Multi-drug-resistant tuberculosis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Overview

Medical therapy for MDR-TB is based on the combination at least 4 drugs, one drug from each of the drug groups for TB. The duration of the treatment should be at least 18 months, depending on the culture results and clinical improvement.

Medical Therapy Adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.

• MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs.
• Medical treatment for MDR-TB consists of at least 4 drugs that have shown effectiveness against MDR. Within these 4 drugs must be included at least one drug from each group.
• Treatment duration will depend on the culture results. The duration of therapy should be > 18 months after culture is negative.
• Chronic cases with severe pulmonary disease may require more than 24 months of therapy.
• Empirical treatment should start immediately and the regimen should be modified according to the DST (Drug susceptibility testing) results.
• Drugs in each group must be used, in order of preference, as shown below.
• The following treatment regimens show daily dosing for each drug.

▸ Click on the following categories to expand treatment regimens.

MDR Tuberculosis   ▸  Adults   ▸  Children

MDR-TB Adults Standard Regimen Group 1: First-line oral drugs ▸ Pyrazinamide 20–30 mg/kg OR ▸ Ethambutol 15–25 mg/kg OR ▸ Rifabutin 5 mg/kg PLUS Group 2: Injectable drugs ▸ Capreomycin 15 mg/kg OR ▸ Kanamycin 15 mg/kg OR ▸ Amikacin 7.5-10 mg/kg OR ▸ Streptomycin 12–18 mg/kg PLUS Group 3: Fluoroquinolones ▸ Levofloxacin 500-1000 mg OR ▸ Moxifloxacin 400 mg OR ▸ Ofloxacin 400 mg PLUS Group 4:Oral bacteriostatic second-line drugs ▸ Ethionamide 15-20 mg/kg OR ▸ Protionamide 15-20 mg/kg OR ▸ Cycloserine 10-15 mg/kg OR ▸ Terizidone 10-20 mg/kg OR ▸ Para-aminosalicylic acid 8-12 g/d divided q8-12h Table adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed. MDR-TB Children Standard Regimen Group 1: First-line oral drugs ▸ Pyrazinamide 20-30 mg/kg (Max: 600 mg) OR ▸ Ethambutol 15-20 mg/kg OR ▸ Rifabutin 5 mg/kg PLUS Group 2: Injectable drugs ▸ Capreomycin 15-30 mg/kg (Max: 1000 mg) OR ▸ Kanamycin 15-30 mg/kg (Max: 1000 mg) OR ▸ Amikacin 15-22.5 mg/kg (Max: 1000 mg) OR ▸ Streptomycin 12-18 mg/kg PLUS Group 3: Fluoroquinolones ▸ Levofloxacin 7.5-10 mg/kg OR ▸ Moxifloxacin 7.5-10 mg/kg OR ▸ Ofloxacin 15-20 mg/kg divided q12h (Max:800 mg) PLUS Group 4:Oral bacteriostatic second-line drugs ▸ Ethionamide 15-20 mg/kg divided q12h (Max: 1000 mg) OR ▸ Protionamide 15-20 mg/kg divided q12h (Max: 1000 mg) OR ▸ Cycloserine 10-20 mg/kg (Max: 1000 mg) OR ▸ Terizidone 10-20 mg/kg (Max: 1000 mg) OR ▸ Para-aminosalicylic acid 150 mg/kg divided q8-12h(Max: 12 000 mg) Table adapted from WHO 2013 Treatment of tuberculosis: guidelines – 4th ed. and Guidance for national tuberculosis programmes on the management of tuberculosis in children

Drugs Used in Drug-Resistant Tuberculosis

Groups	Drugs
Group 1: First-line oral drugs	Pyrazinamide Ethambutol Rifabutin
Group 2: Injectable drugs	Kanamycin Amikacin Capreomycin Streptomycin
Group 3: Fluoroquinolones	Levofloxacin Moxifloxacin Ofloxacin
Group 4: Oral bacteriostatic second-line drugs	Para-aminosalicylic acid Cycloserine Terizidone Ethionamide Protionamide
Group 5: Agents with unclear role in treatment of drug resistant-TB	Clofazimine Linezolid Amoxicillin/clavulanate Thioacetazone Imipenem/cilastatin High-dose isoniazid Clarithromycin
Adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.

