10.2 Treatment regimens in programmatic conditions

Select language:
Enter
Permalink
Descargar
Comment
Return to top
المحتويات

    10.2.1 Short treatment regimens

    Fluoroquinolone-susceptible MDR/RR-TB

    Table 10.2 – Composition of, and eligibility criteria for, STRs for FQ-susceptible MDR/RR-TB[1]Citation 1.World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva 2022.https://www.who.int/publications/i/item/9789240065116, [2]Citation 2.Guglielmetti L, Khan U, et al. endTB: nine-month, all-oral regimens for rifampin-resistant, fluoroquinolone-susceptible tuberculosis. N Engl J Med 2025;392:468-82. 
    https://doi.org/10.1056/NEJMoa2400327     , [3]Citation 3.World Health Organization. Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva. June 2024.https://www.who.int/publications/i/item/B09123

    Regimens

    Composition

    Eligibility criteria

    6BPaLM

     

    		6Bdq-Pa-Lzd-Mfx
    • Age ≥ 14 years
    • No pregnancy or breastfeeding
    • All drugs in the regimen likely effective

    • No miliary TB, osteoarticular TB or TB of the central nervous system (CNS), i.e. brain, spinal cord or meninges

    endTB19Bdq-Lzd-Mfx-Z
    • All drugs in the regimen (except Z) likely effective
    • No miliary TB, osteoarticular TB or TB of the CNS
    endTB29Bdq-Cfz-Lzd-Lfx-Z
    endTB39Bdq-Dlm-Lzd-Lfx-Z
    BEAT Tuberculosis6-9Bdq-Dlm-Lzd-Lfx
    • All drugs in the regimen likely effective
    • No miliary TB, osteoarticular TB or TB of the CNS

     

    Notes:

    • TB facilities must have all the TB drugs mentioned above, in order to provide to each patient one of these STRs, based on their specific needs.
    • For the BpaLM and endTB regimens, the dose of linezolid is reduced after 16 weeks (see Linezolid drug information sheet, Appendix 10).
    • BEAT Tuberculosis should be started with Bdq-Dlm-Lzd-Lfx-Cfz if fluoroquinolone-resistance is unknown at baseline and continued with Bdq-Dlm-Lzd-Lfx once fluoroquinolone-susceptibility is confirmed. Treatment can be extended to 9 months if there is no culture conversion at Month 4[4]Citation 4.https://clinicaltrials.gov/study/NCT04062201#study-overview. 
    • This guide does not recommend the 9-11-month all-oral bedaquiline containing regimens given their complexity (2 phases and potential extension), their high pill burden (7 drugs in intensive phase), their toxicity (in particular when Eto is included), and the inclusion of drugs of uncertain efficacy (Hh and E). 

    Pre-XDR-TB

    Options are the BPaL regimen (6-9Bdq-Pa-Lzd), BEAT Tuberculosis regimen or an LTR (Section 10.2.2).

     

    Notes:

    • In the BPaL regimen, the dose of linezolid is 600 mg per day for 6 months (no dose reduction at 16 weeks as for other STRs).

    • Linezolid causes frequent and often severe adverse effects. Their management includes temporary or permanent interruption of the drug. If interruptions are recurrent or linezolid is stopped early in the treatment, patients will receive a two-drug regimen for a significant period of time, which is not optimal[1]Citation 1.World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva 2022.https://www.who.int/publications/i/item/9789240065116. 

    • BEAT Tuberculosis regimen is recommended by WHO[3]Citation 3.World Health Organization. Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva. June 2024.https://www.who.int/publications/i/item/B09123. It should be started with Bdq-Dlm-Lzd-Lfx-Cfz if fluoroquinolone-resistance is unknown at baseline, and continued with Bdq-Dlm-Lzd-Cfz if fluoroquinolone-resistance is detected. However, unpublished trial results show a high risk of recurrences with this regimen[5]Citation 5.BEAT Tuberculosis Trial: Insights on the effectiveness and safety of new 6-month regimens for DR-TB, Geneva 31st webinar of the European Virtual Medical Consilium on TB, 29th November, 2024.
      https://vmc.euro.who.int/vmc/public/Files/Public/Webinars/2%20Clinical%20trial%20BEAT_TB.pdf      . 

    XDR-TB

    An LTR should be used (Section 10.2.2).
     

    10.2.2 Long treatment regimens

    Eligibility

    All MDR/RR-TB patients not eligible for STRs

    Regimen composition

    The regimen should include a minimum number of likely effective drugs.

     

    Box 10.1 – Number of likely effective drugs required in LTRs

    • At least 4 likely effective TB drugs, including:

      • 3 from Group A
      • 1 from Group B

    • If this optimal combination is not feasible:

      • At least 5 likely effective TB drugs, prioritizing Group A and B drugs and adding Group C drug(s) to bring the total to at least 5 TB drugs.

      • When the minimum number of likely effective drugs cannot be reached, the use of TB drugs under development available for compassionate use should be considered (Appendix 18). 

     

    LTRs may contain more than 5 TB drugs if there is uncertainty of effectiveness in some of the drugs used.

     

    While waiting for full DST results, patients can be treated with:

    • An individualized LTR, or
    • An empiricalaCitation a.An empirical regimen is a regimen designed to treat most patients in a region whilst waiting the full DST results. LTR according to the known resistance profile.

    It may be necessary to switch from an empirical LTR to an individualized LTR, based on the latest DST results and/or clinical evolution during treatment course (e.g. drug intolerance, persistence of a positive culture).

