Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

Multidrug-resistant (MDR) tuberculosis (TB) has been emerging at an alarming rate over the last few years. It has been estimated that about 3% of all pediatric TB is MDR, meaning about 30,000 cases each year. Although most children with MDR-TB can be successfully treated, up to five years ago effective treatment was associated with a high incidence of severe adverse effects and patients with extensively drug-resistant (XDR) TB had limited treatment options and no standard regimen. The main objective of this manuscript is to discuss our present knowledge of the management of MDR- and XDR-TB in children, focusing on the characteristics and available evidence on the use of two promising new drugs: bedaquiline and delamanid. PubMed was used to search for all of the studies published up to November 2020 using key words such as “bedaquiline” and “delamanid” and “children” and “multidrug-resistant tuberculosis” and “extensively drug-resistant tuberculosis”. The search was limited to articles published in English and providing evidence-based data. Although data on pediatric population are limited and more studies are needed to confirm the efficacy and safety of bedaquiline and delamanid, their use in children with MDR-TB/XDR-TB appears to have good tolerability and efficacy. However, more evidence on these new anti-TB drugs is needed to better guide their use in children in order to design effective shorter regimens and reduce adverse effects, drug interactions, and therapeutic failure.


Introduction
Tuberculosis (TB) causes even more deaths each year than any other bacterial infection [1]. In 2018, the World Health Organization (WHO) estimated 10.0 million new cases of TB (range 9-11.1 million). The burden of disease is very heterogeneous among countries, with the global average being around 130 new cases per 100,000 population per year. In the same period, TB deaths among HIV-negative people, in 2018, were estimated to be 1.2 million (range 1.1-1.3 million), and 251,000 deaths (range 223,000-281,000) among HIV-infected people. Children (aged <15 years) accounted for 11% of all TB cases in 2018, with higher rates in developing countries [1,2]. Indeed, in Africa, children contribute approximately 30% of incident TB cases. In countries with high HIV prevalence, the peak age prevalence of TB has shifted towards younger adults. These adults are often parents of young children, increasing the exposure of children to TB [3,4].
Multidrug-resistant (MDR) TB has been emerging at an alarming rate over the last few years. Annually, the new cases of MDR and rifampicin-resistant (RR) TB are estimated to be 500,000 [5]. Although an increased number of children is now being diagnosed and treated for TB, a low number is diagnosed for MDR-TB and little data are available on the occurrence of MDR-TB in children [6,7]. It has been estimated that about 3% of all pediatric TB is MDR, meaning about 30,000 cases each year [8]. MDR-TB is due to strains that are resistant to both isoniazid and rifampicin, while extensively drug-resistant (XDR) TB is characterized by MDR strains which present additional resistance also to fluoroquinolones and second level injectable drugs. Pre-XDR-TB denotes resistance to isoniazid and rifampicin, as well as to at least one fluoroquinolone or one second-line injectable drug.
The main obstacles facing treatment of MDR-and XDR-TB are the low availability of diagnostic tests and lengthy expensive treatment, with frequent appearances of adverse effects, drug interactions, and high rates of therapeutic failure. Although most children with MDR-TB can be successfully treated, up to five years ago effective treatment was associated with a high incidence of severe adverse effects and patients with XDR-TB had limited treatment options and no standard regimen [9][10][11][12].
In this context, over the last few years, the approval of new and repurposed drugs for the treatment of MDR-/XDR-TB have opened the possibility of new effective regimens. The main aim of this manuscript is to discuss our present knowledge of the management of MDR-TB disease in children, focusing on two promising new drugs: bedaquiline and delamanid. All the studies performed using bedaquiline and delamanid have been considered: this manuscript summarizes the main 12 published studies related to adults, as well asl the five studies already published and the five ongoing studies regarded the pediatric population.

