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. Several studies have shown that the combination of rifampicin, isoniazid, pyrazinamide has increase the risk of drug-induced liver injury. In the US only, streptomycin is not considered a first line drug by ATS/IDSA/CDC because of high rates of resistance. The WHO has made no such recommendation. Second line The second line drugs (WHO groups 2, 3 and 4) are only used to treat disease that is resistant to first line therapy (i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB)). A drug may be classed as second-line instead of first-line for one of three 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 effective, but unavailable in many developing countries (e.g., fluoroquinolones): aminoglycosides (WHO group 2): e.g., amikacin (AMK), kanamycin (KM) polypeptides (WHO group 2): e.g., capreomycin, viomycin, enviomycin fluoroquinolones (WHO group 3): e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF) thioamides (WHO group 4): e.g. ethionamide, prothionamide cycloserine (WHO group 4) terizidone (WHO group 5) Third line Third-line drugs (WHO group 5) include drugs that may be useful, but have doubtful or unproven efficacy: rifabutin macrolides: e.g., clarithromycin (CLR); linezolid (LZD); thioacetazone (T); thioridazine; arginine; vitamin D; bedaquiline. These drugs 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. Standard regimen Rationale and evidence Tuberculosis has been treated with combination therapy for over fifty years. Treatments consisting of a single drug are not used (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure. The rationale for using multiple drugs to treat TB is based on simple probability. The rate of spontaneous mutations that confer resistance to an individual drug are well known: 1 mutation for every 107 cell divisions for EMB, 1 for every 108 divisions for STM and INH, and 1 for every 1010