The GDG 2018 assessed the individual contribution to patient outcomes of medicines used in longer MDR-TB regimens, using primarily the estimates of effect from the 2018 IPD meta-analysis and Trial 213 (delamanid) for PICO question 3–2018 (MDR/RR-TB, 2018) (see Annex 5 for the respective GRADE summaries of evidence for each medicine, and the evidence-to-decision framework). Following a thorough assessment of the relative benefits and harms, recommendations were made for each medicine and they were classified into three groups (see Table 3.1, Table 3.2 and Table 3.3).

• Group A: fluoroquinolones (levofloxacin and moxifloxacin), bedaquiline and linezolid were considered highly effective and strongly recommended for inclusion in all regimens unless contraindicated.
• Group B: clofazimine and cycloserine or terizidone were conditionally recommended as agents of second choice.
• Group C: included all other medicines that can be used when a regimen cannot be composed with Group A or Group B agents. The medicines in Group C are ranked by the relative balance of benefit to harm usually expected of each. Other medicines that are not included in Groups A–C are as follows:
• Kanamycin and capreomycin – these medicines were associated with poorer outcomes when used; therefore, they are no longer recommended for use in MDR-TB regimens.
• Gatifloxacin and high-dose isoniazid, and thioacetazone – gatifloxacin and high-dose isoniazid were used in only a few patients, and thioacetazone was not used at all. Currently, quality-assured preparations of gatifloxacin are not available, following its withdrawal from the market due to concerns about dysglycaemias. Thioacetazone is unlikely to have a role in contemporary longer regimens and is not currently available in a quality-assured formulation. High-dose isoniazid may have a role in patients with confirmed susceptibility to isoniazid (see Subgroup considerations).
• Clavulanic acid – this medicine should be included in MDR/RR-TB regimens only as a companion agent to the carbapenems (imipenem–cilastatin and meropenem). When used in this way, it should be given with every dose of carbapenem, and should not be counted as an additional effective TB agent. No recommendation on perchlozone, interferon gamma or sutezolid was possible owing to the absence of final patient treatment outcome data from appropriate patient studies. Regarding the use of bedaquiline in patients aged below 18 years, and considering that exposure– response (efficacy) profiles can be extrapolated from adults to children, the GDG concluded that the doses evaluated in children and adolescents in two trials (Phase 2 trial TMC207-C211 and Phase 1–2 IMPAACT P1108; see Annex 6) do not appear to result in exposures that would put patients aged 6–17 years at increased risk for treatment failure. The safety risk in children aged 6 years and older enrolled in the trials – all of whom were HIV-negative and had limited exposure to other QT intervalprolonging medications – did not appear to exceed that of adults. The variability present in the limited sample size precluded a comment on exposure–response (safety). The GDG 2018 also concluded that the risk–benefit considerations for the use of bedaquiline in patients aged 6–17 years are similar to those considered for adults; however, the GDG stressed the need for more data before considering upgrading this recommendation to “strong”. The GDG review in 2021 determined that the balance between desirable and undesirable effects probably favours the use of bedaquiline in children aged below 6 years. The GDG 2021 highlighted that the benefits may vary depending on specific contexts and population characteristics, such as by nutritional status. The GDG also noted that the potential higher cost of bedaquiline in an MDR/ RR-TB treatment regimen should be considered in the context of the benefits of shorter injectablefree regimens (i.e. less travel, reduced time spent in clinics and fewer AEs). In addition, they judged that equity might increase when bedaquiline becomes available to younger children, because its use would be acceptable to most stakeholders, and that one of the main feasibility aspects would be related to the need for safety monitoring (i.e. access to ECG monitoring, as well as staff capacity for monitoring). However, the panel judged that implementing the use of bedaquiline in young children was probably feasible. With respect to the use of delamanid in children aged below 6 years, the GDG review in 2018 decided that – based on findings in adults, and on the pharmacological and safety data reviewed – extrapolations on efficacy and safety should be restricted to children aged 3–5 years, but not to children aged below 3 years (see Annex 5). Exposure profiles in children aged 3–5 years were comparable to adults, and were no higher than in children aged 6 years and older, for whom past GDGs convened by WHO had already recommended the use of delamanid (15, 26). Based on the laboratory and cardiac data provided, no safety signals distinct from those reported in adults were observed in children aged 3–5 years. The GDG nonetheless had concerns about the feasibility of administering the correct dose to children aged 3–5 years, given that the special formulation used in the trial (25 mg) would not be available in the foreseeable future, and that only the adult tablet (50 mg) is available, which is not bioequivalent and presents challenges to manipulating its contents without compromising its effectiveness. The GDG review in 2021 concluded that the balance between desirable and undesirable effects probably favours the use of delamanid in children aged below 3 years. The GDG 2021 