TABLE 3

Grouping of medicines recommended for use in longer multidrug-resistant (MDR) tuberculosis (TB) regimens

StepsMedicineAbbreviation
Group AInclude all three medicinesLevofloxacin OR
moxifloxacin
Lfx
Mfx
Bedaquiline#,¶Bdq
Linezolid+Lzd
Group BAdd one or both medicinesClofazimineCfz
Cycloserine OR
terizidone
Cs
Trd
Group CAdd to complete the regimen and when medicines from groups A and B cannot be usedEthambutolE
Delamanid,§Dlm
PyrazinamideƒZ
Imipenem–cilastatin OR
meropenem##
Ipm–Cln
Mpm
Amikacin
(OR streptomycin)¶¶
Am
(S)
Ethionamide OR
prothionamide++
Eto
Pto
p-Aminosalicylic acid++PAS

This table is intended to guide the design of individualised longer MDR-TB regimens (the composition of the recommended shorter MDR-TB regimen is largely standardised; see Section 2 on shorter all-oral bedaquiline-containing regimen for multidrug- or rifampin-resistant TB in the guidelines). Medicines in group C are ranked by decreasing order of usual preference for use subject to other considerations. The 2018 individual patient dataset (IPD) meta-analysis for longer regimens included no patients on thioacetazone and too few patients on gatifloxacin and high-dose isoniazid for a meaningful analysis. No recommendation on perchlozone, interferon-γ or sutezolid was possible owing to the absence of final patient treatment outcome data from appropriate studies. #: bedaquiline is usually administered 400 mg orally once daily for the first 2 weeks, followed by 200 mg orally three times per week for 22 weeks (total duration of 24 weeks). Evidence on the safety and effectiveness of bedaquiline use beyond 6 months and below the age of 6 years was insufficient for review in 2018. Therefore, the use of bedaquiline beyond 6 months was implemented following best practices in “off-label” use [46]. New evidence on the safety profile of bedaquiline use beyond 6 months was available to the guideline development group (GDG) in 2019. Based on this evidence, the GDG were not able to assess the impact of prolonged bedaquiline use on efficacy, due to the limited evidence and potential residual confounding in the data. However, the evidence supports the safe use of bedaquiline beyond 6 months in patients who receive appropriate schedules of baseline and follow-up monitoring. It is important to note that the use of bedaquline beyond 6 months still remains as off-label use and in this regard best practices in off-label use still apply. : evidence on the concurrent use of bedaquiline and delamanid was insufficient for review in 2018. In 2019, new evidence on the concurrent use of bedaquiline and delamanid was made available to the GDG. With regards to safety, the GDG concluded that the data suggest no additional safety concerns with regards to concurrent use of bedaquiline and delamanid. Both medicines may be used concurrently among patients who have limited other treatment options available to them, and if sufficient monitoring (including baseline and follow-up ECG and electrolyte monitoring) is in place. The data on the effectiveness of concurrent use of bedaquiline and delamanid were reviewed by the GDG, but due to the limited evidence and potential residual confounding in the data, the GDG were unable to proceed with a recommendation on effectiveness. +: use of linezolid for ≥6 months was shown to increase effectiveness, although toxicity may limit use. The analysis suggested that using linezolid for the whole duration of treatment would optimise its effect (∼70% of patients on linezolid with data received it for >6 months and ∼30% for 18 months or the whole duration). No patient predictors for early cessation of linezolid could be inferred from the IPD sub-analysis. §: evidence on the safety and effectiveness of delamanid beyond 6 months and below the age of 3 years was insufficient for review. Use of delamanid beyond these limits should follow best practices in “off-label” use [30]. ƒ: pyrazinamide is counted as an effective agent only when drug susceptibility test (DST) results confirm susceptibility. ##: every dose of imipenem–cilastatin and meropenem is administered with clavulanic acid, which is available only in formulations combined with amoxicillin. Amoxicillin–clavulanic acid is not counted as an additional effective TB agent and should not be used without imipenem–cilastatin or meropenem. ¶¶: amikacin and streptomycin are to be considered only if DST results confirm susceptibility and high-quality audiometry monitoring for hearing loss can be ensured. Streptomycin is to be considered only if amikacin cannot be used (unavailable or documented resistance) and if DST results confirm susceptibility (resistance to streptomycin is not detectable with second-line molecular line probe assays and phenotypic DST is required). Kanamycin and capreomycin are no longer recommended for use in MDR-TB regimens. ++: these agents showed effectiveness only in regimens without bedaquiline, linezolid, clofazimine or delamanid, and are thus proposed only when other options to compose a regimen are not possible.