8.4 Drugs for drug-resistant tuberculosis

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    Drugs used for DR-TB treatment (except bedaquiline) are taken 7 days a week.

    8.4.1 Group A drugs

    Table 8.3 – Main characteristics of TB drugs Group A

     

    TB drugs

    Classes

    Activity

    Resistance

    Levofloxacin

    Moxifloxacin

    Fluoroquinolones (FQs)

    Bactericidal

    • Resistance common in some regions.
    • Cross-resistance between FQs. 

    Bedaquiline

    Diarylquinolines

    Bactericidal

    • Partial cross-resistance with Cfz.
    • Growing resistance as use increases.

    Linezolid

    Oxazolidinones

    Bactericidal

    Resistance assumed to be rare due to its limited use.

     

    Fluoroquinolones (levofloxacin, moxifloxacin)

    FQs are usually well tolerated.

    They may cause tendinopathy and QT prolongation.

    Moxifloxacin is sometimes used at high dose (Mfxh) in the presence of low-level resistance to FQs.

    Bedaquiline

    Bedaquiline is usually well tolerated. It may cause hepatotoxicity and QT prolongation.

    Bedaquiline has a long half-life (5.5 months). Therefore, adverse effects can persist after the drug is stopped, and if TB is still active, resistance can develop.

    Bedaquiline is metabolized in the liver by the cytochrome P450 (CYP450) system enzymes. Drugs, which induce or inhibit CYP450, can affect bedaquiline plasma concentrations and should be avoided (Appendix 19).

    The extent of cross-resistance bedaquiline/clofazimine and the clinical implications are not fully understood [1] Citation 1. Camus Nimmo, James Millard, Lucy van Dorp, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe 2020; 1: e165–74.
    https://doi.org/10.1016/S2666-5247(20)30031-8
    [2] Citation 2. Thi Van Anh Nguyen, Richard M Anthony, et al. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clinical Infectious Diseases, Volume 66, Issue 10, 15 May 2018, Pages 1625–1630.
    https://doi.org/10.1093/cid/cix992
    [3] Citation 3. Ghodousi A, Rizvi AH, Baloch AQ, et al. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00915-19.
    https://doi.org/10.1128/aac.00915-19
    .

    Linezolid

    Linezolid may cause myelosuppression, dose- and duration-dependent neuropathy and lactic acidosis.

    Pyridoxine supplementation (vitamin B6) is recommended for all patients on linezolid, although there is no evidence that pyridoxine can prevent linezolid-induced neuropathy.

    Adverse effects frequently lead to reducing the dose or discontinuing linezolid. The optimal dose and duration of treatment are not established.

    Linezolid has many interactions and overlapping toxicities with other drugs (e.g. risk of serotonin syndrome when administered with serotonergic drugs [4] Citation 4. Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-356. ). However, it is not always possible to avoid concomitant use of these drugs (e.g. even on linezolid, a patient with depression may require an antidepressant).

    8.4.2 Group B drugs

    Table 8.4 – Main characteristics of TB drugs Group B

     

    TB drugs

    Classes

    Activity

    Resistance

    Clofazimine

    Riminophenazine (anti-leprosy drug)

    Probably bacteriostatic

    • Partial cross-resistance with Bdq.
    • Growing resistance as use increases.

    Cycloserine Terizidone

    Analogue of D-alanine

    Bacteriostatic

    • Resistance common in areas where it has been used extensively.
    • Full cross-resistance between the 2 drugs.

     

    Clofazimine

    Clofazimine is a QT-prolonging drug.

    Orange-pink to brownish-black discolouration of the skin and body fluids occur in almost all patients. These changes are reversible and not harmful.  

    Clofazimine has a long half-life (approximately 70 days). Consequently, its adverse effects can persist for several weeks or months after the drug is stopped.

    Cycloserine or terizidone

    Cycloserine and terizidone are structural analogues used at the same dose.

    Both drugs may cause neurotoxicity including psychiatric adverse events.
    To prevent neurotoxicity, pyridoxine (vitamin B6) should be administered along with these drugs throughout the course of treatment (Appendix 17).

    8.4.3 Group C drugs

    Table 8.5 – Main characteristics of TB drugs Group C

     

    TB drugs

    Classes

    Activity

    Resistance

    Delamanid

    Nitroimidazooxazines

    Bactericidal

    • Potential cross-resistance with pretomanid.
    • Resistance assumed to be rare due to its limited use.

    Ethambutol

     

    Bacteriostatic

    High prevalence of resistance among MDR/RR-TB patients (> 49% in some settings [5] Citation 5. Hoek K G P, Schaaf H S, Gey van Pittius N C, van Helden P D, Warren R M. Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. SAMJ, S. Afr. med. j. 2009 Nov; 99(11): 785-787.
    http://www.samj.org.za/index.php/samj/article/view/3522/2557
    [6] Citation 6. Arshad Javaid, Nafees Ahmad, Amer Hayat Khan, Zubair Shaheen. Applicability of the World Health Organization recommended new shorter regimen in a multidrug-resistant tuberculosis high burden country. European Respiratory Journal Jan 2017, 49 (1) 1601967.
    https://doi.org/​​​​​​​10.1183/13993003.01967-2016
    ).