further stated that when the 25 mg dispersible tablet became available in the future, the resource implications could vary. It was thought that delamanid containing longer treatment regimens could potentially increase equity and be acceptable to stakeholders. In addition, the GDG 2021 judged that it would probably be feasible to use delamanid in children of all ages, especially as the child-friendly formulation of delamanid was expected to become available later in 2021 (this formulation is now available). This judgement also considered that adult tablets cannot be split, crushed or dissolved to ease administration in children without potentially altering bioavailability. As a result of these multiple reviews as new data have gradually become available, the use of bedaquiline and delamanid are no longer restricted by the age of the patient. Subgroup considerations MDR/RR-TB alone or with additional resistance A longer regimen is used where a shorter regimen cannot be used; it is more likely to be effective if its composition is guided by reliable information on drug susceptibility. The design of longer regimens for MDR/RR-TB patients with additional resistance follows a similar logic to that used for other MDR/RR-TB patients. All MDR/RR-TB patients should be tested for resistance to fluoroquinolones as a minimum before starting MDR-TB treatment. If the use of amikacin is being considered in the regimen, then rapid testing for second-line injectable agents should be performed. Other tests that may help to inform regimen choice and composition are those for resistance to agents such as bedaquiline, delamanid, linezolid and pyrazinamide, and for mutation patterns commonly associated with resistance to isoniazid and ethionamide or prothionamide. In many settings, DST for other medicines commonly used for MDR-TB treatment is not usually reliable enough to guide regimen composition. Because of this, other elements may be necessary to determine the likelihood of effectiveness (see Implementation considerations). NTPs should possess or rapidly build the capacity to undertake DST, and all efforts should be made to ensure access to approved rapid molecular tests. Until the capacity for second-line DST – including for bedaquiline, linezolid and clofazimine – becomes available, treatment decisions may need to rely on the likelihood of resistance to medicines, based on an individual patient’s clinical history and surveillance data from the country or region. The analysis for the three PICO questions on the duration of treatment did not show any differences overall in treatment failure or relapse when comparing patients with MDR-TB with or without additional second-line drug resistance, including those with additional resistance to fluoroquinolones and injectable agents. In patients with resistance to amikacin and streptomycin, Recommendation 3.17 does not apply. The duration of treatment may need to be longer than 20 months overall in MDR/ RR-TB cases with extended resistance patterns, subject to the clinical response to treatment. Rifampicin-resistant TB A patient (child or adult) in whom isoniazid resistance is absent needs to be treated with a recommended MDR-TB regimen – either a longer MDR-TB regimen to which isoniazid is added, or a shorter MDR-TB regimen in eligible patients (see also Treatment of drug-resistant TB using 6-month regimens). Although high-dose isoniazid is not included in Groups A–C, given the rarity of its use in contemporary longer regimens for adults with MDR/RR-TB, it may still be used in patients with confirmed susceptibility or in the presence of mutations that do not usually confer complete resistance to isoniazid (82). Highdose isoniazid was shown to be an important component in paediatric regimens in a 2016 evidence review of the WHO guidelines; based on this finding its use in adults was extrapolated (71). In this analysis, high-dose isoniazid was associated with treatment success among children with confirmed MDR-TB (aOR: 5.9, 95% confidence limits [CL]: 1.7–20.5, P=0.007). Children and adolescents The 2018 IPD of longer regimens comprised mainly data from adult patients, with only 181 of the 13 104 (1.4%) cases being in children and adolescents aged below 15 years. Nonetheless, WHO recommendations on longer MDR-TB regimens apply to children as well as adults. Most medicines that are used in longer regimens have been part of MDR-TB regimens for many years, in similar combinations, for both adults and children. The GDG 2021 recommended the use of bedaquiline and delamanid in children of all ages (30). Reproducing the delamanid exposure achieved with the special 25 mg tablet tested in the trial in children aged 3–5 years is expected to be challenging, given that this formulation is not bioequivalent with the 50 mg delamanid adult tablet – the only preparation available at that time (2). There are also concerns that the adult tablet may shatter if attempts are made to split it, and that its contents are exceedingly bitter and unpalatable. Further, bioavailability may be altered when the 50 mg tablet is split, crushed or dissolved. Delamanid is susceptible to oxidation and heat; therefore, retaining pill fragments for use at a time other than the time of initial administration is likely to result in the delivery of lower-than-expected active compound and unspecified oxidation by-products. The avoidance of an injectable-containing regimen is particularly desirable in children, especially those who are very young and those with mild disease (as determined by the absence of malnutrition), serious forms of extrapulmonary disease, cavitation on chest radiography or HIV infection. Hearing loss can have