Management of MDR-TB in Pediatrics
In most cases, a child develops MDR-TB following exposure to an infectious MDR-TB case (primary resistance). Furthermore, as a result of the poor adherence to the therapy or of inadequate or inconsistent therapy, a child with drug-susceptible TB can develop resistance to isoniazid and rifampicin (acquired resistance) [13,14].
Although the efficacy of preventive therapy for child contacts of drug-susceptible TB is well established, preventive treatment of children exposed to MDR-TB is considered on a case-by-case basis for evaluating the risk of infection and of disease progression. However, children in direct household contact with an adult with TB have a high risk of developing the disease and the treatment of MDR-TB in children is complex, long, and associated with frequent and significant side effects. For this reasons, prevention of MDR-TB in children is very important. In two ongoing clinical trials (TB-CHAMP (ISRCTN92TG634082) and PHOENIx MDR-TB (NCT03568383)) the administration of levofloxacin or delamanid, respectively, as MDR-TB preventive therapy in children is being evaluated [15,16].
Similar to adults, even in the pediatric population, the design of an appropriate MDR-TB treatment regimen should consider the following [17,18]: the likely or confirmed infecting Mycobacterium tuberculosis strain, through a drug susceptibility test (DST); previously failed TB treatment either in the child or in a known source case; the resistance profile in the relevant geographic area; the side and the severity of disease; the age of the child; and the ability to take certain drugs or drug formulation.
For MDR-TB, longer treatment regimens are recommended, and the choice of an effective all-oral regimen is suggested in several guidelines. The groupings of medicines recommended for use in longer MDR-TB regimens are reported in Table 1. To build an effective MDR-TB regimen for children, the WHO Groups A and B should be prioritized, as well as delamanid in children aged more than 3 years of age [19]. The Sentinel Project for Pediatric Drug-Resistant Tuberculosis Field Guide provides a suggestion on how to build therapeutic regimens in children based on the age and on the presence of fluoroquinolone resistance. Since TB in children is frequently non-severe and paucibacillary, the duration of treatment should depend upon the site of infection, the severity of disease, and the extent of drug resistance; in children with non-severe disease, treatment can last for 9 to 12 months, while in children with severe disease, a treatment of 12-18 months is required. Injectable-free regimens, especially in very young children and in those with mild disease, should be preferred in order to preserve hearing function. Therefore, greater knowledge of the efficacy and safety of the new drugs bedaquiline and delamanid and the possibility of their use in children may help to treat MDR-TB with all-oral shorter effective and safe regimens [20,21].  [22]. Previously named TMC207 and R207910, it belongs to the family of diarylquinoline. It has a central nucleus of quinolone with lateral aminic and alcoholic chains. Figure 1 shows its structural formula.

Mechanism of Action and Pharmacokinetics
Bedaquiline (molecular formula C32H31BrN2O2) is the first antitubercular agent approved by the FDA since the late 1970s [22]. Previously named TMC207 and R207910, it belongs to the family of diarylquinoline. It has a central nucleus of quinolone with lateral aminic and alcoholic chains. Figure 1 shows its structural formula. Bedaquiline has a strong bactericidal activity as an inhibitor of mycobacterial ATP synthase proton pump [23][24][25]. In fact, it is the only anti-tubercular drug targeted to the energetic metabolism of mycobacteria. It also has an effect on further remodeling bacterial metabolism, which may be due to multiple factors, such as decreasing cellular ATP levels or changes in intracellular redox state [26]. Pharmacokinetic studies in humans have shown that bedaquiline is well absorbed after a single oral administration with a median time to reach peak concentration of 5-6 h after the dose and an effective half-life of more than 24 h [27,28]. The long terminal half-life in humans makes possible intermittent drug Bedaquiline has a strong bactericidal activity as an inhibitor of mycobacterial ATP synthase proton pump [23][24][25]. In fact, it is the only anti-tubercular drug targeted to the energetic metabolism of mycobacteria. It also has an effect on further remodeling bacterial metabolism, which may be due to multiple factors, such as decreasing cellular ATP levels or changes in intracellular redox state [26]. Pharmacokinetic studies in humans have shown that bedaquiline is well absorbed after a single oral administration with a median time to reach peak concentration of 5-6 h after the dose and an effective half-life of more than 24 h [27,28]. The long terminal half-life in humans makes possible intermittent drug administration when combined with other drugs in the regimen against MDR-TB and XDR-TB [29].

