Delamanid (Otsuka Pharmaceutical, Tokyo, Japan) is a nitroimidazole shown to be effective when added to an MDR-TB regimen in a randomized, placebo-controlled phase IIb trial (23). In this phase IIb trial, patients were randomized to receive an optimized background regimen (OBR) with either placebo or delamanid added for 8 weeks. After the initial 8 weeks, there was a 4-week period of continued OBR treatment, and then all participants were offered open-label delamanid for an additional 24 weeks. When participants who received at least 6 months of delamanid were compared with participants who received less than 2 months of delamanid, there were statistically significant differences seen in the time to culture conversion, the rates of culture conversion at both 8 and 24 weeks, and treatment success, with those who had at least 2 months of therapy doing better (24). The drug was well tolerated with mild to moderate QTc prolongation (12.1 ms) observed but no clinical cardiac complications (25). This study led to conditional marketing approval for delamanid in the European Union and Japan in 2013 and later in South Korea (26). A phase III randomized, placebo-controlled trial of delamanid has completed enrollment and the period of study drug administration; treatment outcome results are expected in 2017–2018 (27).

Delamanid was recommended by the WHO in 2014 for treatment of adults with MDR-TB. WHO guidelines state that delamanid may be given to adults with MDR-TB in whom a four-drug regimen plus pyrazinamide cannot be constructed due to resistance or significant intolerance to other medications and that delamanid be given to adults at “high risk” of poor treatment outcomes. These guidelines stress that delamanid should be used as part of programmatic management of MDR-TB under the following conditions: (1) proper patient inclusion; (2) close clinical and programmatic monitoring; (3) used as part of a regimen that follows WHO guidelines; (4) due process followed for informed consent; and (5) active monitoring and management of adverse events. The WHO guidelines offer no recommendation on the use of delamanid in persons less than 18 years old, noting that there was insufficient evidence to make such a recommendation at the time of review in 2014 (28).

Otsuka has led a pediatric development program for delamanid, with enrollment in phase I and II pediatric trials beginning in 2013. Since the WHO interim guidelines were published in 2014, two studies of pharmacokinetics and safety in HIV-uninfected children as young as 6 years old have been presented at international meetings (13, 14). These studies follow an age de-escalation protocol in which the drug is first given to older children and, when shown to be safe with established dosing, it is given to younger children. Although age bands were used to design the study, the ultimate dosing recommendations are based on weight, and weight should guide the dose selection for children. For children at least 13 years of age and weighing at least 35 kg, a dose of 100 mg twice daily was safe and achieved adequate serum concentrations. For children 6–12 years of age and weighing 20–34 kg, a dose of 50 mg of delamanid twice daily achieved adequate serum concentrations. A safety and pharmacokinetics study of delamanid in children 3–5 years old is currently enrolling patients; when dosing and safety are established, then children and infants less than 3 years of age will be evaluated. A pediatric dispersible formulation of delamanid is being assessed as part of these trials. In addition, studies in children who are HIV coinfected are planned. Delamanid is available for pediatric patients at least 6 years of age and with a body weight greater than 20 kg via compassionate use from Otsuka. Of note, there are more pediatric data on the safety and dosing of delamanid than for some other second-line drugs that are frequently used to treat children for MDR-TB, such as cycloserine and clofazimine (29).

Delamanid may be included in the treatment regimens of children at least 6 years old and who weigh at least 20 kg for the same indications as for adults: those with MDR-TB in whom a four-drug regimen plus pyrazinamide cannot be constructed due to resistance or significant intolerance or those with a high risk of treatment failure. Because MDR-TB may be difficult to bacteriologically confirm in children, delamanid may be used in children if they have an MDR-TB source case with known or suspected resistance to second-line agents. Children at high risk for treatment failure include those with immunocompromising conditions (e.g., HIV, diabetes, malnutrition) or those with extensive disease (defined as extrapulmonary TB other than isolated lymphadenitis; or pulmonary TB with bilateral infiltrates and/or cavities) (4). Children in this age and weight group receiving standard MDR-TB therapy and who develop significant toxicity in response to any of their medications should have the causative agent discontinued and delamanid started as a substitute. Avoid adding a single drug to a failing regimen.

Delamanid can be considered on a case-by-case basis in children less than 6 years old and who weigh less than 20 kg, if the children meet the criteria previously described and no suitable alternatives are available. Although studies of delamanid in this age group are ongoing, there may be cases in which the benefits of including delamanid outweigh the risk (30). As with other second-line drugs, the delamanid dose for this age and weight range would have to be extrapolated from the dosages used in older children and adults (31). Until the dispersible tablet is available, administration of delamanid to younger children might involve crushing and mixing the drug, which could affect its stability and bioavailability, although this is true for most second-line drugs. It is recommended that consultation with expert clinicians be sought before administering delamanid to children in this age range. Such consultation is available through the European Respiratory Society–hosted TB Consilium (https://www.tbconsilium.org) (32) or through the Sentinel Project on Pediatric Drug-Resistant Tuberculosis ([email protected]).