    Pyrazinamide

     

    Bactericidal

    High prevalence among MDR/RR-TB patients (> 80% in some areas [7] Citation 7. Matteo Zignol, Anna S Dean, Natavan Alikhanova, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis 2016; 16: 1185–92.
    https://doi.org/10.1016/S1473-3099(16)30190-6
    [8] Citation 8. Kwok Chiu Chang, Wing Wai Yew, Ying Zhang. Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: a Systematic Review with Meta-Analyses. Antimicrobial Agents and Chemotherapy Sep 2011, 55 (10) 4499-4505.
    https://doi.org/10.1128/AAC.00630-11
    ).

    Imipenem/cilastatin Meropenem

    Carbapenems

     

     

    Full cross-resistance between carbapenems.

    Amikacin Streptomycin

    Aminoglycosides

    Bactericidal

    Partial cross-resistance between the 2 drugs.

    Ethionamide Prothionamide

    Thionamides

    Weak bacteriostatic

    • Full cross-resistance between thionamides.
    • Cross-resistance with isoniazid if inhA mutation present.
    • High prevalence of resistance among MDR-TB patients in some areas [9] Citation 9. Lange C, Duarte R, Fréchet-Jachym M, Guenther G, Guglielmetti L, Olaru ID, Oliveira O, Rumetshofer R, Veziris N, van Leth F; European MDR-TB database collaboration. Limited Benefit of the New Shorter Multidrug-Resistant Tuberculosis Regimen in Europe. Am J Respir Crit Care Med. 2016 Oct 15;194(8):1029-1031.
      https://doi.org/10.1164/rccm.201606-1097LE
      .

    Para-aminosalicylate sodium

    Para-­aminosalicylic acid

     

    Weak bacteriostatic

    Common in some regions.

    Isoniazid high-dose

     

     

    Cross-resistance with thionamides if inhA mutation present.

     

    Delamanid

    Delamanid is usually well tolerated.

    It may cause QT prolongation [10] Citation 10. Dooley KE, Rosencrantz SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021.
    https://doi.org/10.1016/S1473-3099(20)30770-2
    .
     

    It is particularly useful in patients with pre-existing hepatic disease (no reported hepatotoxicity) or HIV infection (no significant drug interactions or overlapping toxicities with antiretrovirals).

    It is also useful for replacing a Group A or B drug causing toxicity.

    Ethambutol

    See Section 8.3.1. Vision monitoring is required when ethambutol is administered for more than 2 months (risk of optic neuritis).

    Pyrazinamide

    See Section 8.3.1.

    Carbapenems (imipenem/cilastatin, meropenem)

    Imipenem is always combined with cilastatin. Cilastatin has no antibacterial activity, its role is to inhibit a renal enzyme that inactivates imipenem. 

    Meropenem does not need to be combined with cilastatin, as it is metabolised through a different pathway.

    High cost and difficulty with administration limits the use of carbapenems.

    Carbapenems may cause gastrointestinal disturbances, neurotoxicity and hypersensitivity reactions.

    Meropenem should be used in children and adolescents under 15 years, and if possible, in epileptic patients and patients with TB meningitis (risk of seizures lower than with imipenem/cilastatin).

    The first dose is always administered in a health facility so that an eventual hypersensitivity reaction can be managed. If conditions permit, carbapenems can be continued as an outpatient.

    Amoxicillin/clavulanic acid is routinely administered prior to carbapenems, as clavulanic acid prevents the development of carbapenem resistance.

    Aminoglycosides (amikacin, streptomycin)

    Aminoglycosides should only be used when no alternative is available. Most patients with DR-TB can be treated without aminoglycosides, including some cases of extensively drug-resistant TB (XDR-TB).
    Aminoglycosides are nephrotoxic and ototoxic drugs. Streptomycin is less nephrotoxic than other aminoglycosides, but causes vestibular toxicity [11] Citation 11. British Thoracic Society. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Prepared by members of the Guideline Group on behalf of the British Thoracic Society. Standards of Care Committee and Joint Tuberculosis Committee, Thorax 2010;65:559e570.
    https://doi.org/10.1136/thx.2009.133173
    more frequently. If an aminoglycoside is used, close monitoring is essential (audiometry, electrolytes and renal function). If close monitoring cannot be ensured, aminoglycosides should not be used.

     

    Note: kanamycin and capreomycin are no longer recommended, as their use is associated with higher rates of treatment failure and death [12] Citation 12. World Health Organization. WHO consolidated guidelines on drug resistant tuberculosis treatment. Geneva: World Health Organization; 2019.
    https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1, accessed 20 March 2020
    .