Efficacy
There are numerous observational studies that have reported the compassionate use of bedaquiline culture conversion rates at Week 24 of treatment exceeding 90% [30][31][32][33]. Among these, the main ones are reported in Table 2.
It is important to report a retrospective study supported by Médecins sans Frontières in which MDR-TB treatment containing bedaquiline given through compassionate use programs [34] with linezolid and/or imipenem showed relatively good success rates in this cohort of previously treated patients with extensive and highly resistant TB (54/64-4.4% patients with a positive culture at treatment initiation culture converted; overall success rate 48/82-58.5%) [35]. This figure is confirmed by one of the most extensive retrospective studies conducted in 25 centers and 15 countries and including 428 patients with MDR-TB (45.6% XDR-TB and 22.1% HIV positive), in which success was achieved in 71.3% of patients treated with bedaquiline-containing regimes [36].
It is also interesting to note that, in these results, the highest success rates were achieved in patients with XDR-TB (76.9%) as compared with patients with MDR-TB (67.2%). Prospective clinical studies by Diacon et al. showed a faster crop conversion of the excretion as well as a higher conversion rate as compared with the placebo group [37][38][39]. In the multicenter phase 2 study of Pym et al. conducted on 233 patients (63.5% with MDR-TB, 18.9% with pre-XDR-TB, and 16.3% with XDR-TB), 87.1% of which had previously received second-line treatment, cultural conversion after 120 weeks of treatment occurred in 72.2% of patients treated; the highest success rate was observed in patients with MDR-TB (73.1%) and 23 of 38 patients with XDR-TB (61%) had a response at 120 weeks after the initiation of treatment [40]. Table 2. Principal studies on the effectiveness of bedaquiline treatment in adults.

Authors [Reference] (Year) Type of Study Study Population (Age of Patients) Therapy Results
Diacon et al. [37]

Safety and Tolerability
Among the side effects associated with the use of bedaquiline, most effects reported in the literature are nausea, headache, and arthralgia. It is known that bedaquiline can interfere with cardiac electrical activity by lengthening the QT interval. Furthermore, it is good to remember that these drugs are used in combination with others potentially able to lengthen the QT range, such as clofazimine and fluoroquinolones [41,42]. Current EMA recommendations include the execution of an ECG track before starting treatment with bedaquiline and at least at Weeks 2 and 4, and every following month [43]. Weekly ECG monitoring can be considered if the patient presents other possible risk factors for QT interval lengthening, such as other medications, hypokalemia, hypomagnesemia, hypocalcemia, congenital syndrome of long QT, hypothyroidism, radiation, and heart failure. However, cardiac safety information regarding bedaquiline is limited, often because the monitoring activities have not been reported in a systematic way and in sufficient detail to be easily compared, while numerous studies do not report relevant information about patients' QTc or heart safety more generally.
Bedaquiline remains a well-tolerated drug and a retrospective cohort study found that bedaquiline-containing regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis as compared with regimens that did not contain bedaquiline [44]. In an individual patient data meta-analysis, of 12,030 patients treated for MDR-TB assessed from 25 countries in 50 studies, bedaquiline resulted in being one of the drugs analyzed associated with greater treatment success and reduced death [45]. Further studies have confirmed the safety of bedaquiline in varied settings; a recent prospective comparative study reporting long-term (24-month) treatment-related outcomes in patients with XDR-TB, treated with and without bedaquiline, showed that mortality in the bedaquiline group was more than halved [46,47]. Interruption of bedaquiline occurred in small percentages of patients, of which a minority lengthened the QT range. However, potential adverse effects are one of the main reasons that still limit its use in children [47].

Drug Interactions
Bedaquiline undergoes oxidative metabolism via the CYP3A4, with the formation of N-mono-desmethyl metabolite (M2), which has a high half-life (~230 h) but does not seem to contribute significantly to clinical efficacy. However, clearance of M2 is also thought to be mediated by CYP3A4 [44,48,49]. For this reason, as reported in the WHO interim policy guidance, caution should be exercised in case there is co-administration of bedaquiline and drugs that induce CYP3A (e.g., rifampicin), as it may decrease bedaquiline plasma concentrations resulting in reduced efficacy. Conversely, when bedaquiline is administered together with drugs that may inhibit liver function (e.g., ketoconazole or lopinavir/ritonavir), its plasma concentration may be increased, resulting in toxicity [50].
Limited data concerning the interactions between bedaquiline and antiretroviral medicines are available, and most of these are based on studies conducted in healthy volunteers [51][52][53]. In an observational study performed in HIV-infected and HIV-seronegative adult patients (age ≥18 years) with MDR-TB, Brill et al. showed that nevirapine did not show a relevant effect on bedaquiline and M2 exposure in HIV/MDR-TB co-infected patients. Conversely, ritonavir-boosted lopinavir (LPV/r) significantly increased bedaquiline concentration in HIV/MDR-TB co-infected patients, thus, an adjusted bedaquiline dosing regimen was suggested [54].
Therefore, according to the WHO interim policy guidance, patients with HIV who receive bedaquiline as part of MDR-TB treatment should have their antiretroviral (ART) regimens designed in close consultation with HIV clinicians and ART specialists.