As with adults, programs treating children with delamanid should meet the five conditions recommended by the WHO for its use in adults (28). All children should undergo the standard baseline testing for MDR-TB treatment. They should also undergo a baseline ECG to assess the QTc interval² and a baseline serum albumin level. Children with a baseline QTc interval greater than 500 milliseconds should not be started on delamanid until the interval is corrected by medical management (33). Delamanid is metabolized by albumin and there may be higher rates of adverse events in children with hypoalbuminemia; therefore children with serum albumin levels less than 2.8 g/dl should receive protein supplementation during delamanid therapy. Children with an allergy to delamanid or metronidazole or who have been treated with other nitroimidazole drugs (i.e., pretomanid/PA-824) should not be treated with delamanid. While receiving delamanid, children should undergo a monthly ECG to assess for QTc prolongation, although less frequent monitoring after 8 weeks could be considered in children with a normal baseline and follow-up QTc intervals if access to electrocardiographic monitoring is a challenge. Combination with drugs that also prolong the QTc interval should be done with caution, and substitution of levofloxacin (which has less effect on the QTc interval) for moxifloxacin is advised. Official recommendations are for delamanid to be given for 24 weeks total, although longer courses of therapy have been given to adults and children with limited therapeutic options. In the initial phase IIb trials in adults, a substantial number of individuals (192 of 421) received 8 months of delamanid without any additional safety signals (23). Phase I studies in adults show that delamanid did not have any significant drug–drug interactions with antiretroviral therapy, including tenofovir, efavirenz, and lopinavir–ritonavir (15).

Children tend to tolerate second-line medications better than adults do; however, the second-line injectable medications are problematic (34). Although there are currently no data to support the routine substitution of delamanid for a second-line injectable agent within the MDR-TB regimen, providers could consider using delamanid instead of the injectable drug in the initial regimen in children with MDR-TB. This substitution could substantially benefit children given the risk of permanent sensorineural hearing loss in children (reported in up to 25% of children) due to the second-line injectable agents and the pain and hospitalization requirements that are associated with daily intramuscular injections (34). These drugs have been assessed only when given in combination with other agents; it is therefore challenging to tease out the individual contribution of specific drugs in an MDR-TB regimen (35, 36). However, there is higher quality evidence for the inclusion of delamanid than there is for the inclusion of the injectable given that delamanid has been assessed in randomized placebo-controlled clinical trials for MDR-TB whereas the injectable agents have not. There also exists substantial clinical experience in treating children with nonsevere MDR-TB disease with an injectable-sparing regimen, with good results (3).

Bedaquiline (Janssen Pharmaceuticals, Beerse, Belgium) is a diarylquinoline that was effective when added to an MDR-TB regimen in a randomized, placebo-controlled phase IIb trial (37). In this phase IIb trial, patients were randomized to receive an OBR with either placebo or bedaquiline for 24 weeks. When compared with placebo, bedaquiline was associated with significantly reduced time to culture conversion, increased rates of culture conversion at 24 weeks, and increased cure rates (38). The drug was associated with moderate QTc prolongation (15.7 ms), and although there were higher rates of cure and lower rates of failure and loss to follow-up in the bedaquiline group, there was also a significantly higher rate of all-cause mortality (although the number of deaths was small) in the bedaquiline group compared with the placebo group (39). This study led to conditional approval of bedaquiline for the treatment of MDR-TB by the U.S. Food and Drug Administration (FDA) in 2012 and subsequently by a number of other stringent regulatory authorities in the European Union, South Africa, and India (40). In 2013, the WHO and the U.S. Centers for Disease Control and Prevention (CDC) published interim guidelines on the programmatic use of bedaquiline in specified adult patients with MDR-TB (41, 42). The STREAM-II (Evaluation of a Standard Treatment Regimen of Antituberculosis Drugs for Patients with MDR-TB) trial, which is a phase III randomized, placebo-controlled trial of bedaquiline, began enrolling patients in May of 2016 (27). A number of observational cohort studies confirming the efficacy and safety of bedaquiline have been reported from a variety of settings (5, 6). There are currently more than 3,000 individuals receiving bedaquiline worldwide (43).