a permanent effect on the acquisition of language and the ability to learn at school; therefore, if amikacin or streptomycin use is resorted to in children, regular audiometry is required. The recommendations on treatment duration apply also to children. Given that many patients in the paediatric age group may only be clinically diagnosed or have extrapulmonary disease, it is expected that treatment duration will largely be guided by Recommendation 3.15, subject to response to treatment. Shortening the total treatment duration to less than 18 months may be considered in the case of children without extensive disease (see Definitions). Extrapulmonary TB and TB meningitis The WHO recommendations on longer MDR-TB regimens apply also to patients with extrapulmonary disease. Adjustments may be required, depending on the specific location of the disease. Treatment of MDR/RR-TB meningitis is best guided by DST of the infecting strain and by knowledge of the properties of TB medicines that cross the blood–brain barrier. Levofloxacin and moxifloxacin penetrate the CNS well (83), as do ethionamide or prothionamide, cycloserine or terizidone, linezolid and imipenem–cilastatin (84, 85). Seizures may be more common in children with meningitis treated with imipenem–cilastatin; thus, meropenem is preferred for meningitis cases and in children. High-dose isoniazid and pyrazinamide can also reach therapeutic levels in the cerebrospinal fluid, and they may be useful if the strains are susceptible. P-aminosalicylic acid and ethambutol do not penetrate the CNS well, and they should not be counted on as effective agents for MDR/RR-TB meningitis. Amikacin and streptomycin penetrate the CNS only in the presence of meningeal inflammation. There are few data on the CNS penetration of clofazimine, bedaquiline or delamanid (86–88). In addition, cerebrospinal fluid concentrations may not mirror concentrations in the meninges or brain. Pregnancy Amikacin, streptomycin, prothionamide and ethionamide are usually contraindicated during pregnancy. Because of the potential for teratogenic effects from these medications, including the injectable agents, Recommendation 3.17 is of limited relevance in this subgroup. Following the changes made in the 2018 guidelines update, these agents are expected to be used less frequently in longer regimens. Knowledge about the safety of bedaquiline and delamanid in pregnancy and breastfeeding is sparse. However, new evidence from an observational study in South Africa was presented to the GDG 2019; it included information on 58 mothers who received bedaquiline during pregnancy (61). The results of this study indicated that fetal exposure to bedaquiline in utero was associated with low birth weight47 (45% of babies exposed to bedaquiline had a low birth weight compared with 26% of babies not exposed, P=0.034) (61). However, there were no other significant differences in infant outcomes, pregnancy outcomes or maternal treatment outcomes, including weight gain in the infants until 1 year of age (61). In such cases, it is recommended that a longer regimen be individualized to include components with a better established safety profile. The outcomes of treatment and pregnancy, including data from postpartum surveillance for congenital anomalies, should be documented to help inform future recommendations for MDR-TB treatment during pregnancy HIV infection The composition of the treatment regimen for MDR-TB does not usually differ substantially for PLHIV. With careful attention, it is possible to avoid certain drug–drug interactions (e.g. bedaquiline and efavirenz; see also the HIV drug interactions website of the University of Liverpool (44)). Patients with extensive pulmonary TB disease The duration of treatment post culture conversion may be modified according to the patient’s response to therapy48 (e.g. culture conversion before 2 months of treatment) and other risk factors for treatment failure or relapse. This should be considered in patients with extensive TB disease. Patients on regimens without amikacin or streptomycin In patients on regimens that do not contain injectable agents in the intensive phase, Recommendation 3.17 does not apply, and the length of treatment is determined by recommendations on total duration and on time after culture conversion (i.e. Recommendations 3.15 and 3.16). In the future, this situation is expected to apply to an increasing proportion of patients who are treated with oral-only regimens. If bedaquiline or other agents (e.g. linezolid or delamanid) are given only for the initial part of a regimen, this period does not equate to an “intensive phase” unless an injectable agent is used concurrently, as premised by the meta-analysis that informed Recommendation 3.17. Implementation considerations The implementation of MDR/RR-TB treatment on a large scale is feasible under programmatic conditions, as has been shown by the global expansion in the use of standardized and individualized MDR-TB regimens in low-, middle- and high-income countries worldwide, particularly in the past decade (6). The 2018 revision of the guidelines brought important changes to the grouping of medicines, the composition of longer MDR-TB regimens and the duration of medicine use, but it is expected that implementation of these changes will be feasible. The rapidity with which the new recommendations are applied in (or to) programmes may be influenced by a range of factors, but these should not stand in the way of increased access to life-saving treatment for patients who need it. All of the agents recommended for use are available via the GDF, and most are also available in quality-assured, affordable generic