Bedaquiline Treatment in the Pediatric Population
There are few data on the use of bedaquiline in pediatric population, as all patients <18 years were excluded in the first trials that evaluated and led to the approval of its use in MDR-/XDR-TB [34]. However, Aschar et al. reported on 27 cases in which children and adolescents with MDR-/XDR-TB have been treated with drug regimens that included bedaquiline and described good treatment responses and no cessation caused by adverse effects [55]. Furthermore, Conradie et al., in an open-label, single-group study in which patients ≥14 years of age were eligible for enrollment, showed that the combination of bedaquiline, pretomanid, and linezolid was effective in a high percentage of patients with XDR-TB. This regimen was associated with toxic effects (19 patients, 17%, had serious adverse events), with a high percentage related to linezolid and manageable. No patient had a significant increase in the QT interval related to bedaquiline [56]. Two ongoing pharmacokinetic trials [57,58], a Janssen-sponsored study and a study of the IMPAACT network, are testing optimal dosing and safety of bedaquiline among children and ado-lescents <18 years of age. According to interim results from these studies, in the 2020 WHO consolidated guidelines on tuberculosis, optimal bedaquiline doses are reported that can be used safely in children aged >5 years [59]. Tables 3 and 4 summarize main  data on bedaquiline obtained in children and adolescents, whereas Table 5 shows the recommended dosing.

Mechanism of Action and Pharmacokinetics
Delamanid (molecular formula C 25 H 25 F 3 N 4 O 6 ) is a nitroimidazole agent that inhibits synthesis of mycolic acids (specifically methoxy-mycolic acid and keto-mycolic acid), leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria, with bactericidal activity [60,61]. It is thought to be a prodrug that requires biotransformation via the mycobacterial F420 coenzyme system to mediate its antimycobacterial activity against mycobacteria [62]. Mutations in one of coenzyme F420 genes has been proposed as the mechanism of resistance to delamanid [62] and the spontaneous rate of resistance has been reported as from 6.44 × 10 −6 to 4.19 × 10 −5 [63]. Figure 2 shows its structural formula.

Mechanism of Action and Pharmacokinetics
Delamanid (molecular formula C25H25F3N4O6) is a nitroimidazole agent that inhibits synthesis of mycolic acids (specifically methoxy-mycolic acid and keto-mycolic acid), leading to depletion of mycobacterial cell wall components and destruction of the mycobacteria, with bactericidal activity [60,61]. It is thought to be a prodrug that requires biotransformation via the mycobacterial F420 coenzyme system to mediate its antimycobacterial activity against mycobacteria [62]. Mutations in one of coenzyme F420 genes has been proposed as the mechanism of resistance to delamanid [62] and the spontaneous rate of resistance has been reported as from 6.44 × 10-6 to 4.19 × 10−5 [63]. Figure  2 shows its structural formula. In humans, delamanid absorption was almost two-fold higher when administrated with meals as opposed to in a fasted state [64]. The pharmacokinetics of delamanid are nonlinear, i.e., doubling the dose results in less than twice the exposure. Plasma concentration peaks at around 4-8 h after oral dosing with a half-life of 30-38 h [64]. The absolute oral bioavailability in humans is estimated to range from 25 to 47% [63]. Delamanid has a large apparent volume of distribution (Vz/F of 2100 L) with a binding to total proteins of ≥99.5% [65]. It is primarily metabolized in plasma by albumin, a nonhepatic process, rather than cytochrome P450 enzymes [65]. It is excreted primarily in the stool, with approximately 6% excretion in the urine [66]. Animal studies have indicated that delamanid can pass brain and placental blood barriers and is also excreted in breast milk [66]. In humans, delamanid absorption was almost two-fold higher when administrated with meals as opposed to in a fasted state [64]. The pharmacokinetics of delamanid are nonlinear, i.e., doubling the dose results in less than twice the exposure. Plasma concentration peaks at around 4-8 h after oral dosing with a half-life of 30-38 h [64]. The absolute oral bioavailability in humans is estimated to range from 25 to 47% [63]. Delamanid has a large apparent volume of distribution (Vz/F of 2100 L) with a binding to total proteins of ≥99.5% [65]. It is primarily metabolized in plasma by albumin, a non-hepatic process, rather than cytochrome P450 enzymes [65]. It is excreted primarily in the stool, with approximately 6% excretion in the urine [66]. Animal studies have indicated that delamanid can pass brain and placental blood barriers and is also excreted in breast milk [66].