Bedaquiline

• Bedaquiline is an oral diarylquinoline recently approved by the FDA (Dec 2012) for the treatment of MDR TB when other alternatives are not available.
• This drug should be used with clinical expert consultation as part of combination therapy (minimum four-drug treatment regimen) and administered by direct observation to adults aged ≥18 years with a diagnosis of pulmonary MDR TB.
• Dosage: 400 mg daily PO for 2 weeks, followed by 200 mg three times a week for 22 weeks.

Extensively Drug-Resistant (XDR) Tuberculosis Treatment Adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.

• XDR-TB is defined as resistance to at least isoniazid and rifampicin, to any fluoroquinolone (Group 3), and to any of second-line injectable drugs (Group 4: amikacin, capreomycin, and kanamycin).
• Additional drugs are needed for XDR treatment regimen, these drugs are known to have some action against tuberculosis but are not routinely recommended for treatment of MDR-TB.
• These include clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, imipenem/cilastatin, clarithromycin and high-dose isoniazid.
• The treatment regimen should include from 4 to 6 drugs, based on the suceptibility of the M. tuberculosis and the clinician criteria.
• Treatment duration is not well established, but is longer than MDR-TB. For some cases, at least 43 months are required for XDR-TB treatment to be successful.
• The following treatment regimens show daily dosing for each drug.

▸ Click on the following categories to expand treatment regimens.

XDR Tuberculosis   ▸  Adults   ▸  Children

XDR-TB Adults Standard Regimen Group 1: First-line oral drugs ▸ Pyrazinamide 20–30 mg/kg OR ▸ Ethambutol 15–25 mg/kg OR ▸ Rifabutin 5 mg/kg PLUS Group 4:Oral bacteriostatic second-line drugs ▸ Ethionamide 15-20 mg/kg OR ▸ Protionamide 15-20 mg/kg OR ▸ Cycloserine 10-15 mg/kg OR ▸ Terizidone 10-20 kg/mg OR ▸ Para-aminosalicylic acid 8-12 g/d divided q8-12h PLUS Group 5 Use at least 2 of the following: ▸ Clofazimine 50 mg/d AND 300 mg once a month OR ▸ Amoxicillin/clavulanate 500 mg/125 mg q12h OR ▸ Linezolid 300-600 mg OR ▸ Imipenem 500mg q6h OR ▸ Clarithromycin 500-1000 mg q12h OR ▸ Thioacetazone 2.5 mg/kg OR ▸ Isoniazid (high-dose) 16–20 mg/kg Table adapted from WHO 2013 Treatment of tuberculosis: guidelines – 4th ed. XDR-TB Children Standard Regimen Group 1: First-line oral drugs ▸ Pyrazinamide 20-30 mg/kg (Max: 600 mg) OR ▸ Ethambutol 15 mg/kg OR ▸ Rifabutin 5 mg/kg PLUS Group 4:Oral bacteriostatic second-line drugs ▸ Ethionamide 15-20 mg/kg (Max: 1000 mg) OR ▸ Protionamide 15-20 mg/kg (Max: 1000 mg) OR ▸ Cycloserine 10-20 mg/kg (Max: 1000 mg) OR ▸ Terizidone 10-20 mg/kg (Max: 1000 mg) OR ▸ Para-aminosalicylic acid 150 mg/kg/d divided q8-12h PLUS Group 5 Use at least 2 of the following: ▸ Clofazimine 50 mg/d AND 300 mg once a month OR ▸ Amoxicillin/clavulanate OR ▸ Linezolid 300-600 mg OR ▸ Imipenem 500mg q6h OR ▸ Clarithromycin 500-1000 mg q12h OR ▸ Thioacetazone 2.5 mg/kg OR ▸ Isoniazid (high-dose) 16–20 mg/kg Table adapted from WHO 2013 Treatment of tuberculosis: guidelines – 4th ed. and WHO Guidance for national tuberculosis programmes on the management of tuberculosis in children