Drug-resistant tuberculosis treatment

Concurrent bedaquiline and delamanid use. The GDG 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 with regard to 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. 
With the exception of the carbapenems and bedaquiline in children, the latest WHO model list of 
essential medicines (83) includes all agents required for longer
regimens.
44 
This is the mean terminal half-life of bedaquiline and the M2 metabolite; this longer terminal elimination phase probably reflects the 
slow release of bedaquiline and M2 from peripheral tissues (83). 

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Recommendations 
38
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, which could reliably identify 
resistance to fluoroquinolones, would help clinicians to decide whether the patient is eligible for the 
shorter MDR-TB regimen, and what agents to include in a longer MDR-TB regimen (the GenoType 
MTBDRsl LPA may be used for this purpose). GenoType MTBDRsl can be used in both children 
and adults for testing sputum specimens (direct testing) and cultured isolates of M. tuberculosis 
complex (indirect testing). The latter can be performed on culture isolates from both pulmonary and 
extrapulmonary sites. Direct testing on sputum specimens allows for the earlier initiation of appropriate 
treatment, and it can be applied irrespective of the smear status, although the indeterminate rate 
is higher when testing smear-negative sputum specimens than it is with smear-positive sputum 
specimens. Conventional phenotypic DST can still be used in the evaluation of patients with a negative 
GenoType MTBDRsl result, particularly in populations with a high pretest probability for resistance 
to fluoroquinolones or if the patient is at high risk for fluoroquinolone resistance (or both). The new 
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 based on DST results once they 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 a number of 
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 take into account the relative benefits and harms to 
the individual patient, including drug–drug interactions.