    Individualized long regimens

    To build an individualized LTR, a stepwise process is recommended.

     

    Table 10.3 – Steps to build an LTR

     

    Step 1

    		Use all 3 Group A drugs, unless confirmed resistance or contra-indication.

    1.1 Levofloxacin (Lfx) or moxifloxacin (Mfx)

    • Use Lfx (rather than Mfx) if the patient takes other QT-prolonging drugs.
    • High dose moxifloxacin (Mfxh) can be used:
      • if low-level resistance to FQs is detected, but not counted as a likely effective drug[1]Citation 1.World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment, 2022 update. Geneva 2022.https://www.who.int/publications/i/item/9789240065116.
      • with other QT-prolonging drugs, but only if options are very limited (weigh benefits/risks and discuss with the patient).

    1.2 Bedaquiline (Bdq)

    1.3 Linezolid (Lzd)

    Step 2

    		Add 1 or 2 Group B drug(s), unless confirmed or suspected resistance or contra-indication.

    2.1 Clofazimine (Cfz)

    Use Cfz rather than Cs or Trd if possible (better safety profile).

    2.2 Cycloserine (Cs) or terizidone (Trd)
    Interchangeable and used at the same dose.

    Step 3

    		Add Group C drugs when the combination of 3 Group A drugs and at least 1 Group B drug is not feasible, to bring the regimen to 5 likely effective drugs.

    3.1 Delamanid (Dlm)

    First choice (good safety profile and still limited drug resistance).

    3.2 First-line drugs: ethambutol (E), pyrazinamide (Z)

    3.3 Imipenem/cilastatin (Ipm/Cln) or meropenem (Mpm)

    • If no other option (high cost and difficult to administer).
    • Always administered with amoxicillin/clavulanic acid (Amx/Clv).
    • Use Mpm in patients < 15 years or with a history of epilepsy.

    3.4 Amikacin (Am) or streptomycin (S)

    • If no other option and confirmed susceptibility.
    • Use Am rather than S. Use S if Am is unavailable or the strain is resistant to Am.

    3.5 Ethionamide (Eto) or prothionamide (Pto)

    Interchangeable and used at the same dose.

    3.6 Para-aminosalicylic acid or sodium (PAS)

    3.7 High-dose isoniazid (Hh)

    Can be used if low-level resistance to H, but not counted as a likely effective drug.

     

    Note: isoniazid standard dose can be administered to patients with RR-TB when isoniazid susceptibility is documented. When isoniazid is used in this manner it can be counted as a likely effective drug.

    Empirical long regimens

    Table 10.4 – Examples of empirical long regimens at treatment initiation

     

    Resistance profiles

    Examples

    Group A and B drugs likely effective

    18Lfx-Bdq-Lzd-Cfz

    If Bdq is contra-indicated: 18Lfx-Lzd-Cfz-Cs-Dlm 

    If Lzd is contra-indicated: 18Lfx-Bdq-Cfz-Cs-Dlm 

    FQs not likely effective

    Other Group A and B drugs likely effective

    18Bdq-Lzd-Cfz-Cs-Dlm-[Mfxh]bCitation b.Moxifloxacin high dose can be used, but not counted if low-level FQ resistance is suspected or found on DST.

    If Bdq is contra-indicated: 18Lzd-Cfz-Cs-Dlm-Ipm/Cln

    Duration of treatment

    Treatment should last at least for 18 months, with at least 15 months after culture conversion (for definition, see Chapter 17). If well tolerated, all drugs should be taken for the full treatment duration[6]Citation 6.endTB. Bedaquiline- and delamanid-containing regimens achieve excellent interim treatment response without safety concerns: endTB interim analysis. July 2018.http://www.endtb.org/sites/default/files/2018-07/endTB%20interim%20analysis%20%2813%20July%202018%29.pdf, [7]Citation 7.Guglielmetti L, Jaspard M, Le Dû D, et al. French MDR-TB Management Group. Long-term outcome and safety of prolonged bedaquiline treatment for multidrug-resistant tuberculosis. Eur Respir J. 2017 Mar 22;49(3):1601799.
    https://doi.org/10.1183/13993003.01799-2016    .

     

    Preliminary evidence suggests that stopping bedaquiline at 6 months is associated with high rates of culture reversion (for definition, see Chapter 17) in patients with resistance to several drugs or extensive lung damage[8]Citation 8.Hewison C, et al. Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia. Int J Tuberc Lung Dis. 2018 Jul 1;22(7):766-772.
    https://doi.org/10.5588/ijtld.17.0840    . No safety issues have been reported with bedaquiline treatment longer than 6 months[9]Citation 9.World Health Organization. WHO operational handbook on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva 2020.
    ​​​​​​​https://www.who.int/publications/i/item/9789240006997    , [6]Citation 6.endTB. Bedaquiline- and delamanid-containing regimens achieve excellent interim treatment response without safety concerns: endTB interim analysis. July 2018.http://www.endtb.org/sites/default/files/2018-07/endTB%20interim%20analysis%20%2813%20July%202018%29.pdf    .

    Carbapenems are commonly used for a minimum of 2 months after culture conversion. When the number of likely effective drugs included in the regimen is limited, a carbapenem may be required for the entire duration of treatment.

     
    الهوامش
    • (a)An empirical regimen is a regimen designed to treat most patients in a region whilst waiting the full DST results.
    • (b)

      Moxifloxacin high dose can be used, but not counted if low-level FQ resistance is suspected or found on DST.

    المراجع
    Path