    Thionamides (ethionamide, prothionamide)

    Ethionamide and prothionamide are used at the same dose.
    They may cause gastrointestinal disturbances, hypothyroidism (especially if co-administered with para-­aminosalicylic acid), neuropathy and hepatotoxicity.
    In patients with diabetes, the dose of antidiabetics may need to be adjusted.

    Para-aminosalicylate sodium or para-aminosalicylic acid

    PAS often causes gastrointestinal disturbances and can decrease the absorption of other TB drugs. It may also cause hypothyroidism, especially when co-administered with a thionamide.

    High-dose isoniazid

    See Section 8.3.1. There is limited evidence to support the use of high-dose isoniazid.
    High-dose isoniazid may cause more adverse effects than the standard dose.
    It has overlapping toxicity with linezolid (neuropathy) and hepatotoxic drugs.
    To prevent peripheral neuropathy, pyridoxine (vitamin B6) should be administered to all patients throughout the course of treatment (Appendix 17).

    8.4.4 Ungrouped drugs

    Pretomanid

    Pretomanid belongs to the same class as delamanid and has bactericidal activity.

    It is used only as part of standard regimens for DR-TB in the following combinations: BPaLM, BPaL (and BPaLC in operational research conditions), see Chapter 10.

    Regimens that include bedaquiline, pretomanid and linezolid may cause hepatotoxicity, lactic acidosis, myelosuppression, neuropathy and QT prolongation.
    Pretomanid/delamanid cross-resistance is likely.

    8.4.5 Other drugs

    Amoxicillin/clavulanic acid

    Amoxicillin/clavulanic acid is administered before each dose of carbapenem.

    The clavulanic acid component prevents the development of carbapenem resistance.

    Only formulations with a ratio of 4:1 (e.g. 500/125 mg) or 2:1 (e.g. 250/125 mg) are suitable for this indication. Do not use formulations with a ratio of 8:1 or 7:1.

     

    References
    • 1.Camus Nimmo, James Millard, Lucy van Dorp, et al. Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis. Lancet Microbe 2020; 1: e165–74.
      https://doi.org/10.1016/S2666-5247(20)30031-8
    • 2.Thi Van Anh Nguyen, Richard M Anthony, et al. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clinical Infectious Diseases, Volume 66, Issue 10, 15 May 2018, Pages 1625–1630.
      https://doi.org/10.1093/cid/cix992
    • 3.Ghodousi A, Rizvi AH, Baloch AQ, et al. Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00915-19.
      https://doi.org/10.1128/aac.00915-19
    • 4.Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-356.
    • 5.Hoek K G P, Schaaf H S, Gey van Pittius N C, van Helden P D, Warren R M. Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. SAMJ, S. Afr. med. j. 2009 Nov; 99(11): 785-787.
      http://www.samj.org.za/index.php/samj/article/view/3522/2557
    • 6.Arshad Javaid, Nafees Ahmad, Amer Hayat Khan, Zubair Shaheen. Applicability of the World Health Organization recommended new shorter regimen in a multidrug-resistant tuberculosis high burden country. European Respiratory Journal Jan 2017, 49 (1) 1601967.
      https://doi.org/​​​​​​​10.1183/13993003.01967-2016
    • 7.Matteo Zignol, Anna S Dean, Natavan Alikhanova, et al. Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project. Lancet Infect Dis 2016; 16: 1185–92.
      https://doi.org/10.1016/S1473-3099(16)30190-6
    • 8.Kwok Chiu Chang, Wing Wai Yew, Ying Zhang. Pyrazinamide Susceptibility Testing in Mycobacterium tuberculosis: a Systematic Review with Meta-Analyses. Antimicrobial Agents and Chemotherapy Sep 2011, 55 (10) 4499-4505.
      https://doi.org/10.1128/AAC.00630-11
    • 9.Lange C, Duarte R, Fréchet-Jachym M, Guenther G, Guglielmetti L, Olaru ID, Oliveira O, Rumetshofer R, Veziris N, van Leth F; European MDR-TB database collaboration. Limited Benefit of the New Shorter Multidrug-Resistant Tuberculosis Regimen in Europe. Am J Respir Crit Care Med. 2016 Oct 15;194(8):1029-1031.
      https://doi.org/10.1164/rccm.201606-1097LE
    • 10.Dooley KE, Rosencrantz SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021.
      https://doi.org/10.1016/S1473-3099(20)30770-2
    • 11.British Thoracic Society. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Prepared by members of the Guideline Group on behalf of the British Thoracic Society. Standards of Care Committee and Joint Tuberculosis Committee, Thorax 2010;65:559e570.
      https://doi.org/10.1136/thx.2009.133173
    • 12.World Health Organization. WHO consolidated guidelines on drug resistant tuberculosis treatment. Geneva: World Health Organization; 2019.
      https://apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf?ua=1, accessed 20 March 2020