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]; Marjan Khan M.B.B.S.[3]

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.

Drug-resistant tuberculosis

Type of Drug-Resistant TB

• Rifampicin-resistant TB (RR-TB) is caused by TB bacteria that are resistant to at least rifampicin. These patients need second-line treatment similar to MDR-TB patients
• Multidrug-resistant TB (MDR-TB) is caused by TB bacteria that are resistant to at least isoniazid and rifampicin. These patients need second-line treatment
• Extensively drug-resistant TB (XDR-TB) is a form of MDR-TB that is also resistant to any fluoroquinolone and any of the second–line anti-TB injectable agents such as amikacin, kanamycin, or capreomycin.

Cause of Drug-Resistant TB

Drug-resistant TB can occur when the drugs used to treat TB are misused or mismanaged. Examples of misuse or mismanagement include;

• People do not complete a full course of TB treatment
• Health care providers prescribe the wrong treatment (the wrong dose or length of time)
• Drugs for proper treatment are not available
• Drugs are of poor quality

Drug-resistant TB is more common in people who:

• Do not take their TB drugs regularly
• Do not take all of their TB drugs
• Develop TB disease again, after being treated for TB disease in the past
• Come from areas of the world where drug-resistant TB is common
• Have spent time with someone known to have drug-resistant TB disease

Multiple Drug-Resistant (MDR) Tuberculosis

• 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 5 drugs that have shown effectiveness against MDR. Within these 5 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 the culture is negative.
• Chronic cases with severe pulmonary disease may require more than 24 months of therapy.
• WHO updated its treatment guidelines for drug-resistant TB in May 2016 and included a recommendation on the use of the shorter MDR-TB regimen under specific conditions.

A recommendation on the use of the shorter MDR-TB regimen

• 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.

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, 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 susceptibility 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.

Pretomanid

• The U.S. Food and Drug Administration has approved Pretomanid Tablets in combination with bedaquiline and linezolid for the treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs.
• In a study of 109 patients with extensively drug-resistant, treatment intolerant, or non-responsive multidrug-resistant pulmonary TB (of the lungs). Of the 107 patients who were evaluated six months after the end of therapy, 95 (89%) were successes, which significantly exceeded the historical success rates for the treatment of extensively drug-resistant TB.
• Adverse reactions observed in patients treated with Pretomanid in combination with bedaquiline and linezolid included peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased liver enzymes, dyspepsia, rash, increased pancreatic enzymes , visual impairment, hypoglycemia, and diarrhea.
• Pretomanid used in combination with bedaquiline and linezolid should not be used in patients with hypersensitivity to bedaquiline or linezolid.

▸ 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

• In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended including:
  • Pyrazinamide and four core second-line TB medicines (one chosen from Group A, one from Group B, and at least two from Group C2)
  • If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five
• In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence).
• It is recommended that any patient child or adult with RR-TB in whom isoniazid resistance is absent or unknown be treated with a recommended MDR-TB regimen. It could either be a shorter MDR-TB regimen, or a longer MDR-TB regimen to which isoniazid is added.

Groups	Drugs
Group A Fluoroquinolones	Levofloxacin Moxifloxacin Gatifloxacin
Group B Second-line injectable agents	Kanamycin Amikacin Capreomycin Streptomycin
Group C Other core second-line agents	Ethionamide or (prothionamide) Cycloserine or (terizidone) Linezolid Clofazimine NOTE: In children with non- severe disease Group B medicines may be excluded
Group D2 Add-on agents (not part of the core MDR-TB regimen)	Bedaquiline Delamanid Note: The WHO policy on the role of D2 agents, including their potential use in children, was under review
Group D3 Add-on agents (not part of the core MDR-TB regimen)	Para-aminosalicylic acid Amoxicillin/clavulanate Imipenem/cilastatin Meropenem Thioacetazone
WHO treatment guidelines for drug- resistant tuberculosis 2016 update

Medical therapy

• 1. RR-TB or MDR-TB Tuberculosis

• 1.1 Adult

• Preferred regimen: At least 5 agents combination

• Agent 1: Pyrazinamide 20–30 mg/kg
• Agent 2: Levofloxacin 500-1000 mg OR Moxifloxacin 400 mg OR Gatifloxacin 400mg
• Agent 3: Amikacin 7.5-10 mg/kg OR Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Streptomycin 12–18 mg/kg
• Agent 4: [Ethionamide]] 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 mg/kg OR Clofazimine 100mg
• Agent 5: Bedaquiline 200-400mg OR Delamanid
• Agent 6: Para-aminosalicylic acid 150 mg/kg/day q8-12h OR Imipenem/Cilastatin 250mg/250mg-750mg/750mg {{or} Meropenem 20-40mg/kg OR Amoxicillin clavulanate 500mg-125mg OR Thioacetazone 150mg
• Note: Pyrazinamide and four core second-line TB medicines (one chosen from Group A, one from Group B, and at least two from Group C2)
• Note: If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five

• 1.2 Pediatric

• Preferred regimen: At least 5 agents combination

• Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg)
• Agent 2 (Group A): Levofloxacin 7.5-10mg/kg OR Moxifloxacin 7.5-10mg/kg OR Gatifloxacin 10 mg/kg (maximum 600 mg)
• Agent 3 (Group B): Amikacin 7.5-10 mg/kg OR Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Streptomycin 12–18 mg/kg
• Agent 4 (Group C): [Ethionamide]] 15-20 mg/kg/day q12h (Maximum: 1000 mg)OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg Maximum: 1000 mg) OR Clofazimine 100mg
• Agent 5: (Group D3): Para-aminosalicylic acid 150 mg/kg/day q8-12h(Maximum: 12,000 mg) OR Imipenem/Cilastatin 250mg/250mg-750mg/750mg {{or} Meropenem 20-40mg/kg OR Amoxicillin clavulanate 500mg-125mg OR Thioacetazone 50mg
• Note: Pyrazinamide and four core second-line TB medicines (one chosen from Group A, one from Group B, and at least two from Group C2)
• Note: If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five