Efficacy
Preclinical studies have shown in vitro activity against MDR-TB of delamanid [67,68]. In mouse and guinea pig models, adding delamanid to the MDR-TB treatment regimen resulted in significantly accelerated eradication of bacilli [69]. On the basis of the promising preclinical data, delamanid was moved into clinical development (Table 6). A trial to assess early bactericidal activity (EBA) in a group of uncomplicated, smear-positive, pulmonary TB adult patients showed a steady decline in CFU from baseline over 14 days of daily delamanid monotherapy [67].
A phase IIb, randomized, placebo-controlled, multinational clinical trial, showed that delamanid increased the two-month sputum culture conversion rates when added to an optimized background regimen (OBR) in adult MDR-TB patients [70]. Among patients who received a background drug regimen plus delamanid, 45.4% had sputum-culture conversion at 2 months as compared with 29.6% of patients who received a background drug regimen plus placebo. Other phase IIb trials comparing patients receiving 6 months (i.e., 6 or 8 months) of treatment with delamanid in combination with OBR to patients receiving 2 months of treatment (i.e., 0 or 2 months) showed that the first group had a significantly higher proportion of favorable outcomes (75% vs. 55%) and lower mortality (3% vs. 12%) [71,72]. In contrast, a recent large randomized, double-blind, placebocontrolled trial showed that the reduction in median time to sputum culture conversion over 6 months was not significant in the delamanid arm. It is important to note that this result could be misrepresented by the over performance of the placebo, given the already highly effective background treatment [73]. Table 6. Principal studies on the effectiveness of delamanid treatment in adults.

Authors [Reference] (Year) Type of Study Study Population (Age of Patients) Therapy Results
Diacon et al. [

Safety and Tolerability
Preclinical studies have shown that delamanid is well tolerated, and likely has no genotoxicity or carcinogenicity [64]. During the first trial in humans, in which delamanid was administrated in daily monotherapy for 14 days to MDR-TB adult patients, no serious treatment-emergent adverse events (AEs) occurred [67]. In a three-month randomized, double-blind, placebo-controlled, phase IIb trial on MDR-TB adult patients, treatment emergent AEs for which the incidence in the delamanid arm was higher by >5% as compared with the placebo included: nausea, vomiting, headache, and prolonged QTcF interval [70].
No clinical cardiac events were reported. Data on safety of delamanid in children are still forthcoming as several clinical trials are in the process of recruiting patients and have not yet published their results (Table 8).
Few pediatric case reports or case series are reported in the literature. In a study that enrolled 16 children treated with delamanid on compassionate basis, no adverse event was reported in fifteen of them, while a child treated with a combination of delamanid, capreomycin, ethionamide, cycloserine, clofazimine, imipenem, amoxicillin/clavulanate, and pyrazinamide experienced vomiting, renal impairment, electrolyte disturbances, and prolonged QTc on the Fridericia formula [74]. In another case series, 36 children (0-17 years) treated with delamanid at two sites in the Philippines and one site in South Africa well tolerated the treatment [75]. Shah et al. described two children with XDR-TB treated with bedaquiline and delamanid who developed prolonged QTc on the Bazett formula but normal QTc on the Fridericia formula, without any other adverse effects [76].
Since the primary safety concern of delamanid is QTc prolongation, ECG and electrolytes should be monitored before starting treatment. As hypoalbuminemia may increase the potential of delamanid to prolong QT, serum albumin levels should also be monitored [62]. Although the reported cases do not show a high incidence of adverse effects, the limited data available does not allow definite conclusions to be drawn on the safety of the drug. Thus, close monitoring and further investigations are needed to establish the safety profile in the pediatric population.