formulations from other sources. Bedaquiline was available via a donation programme until March 2019; it is now available via the GDF, and a decrease in price has been negotiated with the manufacturer for low-resource settings. The evidence assessed during the GDG meeting in November 2019 did not allow the group to make any judgements about the efficacy or effectiveness of bedaquiline when used for longer than 6 months; however, it did allow the GDG to determine that the safety profile of bedaquiline use for longer than 6 months is becoming clearer. The group concluded that bedaquiline can be safely used in patients beyond 6 months, if decided by the programme or treating clinician, and if appropriate schedules of baseline testing and monitoring are in place. In addition, the treating clinician should be aware of the use of other potentially QT-prolonging medications in any MDR/RR-TB regimen, and the comparatively long halflife of bedaquiline, which means that bedaquiline will remain in human tissue beyond the duration of its use. The half-life of bedaquiline is about 6 months, and the half-life of the N-monodesmethyl metabolite (M2) is about 5.5 months (90) Concurrent bedaquiline and delamanid use The GDG 2019 felt that there was insufficient evidence to assess the efficacy or effectiveness of the concurrent use of bedaquiline and delamanid. However, the group concluded that the safety data assessed in 2019 suggest there are no additional safety concerns regarding the concurrent use of bedaquiline and delamanid. Therefore, bedaquiline and delamanid may be used in patients who have limited options for other treatment; that is, for patients with a small number of other effective drugs included in their regimen, probably due to an extensive drug-resistance profile or intolerance to other second-line TB medications. Appropriate schedules of safety monitoring (at baseline and throughout treatment) should be in place for these patients, including ECG and electrolyte monitoring, and clinicians should be cognizant of other medicines in the regimen that can either prolong the QT interval or cause other potential adverse events. The 2021 WHO model list of essential medicines (91) includes all agents required for longer regimens. Drug susceptibility testing These guidelines stress past advice that a patient’s MDR/RR-TB strain should be tested for susceptibility to medicines planned for inclusion in the regimen, so that effectiveness can be maximized. Access to rapid diagnostic testing would help clinicians to decide whether the patient is eligible for a specific MDR/RR-TB regimen, and what agents to include in a longer MDR-TB regimen. The recommendations on regimen design need to be accompanied by continued efforts to increase access to DST for medicines for which there are reliable methods, and by the development and roll-out of DST for the newer medicines. However, potentially life-saving treatment should not be withheld until all DST results become available, and empirical treatment with a regimen that is likely to be effective may need to be started, then adjusted once DST results become available. An important observation in the 2018 IPD meta-analysis for longer regimens is that when a DST result indicates resistance to an agent, it is better to replace that agent. This also applies to medicines for which DST or the DST method used is known to be unreliable for clinical decision-making. Although DST is important for guiding effective treatment, DST results present uncertainties for several regimen components (e.g. cycloserine, streptomycin and ethambutol). “Likelihood of effectiveness” is generally assessed in the programmatic setting on the basis of one or more of the following: confirmed susceptibility in the individual patient, confirmed susceptibility in the presumed source case, no known resistance to another drug that has cross-resistance to the medicine, rare use of the medicine in an area (possibly supported by low drug-resistance levels from surveillance activities), and no previous use of the medicine in a regimen that failed to cure that same patient. When there is uncertainty about the effectiveness of a certain agent, that agent may still be included in the regimen, but it should not be considered as one of the target number of medicines needed; clinical judgement should be used to decide whether the benefit from its inclusion outweighs any added toxicity, pill burden or other disadvantages. The design of the regimen must consider the relative benefits and harms to the individual patient, including drug–drug interactions. Dosage and duration The guidelines update in 2018 revised the weight-based dosage schedules for medicines used in MDR-TB regimens for both children and adults (see the WHO consolidated operational handbook on tuberculosis. Module 4: Treatment and care (8)). The update to the dosages benefited from the expertise of the GDG members, and from an extensive consultation with other specialists in different fields. It was based on the latest knowledge available about the optimal use of the medicines involved (92). Adherence to the schedules is advised as far as possible. Manipulation of tablets (e.g. splitting, crushing or dissolving in water) outside their indications is to be avoided because this may interfere with the bioavailability of the drugs.50 It is important to prevent treatment interruption, to increase the likelihood of treatment success. One measure that can help to increase retention is supporting patient adherence, either by facilitating patient visits to health care facilities or home visits by health care staff, or by using digital technologies for daily communication (93).