Antituberculous Drugs

A combination of drugs is used to accelerate the response of tuberculosis to treatment and shorten the length of therapy needed for cure.¹
Unsupervised treatment involves daily dosing whereas supervised treatment is often given 3 times per week. Both dosing regimens are equally effective. Combination preparations should be used whenever possible to improve compliance and prevent accidental monotherapy.² Care must be taken when prescribing as many different compounds have similar trade-names eg, Rifinah™, Rimactazid™, Rifater™.³

First line drugs⁴

Isoniazid is able to kill dividing bacteria within host cells and is the most potent bactericidal drug. It has good penetration of tuberculous lesions and is excreted by the kidneys.
Rifampicin is a potent mycobacterial RNA polymerase inhibitor. It has good tissue penetration and gives an orange discoloration to body fluids. Patients should be warned that it can also stain contact lenses. It is metabolised by the liver and excreted in urine and bile. Rifampicin is a cytochrome P450 enzyme inducer and therefore interacts with other drugs.
Pyrazinamide is bacteriostatic against semi-dormant, intracellular mycobacteria and is excreted by the kidneys.
Ethambutol gradually inhibits mycobacterial growth and is excreted in urine and faeces.

Initial phase²

Initial treatment for 2 months should consist of isoniazid, rifampicin, pyrazinamide and ethambutol.
The concurrent use of 3 or more drugs during the initial treatment phase reduces the bacterial population rapidly and hence infectivity. This approach also prevents emergence of drug resistant strains.
Isoniazid and rifampicin are most important for preventing emergence of resistance to other drugs. Ethambutol prevents microbial selection for rifampicin resistance if there is established isoniazid resistance. It can be omitted only if there is a very low chance of resistance to isoniazid. Such patients must be:²

• White and have been born in the UK
• Had no previous treatment for TB
• HIV negative (or low risk)
• No previous contact with multi-drug resistant tuberculosis (MDRTB).

Continuation phase²

Once sensitivity profiles are available and initial treatment complete, treatment is reduced to 2 antituberculous drugs. Treatment is continued for a further 4 months with isoniazid and rifampicin.

Duration of treatment

Drug treatment usually lasts for 6 months. The choice of treatment regimen depends on:²

• Organ/ system affected
• Drug resistance profile
• Compliance
• Drug intolerance
• Immune status.

As a general rule:

• Respiratory tuberculosis - usually 4 drugs are given for 2 months, followed by 2 drugs for 2 months or until susceptibility reports if sputum culture positive.² Nine months may be needed if pyrazinamide is not prescribed or not tolerated.
• Peripheral lymph node TB (non-respiratory TB) - 6 months is as effective as 9.²
• Bones and joints. - the sine is the commonest site. 6 months of therapy as for respiratory TB is effective.
• Pericarditis - 6 months of treatment is usually given. Corticosteroids may be required in acute constrictive tuberculous pericarditis.
• Meningitis - there is lack of trial evidence, but experience suggests 12 month regimens. There is no evidence of need for intrathecal streptomycin.²
• Disseminated TB - 6 months is given unless there is central nervous system involvement (which can be excluded with lumbar puncture).
• Other sites - the duration of treatment is generally 6 months.

Extended regimens²

If treatment is altered due to adverse effects or drug resistance, regimens are often extended. For example if pyrazinamide is not tolerated, ethambutol must be given initially and treatment is extended to 9 months.
Non-respiratory TB is usually treated with a 6-month regimen but the management of some infections is more complex. CNS infection including meningitis requires 12 months of treatment as antituberculous drugs penetrate poorly into the CSF and meninges.

Second line drugs³

Second line agents are used by specialists in situations involving drug resistant organisms or intolerance to first line agents.
Streptomycin is unlicensed and now rarely used in the UK. Resistance to streptomycin is very common overseas. It is given intramuscularly and dose must be adjusted according to age, weight and renal function. Other drugs include amikacin, capreomycin, cycloserine, macrolides (azithromycin, clarithromycin) and quinolones (moxifloxacin, levofloxacin).

Side-effects²

Drug reactions occur in 10% of patients treated for TB, with a high proportion requiring modification of treatment. Such reactions are more common in those who are not receiving standard treatment or are HIV-positive.
Some serious complications are listed here (see drug monographs for full details):
Isoniazid can cause peripheral neuropathy. It is recommended that patients at increased risk are given prophylactic pyridoxine. This includes diabetics, alcoholics, malnourished and HIV-positive patients and those with chronic renal failure.
Rifampicin can cause shock, acute renal failure and thrombocytopaenic purpura. If these occur, rifampicin must be immediately withdrawn and not reintroduced. Rifampicin accelerates the metabolism of corticosteroids, protease inhibitors, sulphonylureas, anticoagulants, the combined oral contraceptive pill (COCP) and other medications. These drug doses should be adjusted accordingly and alternative contraceptive advice offered.
Ethambutol can cause rare but serious visual disturbances including reduced visual acuity, colour blindness and restriction of visual fields. The risk is increased with higher doses and renal impairment. Patients should discontinue treatment immediately if they notice visual deterioration. Sight is usually recovered after treatment cessation.

