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Drug therapy has transformed tuberculosis from a disabling and often fatal disease into one in which almost 100% cure is obtainable, although the recent emergence of multiple drug resistant strains of Mycobacterium tuberculosis (MDRTB) in developed countries will disturb this optimistic view. Chemotherapy was formerly protracted, but a better understanding of the mode of action of antituber-culous drugs has allowed the development of effective short-course regimens.

Principles of antituberculosis therapy

• A large number of actively multiplying bacilli must be killed: isoniazid achieves this.

• Treat persisters, i.e. semidormant bacilli that metabolise slowly or intermittently: rifampicin and pyrazinamide are the most efficacious.

• Prevent the emergence of drug resistance by multiple therapy to suppress single-drug-resistant mutants that may exist de novo or emerge during therapy in all large bacterial populations: isoniazid and rifampicin are best.

• Combined formulations are used to ensure that poor compliance does not result in monotherapy with consequent drug resistance.

Most contemporary regimens employ an initial phase with administration of at least three drugs to reduce the bacterial load as rapidly as possible (usually for 2 months), followed by a continuation phase with usually two drugs given for 4 months.

All short-course regimens include isoniazid, pyrazinamide and rifampicin. After extensive clinical trials, the following three have been found satisfactory:

1. An unsupervised regimen of daily dosing comprising isoniazid and rifampicin for 6 months, plus pyrazinamide for the first 2 months.

2. A supervised (directly observed) regimen for patients who cannot be relied upon to comply with treatment, comprising thrice-weekly dosing with isoniazid and rifampicin for

6 months, plus pyrazinamide for the first 2 months (isoniazid and pyrazinamide are given in higher dose than in the unsupervised regimen).

With both the above regimens, ethambutol by mouth or streptomycin i.m. should be added for the first 2 months if there is a likelihood of drug-resistant organisms, or if the patient is severely ill with extensive active lesions.

3. A less costly, yet still effective, regimen favoured by some countries comprises supervised daily administration of isoniazid, rifampicin, pyrazinamide and either ethambutol or streptomycin for 2 months followed by 6 months of unsupervised daily isoniazid and thiacetazone.

All the regimens are highly effective, with relapse rates of 1-2% in those who continue for 6 months; even if patients default after, say, 4 months, tuberculosis can be expected to recur in only 10-15%. Drug resistance seldom develops with any of these regimens.

Although compliance is often a concern with multiple drug therapy given for long periods, especially in the Developing World, directly observed therapy (DOT) has surprisingly not been proven to improve relapse rates in many trials. Combination therapy is assumed to improve compliance: some commonly used combinations include Rifater (rifampicin, isoniazid plus pyrazinamide), and Rifinah or Rimactazid (rifampicin plus isoniazid).

Special problems

Resistant organisms. Initial resistance occurs in about 4% of isolates in the UK, usually to isoniazid. Multiple-drug-resistant tuberculosis, i.e. resistant to rifampicin and isoniazid at least, should be treated with three or four drugs to which the organisms are sensitive and should extend for 12-24 months after cultures become negative. Treatment of such cases requires expert management. Atypical mycobacteria are often resistant to standard drugs; their virulence is low but they can produce serious infection in immunocompromised patients which may respond, e.g. to clarithromycin or a quinolone, often in combination.

Chemoprophylaxis may be either

• primary, i.e. the giving of antituberculosis drugs to uninfected but exposed individuals, which is seldom justified; or

• secondary, which is the treatment of infected but symptom-free individuals, e.g. those known to be in contact with the disease and who develop a positive tuberculin reaction. Secondary chemoprophylaxis may be justified in children under the age of 3 because they have a high risk of disseminated disease; isoniazid alone for 6 months may be used since there is little risk of resistant organisms emerging because the organism load is low.

Pregnancy. Drug treatment should never be interrupted or postponed during pregnancy. On the general principle of limiting exposure of the fetus, the standard three-drug, 6-month course (1 above) is best. Streptomycin should be excluded from any regimen (danger of fetal eighth cranial nerve damage).

Nonrespiratory tuberculosis. The principles of treatment, i.e. multiple therapy and prolonged follow-up, are the same as for respiratory tuberculosis. In only a few cases is surgery now necessary. It should always be preceded and followed by chemotherapy. Many chronic tuberculous lesions may be relatively inaccessible to drugs as a result of avascularity of surrounding tissues; treatment frequently has to be prolonged and dosage high, especially if damaged tissue cannot be removed by surgery, e.g. tuberculosis of bones.

Meningeal tuberculosis. It is essential to use isoniazid and pyrazinamide which penetrate well into the CSF. Rifampicin enters inflamed meninges well but noninflamed meninges less so. An effective regimen is isoniazid, rifampicin, pyrazinamide and streptomycin. Treatment may need to continue for much longer than modern short-course chemotherapy for pulmonary tuberculosis.

Adrenal steroid and tuberculosis. In pulmonary tuberculosis a corticosteroid may be given to severely ill patients. It reduces the injurious reaction of the body to tuberculoprotein and buys time for the chemotherapy to take effect. It also causes the patient to feel better much more quickly. In the absence of effective chemotherapy, an adrenal steroid will cause tuberculosis to extend and it should never be used alone, e.g. for another disease, if tuberculosis is suspected.

Tuberculosis in the immunocompromised. Immunocompromised patients require special measures because they may be infected more readily when exposed, their infections usually involve large numbers of tubercle bacilli (multibacillary disease), and in the case of patients with AIDS, are more likely to be infected with multiply antibiotic resistant strains. Usually at least four drugs are started, and patients are isolated until bacteriological results are obtained and they have shown clinical improvement. If infections are proved to involve antibiotic susceptible mycobacteria, therapy can continue with a conventional 6-month regimen with careful follow-up. Particular problems may occur with multiple drug interactions during antituberculous treatment of patients receiving antiretroviral therapy.

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