The WHO and CDC guidelines state that bedaquiline may be offered to adults with MDR-TB in whom a four-drug regimen plus pyrazinamide cannot be constructed for reasons of resistance or significant intolerance to other medications. The WHO guidelines also stress that bedaquiline should be used as part of programmatic management of MDR-TB under the same five conditions as delamanid, although they specify the need for a signed informed consent for bedaquiline. The WHO guidelines state there was not sufficient evidence to make a recommendation regarding bedaquiline use in persons less than 18 years old at the time the evidence was reviewed in 2013 (41). The CDC also stated that there is insufficient evidence to provide guidelines for the use of bedaquiline in children, but that its use can be considered on a case-by-case basis, given the high mortality and limited treatment options for MDR-TB (42).

Bedaquiline has not yet been formally assessed in children less than 18 years old. However, a Janssen Pharmaceuticals safety and pharmacokinetics study in children (ages 5–11 yr) and adolescents (ages 12–18 yr) opened for enrollment in South Africa in May of 2016 (27). Younger children will be included in this trial, based on the data obtained from older children and following an age de-escalation protocol. A 20-mg dispersible tablet formulation will be assessed in this trial. A second trial of bedaquiline in HIV-infected and uninfected children sponsored by the U.S. National Institutes of Health (NIH) IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) network, is being planned and may begin enrolling in 2016 (44). A compassionate use protocol for children is also being developed by Janssen Pharmaceuticals.

There has been some programmatic experience using bedaquiline in adolescents not exceeding 12 years of age (16, 17). When adolescents weighing at least 33 kg have been given bedaquiline, they have received the same dosages that are given to adults: 400 mg daily for 14 days followed by 200 mg three times weekly for 22 weeks.

Bedaquiline could be considered for the treatment of children at least 12 years old and weighing at least 33 kg for the same indications extrapolated from adults: those with MDR-TB in whom a four-drug regimen plus pyrazinamide cannot be constructed due to resistance or significant intolerance. Bedaquiline may be included in treatment regimens for children with probable MDR-TB if they have a source case who meets these criteria. Children in this age group receiving standard MDR-TB therapy and who develop clinically significant toxicity in response to any of their medications should have the causative agent discontinued and bedaquiline started as a substitute, but it should not be added as a single drug to a failing regimen. The adult dose of bedaquiline should be given (400 mg daily for 14 d and then 200 mg three times per week for 22 wk).

Bedaquiline could be considered in children less than 12 years old if the children meet the criteria described previously and no suitable alternatives are available. Delamanid, however, is the preferred novel agent in this population, given that there are more data on safety and dosing of delamanid. As with other second-line drugs, the bedaquiline dosage for these lower age and weight ranges would have to be extrapolated from adult dosages. Furthermore, there is no currently available pediatric formulation of bedaquiline, and administration of this drug to younger children would involve crushing and mixing of the drug, which could affect stability and bioavailability. It is recommended that consultation with expert clinicians be sought before administering bedaquiline to children in this age range.

As with adults, programs treating children with bedaquiline should meet the five conditions recommended by the WHO (41). All children being considered for bedaquiline should undergo the baseline testing normally undertaken before MDR-TB treatment but should also undergo a baseline ECG to assess the QTc interval. Contraindications for bedaquiline use are a baseline QTc interval greater than 450 milliseconds that does not correct with medical management, a patient or family history of arrhythmia, or severe cardiac disease. While receiving bedaquiline, children should undergo a monthly ECG to assess for QTc prolongation and should also have monthly potassium levels determined. As with delamanid, caution should be used when other QTc-prolonging medications are used and levofloxacin should be substituted for moxifloxacin. Guidelines recommend that bedaquiline be given for 24 weeks total, although longer courses have been given to individuals with limited therapeutic options (45).

Studies in adults show that bedaquiline should not be given with efavirenz, as efavirenz reduces bedaquiline levels. Therefore, children receiving antiretroviral therapy and for whom bedaquiline is being considered should be switched to a regimen containing nevirapine or raltegravir for the duration of bedaquiline therapy (46). If a nevirapine- or raltegravir-containing regimen is not appropriate, a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen could be considered, keeping in mind the lower potency of such regimens. Of note, lopinavir–ritonavir is used in adults receiving bedaquiline, but two- to threefold higher concentrations of bedaquiline are predicted and have been observed when the two are given together (47). Although the clinical implications of this are unknown, this combination should be avoided if possible in children until more data and experience are available.

Case reports of successful use of the combination of bedaquiline and delamanid in adults are emerging (48, 49). Treatment regimens containing both bedaquiline and delamanid in children could be considered on a case-by-case basis, if no other treatment options exist, in consultation with expert clinicians. The use of combined delamanid and bedaquiline in this population should follow more recently proposed guidelines, which recommend it be used only when an effective regimen cannot otherwise be designed; the clinical center has expertise with treatment of MDR-TB; the patient and caregivers are counseled as part of informed consent for both drugs; pharmacovigilance is in place; and an independent, qualified organization considers the use of both drugs to be appropriate (50).