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 Section 3.5). 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.
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 Sections 1 and 2). 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 (68). High-dose 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 (56). 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).
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 (31). 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 (12). 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 (69), as do ethionamide or prothionamide, cycloserine or terizidone, linezolid and imipenem–cilastatin (70, 71). 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 (72–74). In addition, cerebrospinal fluid concentrations may not mirror concentrations in the meninges or brain.
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 (51). The results of this study indicated that fetal exposure to bedaquiline in utero was associated with low birth weight36 (45% of babies exposed to bedaquiline had a low birth weight compared with 26% of babies not exposed, P=0.034) (51). 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 (51). 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.
The composition of the treatment regimen for MDR-TB does not usually differ substantially for People with HIV. 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 (36)).
Patients with extensive pulmonary TB disease
The duration of treatment post culture conversion may be modified according to the patient’s response to therapy37 (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.
36 Low birth weight was defined as less than 2 500 g.
37 “Bacteriological response” refers to bacteriological conversion with no reversion; “bacteriological conversion” describes a situation in a patient with bacteriologically confirmed TB where at least two consecutive cultures (for DR-TB and drug-susceptible TB) or smears (for drug-susceptible TB only), taken on different occasions at least 7 days apart, are negative; and “bacteriological reversion” describes a situation where at least two consecutive cultures (for DR-TB and drug-susceptible TB) or smears (for drug-susceptible TB only), taken on different occasions at least 7 days apart, are positive either after the bacteriological conversion or in patients without bacteriological confirmation of TB. (75)