculous drugs reliably without supervision by a healthcare worker. Children and families who are unlikely to comply with daily administration of antituberculous drugs should be treated with the regimen described under Supervised Treatment.

Recommended dosage for standard unsupervised 6-month treatment
Isoniazid (for 6 months) Child 1 month–18 years 10 mg/kg (max. 300 mg) once daily

Rifampicin (for 6 months) Child 1 month–18 years 15 mg/kg once daily (max. 450 mg daily if body-weight under 50 kg; max. 600 mg daily if body-weight 50 kg and over)

Pyrazinamide (for 2-month initial phase only) Child 1 month–18 years 35 mg/kg once daily (max. 1.5 g daily if body-weight under 50 kg; max. 2 g daily if body-weight 50 kg and over)

Ethambutol (for 2-month initial phase only) Child 1 month–18 years 20 mg/kg once daily

Note In general, doses should be rounded up to facilitate administration of suitable volumes of liquid or an appropriate strength of tablet. The exception is ethambutol due to the risk of toxicity. Doses may also need to be recalculated to allow for weight gain in younger children.
The fixed-dose combination preparations (Rifater®, Rifinah®) are unlicensed for use in children. Consideration may be given to use of these preparations in older children, provided the respective dose of each drug is appropriate for the weight of the child.

Pregnancy

The standard regimen (above) may be used during pregnancy. Streptomycin should not be given in pregnancy.

Breast-feeding

The standard regimen (above) may be used during breast-feeding.

Neonates

Congenital tuberculosis is acquired from maternal extrapulmonary sites at birth, particularly the genital tract; if infection is suspected, the baby will require treatment with isoniazid 10 mg/kg once daily, rifampicin 15 mg/kg once daily, pyrazinamide 35 mg/kg once daily, and ethambutol 20 mg/kg once daily. Isoniazid, rifampicin, pyrazinamide, and ethambutol are used for 2 months during the initial phase of treatment. After the initial phase, treatment is continued for a further 4 months with isoniazid and rifampicin.

Supervised treatment

Drug administration needs to be fully supervised by a healthcare worker (directly observed therapy, DOT) in children or families who cannot comply reliably with the treatment regimen. These patients are given isoniazid, rifampicin, pyrazinamide and ethambutol (or streptomycin) 3 times a week under supervision for the first 2 months followed by isoniazid and rifampicin 3 times a week for a further 4 months.

Recommended dosage for intermitttent supervised 6-month treatment
Isoniazid (for 6 months) Child 1 month–18 years 15 mg/kg (max. 900 mg) 3 times a week

Rifampicin (for 6 months) Child 1 month–18 years 15 mg/kg (max. 900 mg) 3 times a week

Pyrazinamide (for 2-month initial phase only) Child 1 month–18 years 50 mg/kg 3 times a week (max. 2 g 3 times a week if body-weight under 50 kg; max. 2.5 g 3 times a week if body-weight 50 kg and over)

Ethambutol (for 2-month initial phase only) Child 1 month–18 years 30 mg/kg 3 times a week

Note In general, doses should be rounded up to facilitate administration of suitable volumes of liquid or an appropriate strength of tablet. The exception is ethambutol due to the risk of toxicity. Doses may also need to be recalculated to allow for weight gain in younger children.
The fixed-dose combination preparations (Rifater®, Rifinah®) are unlicensed for use in children. Consideration may be given to use of these preparations in older children, provided the respective dose of each drug is appropriate for the weight of the child.

Immunocompromised patients

Multi-resistant Mycobacterium tuberculosis may be present in immunocompromised children. The organism should always be cultured to confirm its type and drug sensitivity. Confirmed M. tuberculosis infection sensitive to first-line drugs should be treated with a standard 6-month regimen; after completing treatment, children should be closely monitored. The regimen may need to be modified if infection is caused by resistant organisms, and specialist advice is needed.

Specialist advice should be sought about tuberculosis treatment or chemoprophylaxis in a HIV-positive individual; care is required in choosing the regimen and in avoiding potentially serious interactions. Starting antiretroviral treatment in the first 2 months of antituberculosis treatment increases the risk of immune reconstitution syndrome.

Infection may also be caused by other mycobacteria e.g. M. avium complex in which case specialist advice on management is needed.

Corticosteroids

A corticosteroid should be given (in addition to antituberculosis therapy) for meningeal or pericardial tuberculosis.

Prevention of tuberculosis

Chemoprophylaxis may be required in children who are close contacts of a case of smear-positive pulmonary tuberculosis and who are severely immunosuppressed (including congenital immunodeficiencies, cytotoxic or immunosuppressive therapy) and in those who have evidence of latent tuberculosis and require treatment with immunosuppressants; expert advice should be sought.

Chemoprophylaxis involves use of either isoniazid alone for 6 months or of isoniazid and rifampicin for 3 months..

Monitoring

Since isoniazid, rifampicin and pyrazinamide are associated with liver toxicity, hepatic function should be checked before treatment with these drugs. Those with pre-existing liver disease 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.

In view of the need to comply fully with antituberculous treatment on the one hand and to guard against serious liver damage on the other, children and their carers should be informed carefully how to recognise signs of liver disorders and advised to discontinue treatment and seek immediate medical attention should symptoms of liver disease occur.

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 (see below).

Major causes of treatment failure are incorrect prescribing by the physician and inadequate compliance by the child or their carer. Monthly tablet counts and urine examination (rifampicin imparts an orange-red coloration) may be useful indicators of compliance with treatment. Avoid both excessive and inadequate dosage. Treatment should be supervised by a specialist paediatrician.

RECOMMENDATIONS FROM WHO AND EUROPEAN MEDICINES AGENCY.

G.Mohan.