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

Abstract

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.

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

“…Today, treatment for multidrug-resistant (MDR) tuberculosis (TB) has become a real challenge [ 156 ]. Tuberculosis is an infection caused by gram-positive bacteria mycobacterium tuberculosis.…”

Pediatric Tuberculosis Management: A Global Challenge or Breakthrough?

“…Bedaquiline and delamanid are new drugs that have shown acceptable outcomes in the treatment of drug-resistant TB strains in children and adolescents, but unfortunately, there is limited access to these remedies [ 254 , 255 , 256 ].…”

“…It is classified as a diarylquinoline and registered by Janssen Pharmaceuticals as Sirturo ® . It is a strong bactericidal agent that acts by interfering with the mycobacterial ATP synthase and is known to be effective against drug-resistant Mtb strains when included in TB regimens [ 256 , 257 , 258 ]. It is selective for Mtb in that its c-subunit differs from that of humans by three amino acid residues, which creates a binding site that is unique to bedaquiline [ 259 , 260 ].…”

“…Pharmacokinetic studies in humans, particularly adults, have revealed that post single oral administration, bedaquiline is well absorbed with an average peak plasma concentration time of 5–6 h and an effective half-life of greater than 24 h. Its lengthy terminal half-life in human beings makes alternating drug administration schedules possible when used in combination with other TB antibiotics as part of the MDR-TB and XDR-TB regimens [ 256 ]. The initial clinical trials on the use of bedaquiline for the treatment of drug-resistant TB for its approval by the WHO in 2013 excluded children under the age of eighteen [ 262 ].…”

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

“…Drugs in phase III clinical trials include sutezolid 28 , tedizolid 29 , FS-1 30 , rifabutin 31 , and clarithromycin 32 . And 12 drugs have been approved in the market including isoniazid 33 , rifampicin 34 , pyrazinamide 35 , ethambutol 36 , kanamycin 37 , amikacin 38 , capreomycin 39 , levofloxacin 40 , ethylthiamine 41 , cycloserine 42 , bedaquiline 35 , and delamanid 43 ( Fig. 1 ).…”