Monitoring and precautions²

Renal function must be checked before treatment with ethambutol or streptomycin. These drugs are best avoided if renal function is impaired but if they are necessary, reduced dosages are used and serum drug concentrations must be closely monitored. Isoniazid, rifampicin and pyrazinamide can be given in standard doses in renal impairment.
Pre-treatment liver function tests (LFTs) must be performed, as isoniazid, rifampicin and pyrazinamide are all potentially hepatotoxic. Note however that modest elevation of pre-treatment transaminases is not uncommon in TB patients. If baseline LFTs are normal and there is no evidence of chronic liver disease then further monitoring is not required. Otherwise, weekly or fortnightly monitoring of LFTs is necessary as per BTS guidelines.
Treatment should be stopped and LFTs rechecked if:

• There is fever, malaise, vomiting, unexplained deterioration or jaundice.
• Transaminases are > 5 x normal.
• Bilirubin levels are raised.

If the patient is unwell or TB is still infectious then admission is needed for treatment with second line drugs. When LFTs are back to normal, first line drugs can be cautiously reintroduced.
Visual acuity should be measured using a Snellen chart prior to ethambutol use. Ethambutol should only be used in patients who can appreciate and report visual deterioration. It is therefore not recommended in children under 5 and should be used cautiously in unconscious patients.

Multidrug resistant TB

The treatment of MDR-TB takes longer and is much more difficult.⁵ The epidemiological picture is somewhat confusing. There is a significant increase in new cases seen in countries of the former Soviet Union and in some provinces of China, whilst the USA and Hong Kong have reported a significant decrease. There are large gaps in data globally and baseline information from some countries is urgently needed.⁶ Current optimal drug therapy for MDR-TB only offers a 60-70% cure rate.⁷ Management is specialised, complex and expensive and should only be undertaken in recognised, experienced centres with isolation facilities.⁷ Treatment must be monitored closely because of increased drug toxicity and to ensure compliance. All patients must therefore participate in DOT for the entire treatment course.²
If MDR-TB is suspected, the patient should be started on 5 or more drugs to which the organism is likely to be susceptible while the actual sensitivity profiles are investigated. These drugs are continued until sputum cultures are negative and the patient is no longer infectious. When the specific drug resistance is determined the regime is reduced to 3 or more drugs to which the organism is known to be sensitive and continued for a minimum of 9 months. Treatment may even extend beyond 2 years. Surgical excision of pulmonary lesions may be useful if the disease is unresponsive to medical therapy.²

Immuno-compromised patients²

TB is an AIDS-defining illness and HIV testing should be considered. Patients with advanced disease are more likely to develop disseminated TB and predictably, TB patients with concurrent HIV infection have a worse prognosis. Patients with HIV show a good response to chemotherapy. Patients should be prescribed the standard treatment unless MDR-TB is suspected but treatment may be prolonged.

Pregnancy²

Women must be aware of the reduced efficacy of the COCP with rifampicin-based chemotherapy. No first line medications have been shown to be teratogenic and conception whilst on treatment is therefore not an indication for TOP. Second line drugs of ethionamide and prothionamide may be teratogenic and are best avoided. Streptomycin and other aminoglycosides should also be avoided during pregnancy. as they may be ototoxic to the fetus. Mothers may breastfeed normally while taking antituberculous treatment.⁷

Corticosteroids

Enzyme induction requires maintainance dose of corticosteroids (taken for accompanying conditions) to be doubled if rifampicin is taken. Corticosteroids are used for:

• Pericarditis
• Meningitis (stages II and III)
• Endobronchial disease in children
• TB affecting ureters
• Pleural effusions
• Extensive pulmonary disease
• Hypersensitivity to anti-TB drugs

Renal disease

Rifampicin, isoniazid and pyrazinamide can be given at standard doses, but reduced doses of streptomycin and ethambutol are used (with monitoring of serum levels).1 Dialysis affects clearance of drugs and requires dose modification.²

Diabetes

Incidence of TB is increased in diabetes and pulmonary disease is often more extensive. Standard regimens can be used. Sulphonylureas have reduced efficacy with rifampicin.

Children²

The management of respiratory and non-respiratory TB is similar to the standard adult regimens. Doses however must be calculated by weight and are generally rounded up for ease of prescribing. Ethambutol is used with caution for fear of visual disturbances. Supplemental pyridoxine is only recommended for breast-fed or malnourished children.⁷

In the UK, treatment of fully sensitive organisms with good patient compliance has very low failure and relapse rates. If such a patient is well after completion of treatment then no formal follow up or surveillance is necessary. The patient will be referred back to clinic by his GP should any problems arise. If relapse does occur, the organism is usually fully sensitive and the same treatment regimen can be used.²However, treatment failure or relapse after therapy is usually due to poor patient compliance. This will also increase the risk of drug resistance. Cultures and drug sensitivity profiles must therefore be repeated and consideration given to rapid molecular determination of rifampicin resistance. Further treatment must be fully supervised and is similar to regimens used in MDR-TB.⁷

Chemoprophylaxis

- Is available for patients with evidence of tuberculous infection but not clinical disease. Although similar drugs are used, chemoprophylaxis therapy is less intense than TB treatment regimens. Routine chemoprophylaxis involves isoniazid for 6 months or isoniazid plus rifampicin for 3 months.
Patients who are likely to benefit most include:

• Children under 16 years of age with strongly positive Heaf tests
• Children under 2 years of age, with close contact with smear positive (infectious) TB case, including babies of infectious mothers
• Patients with recent tuberculin conversion
• HIV-positive close contacts of infectious TB case.

Chemoprophylaxis is not routinely recommended for contacts of MDR-TB because of limited drug options and drug toxicity.

Further guidance

The National Institute of Clinical Effectiveness (NICE) has produced draft guidelines for consultation. The consultation period ended in October 2005. The final guidance is still awaited.⁸