Drug Interactions
As reported above, delamanid is largely metabolized by albumin rather than cytochrome P450 enzymes, making it an attractive option to minimize drug-drug interactions [61]. There is no known drug-drug interaction with antiretroviral drugs [77].
Caution should be applied while combining delamanid with other drugs that have the potential of prolonging QT. The recent data review for the WHO guidelines suggested that there are no additional safety concerns for concurrent use of delamanid with bedaquiline [19]. The combined QT effects of bedaquiline and delamanid, compared with bedaquiline or delamanid alone (added to multidrug background therapy), were evaluated in a randomized controlled trial of 75 patients (>3000 ECGs). The average QTcF prolongation attributable to bedaquiline was 12.3 ms, and to the combination of bedaquiline and delamanid was 20.7 ms. No participants had grade 3 or 4 of QT prolongation [78].

Delamanid Treatment in the Pediatric Population
The first case of a child treated with delamanid documented a favorable clinical, microbiological, and radiological response [79,80]. A subsequent case series, describing 16 children who received delamanid on a compassionate basis, reported a favorable outcome in terms of culture conversion in all of them [74]. Another study reported favorable outcomes in two children with PreXDR-TB and XDR-TB after 24 weeks of treatment with delamanid plus background regimen [81]. Furthermore, results of other retrospective studies in which pediatric patients were included in delamanid-treated cohorts, have shown good tolerability and treatment response [82,83].
In 2016, the WHO issued an interim policy guidance on the use of delamanid in the treatment of MDR-TB in children and adolescents [84], recommending that delamanid may be added to background regimen for MDR-/XDR-TB for those patients who have previously received treatment with second-line anti-TB medicines, or who have isolates with additional resistance to fluoroquinolones or second-line injectable agents, or in whom components of the shorter MDR-TB regimen were contraindicated. Children with QTcF > 500 msec should not receive the drugs; moreover, proper pharmacovigilance and monitoring of adherence should be ensured [84].
Although results are encouraging, data on delamanid efficacy in children are still scarce and further research is needed. As such, current WHO guidelines recognize delamanid as a Group C drug in children aged 3 years or more [19]. Table 7 summarizes main data on delamanid obtained in children and adolescents, More evidence on the efficacy of delamanid would be helpful to better guide its use and several clinical trials with this purpose are ongoing [85][86][87] (Table 8). Table 9 summarizes recommended dosing. Administration in children <6 years may be difficult because 50 mg tablets cannot be split accurately (may affect bioavailability); in addiction, the contents are bitter and unpalatable. Treatment should continue for 6 months (intensive phase) and be given after meals.

Conclusions
TB is still one of the most difficult infectious diseases to treat, and the second most frequent cause of death due to infectious disease throughout the world. The number of cases of MDR-/XDR-TB, which are characterized by high mortality rates, is increasing. The therapeutic management of children with MDR-and XDR-TB is complicated by a lack of knowledge, and the fact that many potentially useful drugs are not registered for pediatric use and there are no formulations suitable for children in the first years of life. Furthermore, most of the available drugs are burdened by major adverse events that need to be taken into account, particularly in the case of prolonged therapy. Interestingly, studies around the world have shown controversies in the definition of bedaquiline and delamanid resistance [88,89]. Unfortunately, up to now, resistance to both of the drugs has been reported in vitro, but standardized drug susceptibility testing has not been developed and agreed upon. Known mechanisms of resistance to bedaquiline include mutations within the atpE, Rv0678, and pepQ genes [88], whereas delamanid-resistant bacilli have mutations in one of the five genes in the F420-dependent bio-activation pathway [89].
Although data on pediatric population are limited and more studies are needed, our review shows the efficacy and safety of bedaquiline and delamanid in adolescent children with MDR-TB and XDR-TB. However, more evidence on these new anti-TB drugs is needed to better guide their use in children, design effective shorter regimens and reduce adverse effects, drug interactions, and therapeutic failure. Furthermore, the development of standardized drug susceptibility testing for bedaquiline and delamanid is urgently needed.