Treatment

From DrugPedia: A Wikipedia for Drug discovery

Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis has a mortality rate of less than 5% (or less in developed countries where intensive supportive measures are available).

The standard "short" course treatment for tuberculosis (TB), if it is active, is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.

Drugs

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:

• ethambutol is EMB or E,
• isoniazid is INH or H,
• pyrazinamide is PZA or Z,
• rifampicin is RMP or R,
• streptomycin is STM or S.

The US commonly uses abbreviations and names that are not internationally recognised: rifampicin is called rifampin and abbreviated RIF; streptomycin is commonly abbreviated SM.

Drug regimens are similarly abbreviated in a standardised manner. The drugs are listed using their single letter abbreviations (in the order given above, which is roughly the order of introduction into clinical practice). A prefix denotes the number of months the treatment should be given for; a subscript denotes intermittent dosing (so ₃ means three times a week) and no subscript means daily dosing. Most regimens have an initial high-intensity phase, followed by a continuation phase (also called a consolidation phase or eradication phase): the high-intensity phase is given first, then the continuation phase, the two phases divided by a slash.

So,

2HREZ/4HR₃

means isoniazid, rifampicin, ethambutol, pyrazinamide daily for two months, followed by four months of isoniazid and rifampicin given three times a week.

These standard abbreviations are used in the rest of this article.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of two possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones):

• aminoglycosides: e.g., amikacin (AK), kanamycin;
• polypeptides: e.g., capreomycin, viomycin, enviomycin;
• fluoroquinolones: e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);
• thioamides: e.g. ethionamide, prothionamide
• cycloserine (the only antibiotic in its class);
• p-aminosalicylic acid (PAS or P).

Other drugs that may be useful, but are not on the WHO list of SLDs:

• rifabutin
• macrolides: e.g., clarithromycin (CLR);
• linezolid (LZD);
• thioacetazone (T);
• thioridazine;
• arginine;
• vitamin D;
• R207910.

These drugs may be considered "third-line drugs" and are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

The standard regimen

Rationale and evidence for the standard regimen

Tuberculosis has been treated with combination therapy for over fifty years. Drugs are not used singly (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure.<ref name="MRC1948">Medical Research Council Streptomycin in Tuberculosis Trials Committee (1948). "Streptomycin treatment for pulmonary tuberculosis". Brit Med J ii: 769–82. </ref><ref name="Wang2006">Wang J-Y, Hsueh P-R, Jan I-S, et al. (2006). "Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas". Thorax 61: 903–8. doi:10.1136/thx.2005.056887. PMID 16809417. </ref> The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 10⁷ for EMB, 1 in 10⁸ for STM and INH, and 1 in 10¹⁰ for RMP.<ref name="David1970">David H. L. (1970). "Probability Distribution of Drug-Resistant Mutants in Unselected Populations of Mycobacterium tuberculosis". Appl Microbiol 20 (5): 810–4. PMID 4991927. </ref>