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

Drug-resistant tuberculosis is caused by M. tuberculosis organisms that are resistant to at least one first-line anti-TB drug. Multidrug-resistant TB (MDR TB) is resistant to more than one anti-TB drug and at least isoniazid (INH) and rifampin (RIF). Treatment should be started with an empirical treatment of at least 4 drugs based on expert advice as soon as drug-resistant TB disease is suspected.

Multiple Drug-Resistant (MDR) Tuberculosis 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

Further information: [[:Multi-drug-resistant tuberculosis]]

Extensively Drug-Resistant (XDR) Tuberculosis 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

Extremely Drug-Resistant (XXDR) Tuberculosis

• XXDR-TB or TDR-TB (totally drug resistant TB) is defined as resistance to all first-line (Group 1) and second-line (Groups 2-4) tuberculosis drugs.
• Cases of XXDR-TB have been reported in Italy, India and Iran.
• There is no drug regimen for patients with extremely drug resistant TB that has shown successful response.

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.