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Specific Infections in Children
Published in Miriam Orcutt, Clare Shortall, Sarah Walpole, Aula Abbara, Sylvia Garry, Rita Issa, Alimuddin Zumla, Ibrahim Abubakar, Handbook of Refugee Health, 2021
Neal Russell, Sarah May Johnson, Andrew Chapman, Christian Harkensee, Sylvia Garry, Bhanu Williams
In refugee children, resistance rates in the country of origin, microbiology from known TB contacts, and previous completed/interrupted treatment should be considered. Drug-resistant TB, an estimated 3% of paediatric TB cases,20 is challenging due to length of therapy, drug formulations and dosing, and side effects (especially from injectable agents). In addition, there is currently insufficient safety and pharmacokinetic data for newer treatments such as delamanid and bedaquiline, which are currently recommended by the WHO only for children older than 3 and 6 years, respectively.21 National guidelines and specialist advice are recommended for managing children with multi-drug resistant TB (MDR-TB) or extensively drug resistant TB (XDR-TB).
New Developments in Drug Treatment
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
The US FDA approval of bedaquiline is a milestone in the development of new anti-tuberculosis drugs [8]. Bedaquiline is highly selective for mycobacteria, but its target ATP synthase is an essential energy-generating mechanism found throughout all kingdoms of life. Modification of bedaquiline has led to compounds active against other clinically important bacteria [116,117], so it also represents the discovery of a novel class of antibiotics. It is reminiscent of the discovery of streptomycin in 1943 as part of a search for anti-tuberculosis drugs; this not only led to the first effective regimen for the treatment of tuberculosis in combination with isoniazid and para-aminosalicylic acid but also spawned a class of antibiotics, aminoglycosides [118], that have found wide therapeutic applications in infectious diseases. It is plausible that bedaquiline in combination with other new or repurposed compounds may herald the beginning of a similar era in the advancement of tuberculosis treatment last seen in the 1950s and 1960s.
Bedaquiline
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Jeffrey A. Tornheim, Kelly E. Dooley
Bedaquiline (previously R207910, then TMC207) is a first-in-class diarylquinolone antibiotic that was initially approved for the treatment of multidrug-resistant tuberculosis (MDR-TB), tuberculosis (TB) resistant to isoniazid and rifampicin, by the US Food and Drug Administration (FDA) in 2012 and the European Medicines Agency (EMA) in 2014. It is currently recommended for use by the World Health Organization (WHO) for patients with MDR-TB who lack other treatment options (WHO, 2013); it is commonly used in patients infected with TB that is extensively drug resistant (XDR) (resistant to isoniazid, rifampicin, fluoroquinolones, and injectable agents). Bedaquiline causes QT interval prolongation, as do several second-line anti-TB drugs, so caution must be exercised when designing a combination antimicrobial regimen that includes bedaquiline (Janssen Products, 2015). In addition, bedaquiline was registered in several countries after a phase II trial data demonstrated the microbiologic activity of this agent (Diacon et al., 2014) prior to the availability of phase III trial results. This expedited approval was granted in large part because of the great unmet medical need for drugs to treat MDR- and XDR-TB. In the small phase II randomized clinical trial, though, mortality was higher in the bedaquiline than in the placebo arm (Diacon et al., 2014). This “mortality imbalance” remains unexplained—deaths often occurred late (after completion of bedaquiline treatment), causes of death were widely variable, and mortality in the placebo arm was surprisingly low—and has complicated this drug’s introduction globally. Up to now, higher-than-expected mortality has not been seen in post-marketing pharmacovigilance studies (Ndjeka et al., 2015).
Targeting ATP Synthase by Bedaquiline as a Therapeutic Strategy to Sensitize Ovarian Cancer to Cisplatin
Published in Nutrition and Cancer, 2023
Hongyan Zhu, Qitian Chen, Lingling Zhao, Pengchao Hu
Oxidative phosphorylation is a process that generate ATP through mitochondrial respiratory complexes I, II, III, IV and together with the F1F0 ATP synthase (complex V). Substantial evidence shows that oxidative phosphorylation is the main form of energy metabolism in some cancers, such as leukemia, ovarian cancer and renal cell carcinoma, and critically contributes to tumor progression and resistance (7–10). Specific agents targeting oxidative phosphorylation have been tested in pre-clinical and clinical settings to attenuate tumor progression, enhance chemosensitization and eradicate cancer stem cells in many cancers (5, 11). Bedaquiline is a FDA-approved antibiotic for treating pulmonary multidrug-resistant tuberculosis with the mechanism of action targeting ATP synthase and inducing energy crisis (12–14). Recent studies have revealed that bedaquiline decreased level of ATP synthase subunit, ATP5F1C in cancer cells, leading to mitochondrial respiration inhibition and ATP reduction, and subsequent growth arrest and inhibition of metastasis (15–17). Given the ability in inhibiting oxidative phosphorylation, we speculated that bedaquiline might be active against ovarian cancer. We thus systematically assessed the efficacy of bedaquiline using cell culturing and xenograft mouse models, and investigated the underlying mechanisms of bedaquiline focusing on oxidative phosphorylation.
The pharmacotherapeutic management of pulmonary tuberculosis: an update of the state-of-the-art
Published in Expert Opinion on Pharmacotherapy, 2022
Ginenus Fekadu, Dilys Yan-wing Chow, Joyce H.S. You
The WHO has recommended including bedaquiline in the anti-TB therapy for adult patients with MDR-TB since 2013 [31]. Clinical findings have shown a higher treatment success rate and a lower adverse event incidence in patients on regimens containing bedaquiline than patients treated with injectable agents [29,32–34]. Recently, a review of 11 studies (5 prospective clinical trials and 7 retrospective studies) showed that MDR-TB patients who were treated by the bedaquiline-containing regimen had a high rate of conversion in sputum culture (65–100%) [35]. The prolonged QT interval and increased deaths reported in patients receiving bedaquiline in one randomized control trial [29] have led to the recommendation that all patients treated with bedaquiline have regular ECG monitoring, yet few patients (0.6%) had to discontinue bedaquiline due to prolonged QT interval [36,37]. The 2018 meta-analysis of individual patient data for longer MDR-TB regimens showed significantly reduced risk of unfavorable outcomes (treatment failure/relapse) versus successful treatment (number treated by bedaquiline = 1,391) (adjusted OR 0.3; 95%CI 0.2–0.4), and mortality versus successful treatment (number treated by bedaquiline = 1,480) (adjusted OR 0.2; 95%CI 0.2–0.3) in patients treated with bedaquiline. The median absolute risk of serious adverse event for bedaquiline (2.4%) was the lowest of all medicines recommended in the longer regimens [10].
Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Katharigatta N. Venugopala, Sandeep Chandrashekharappa, Pran Kishore Deb, Christophe Tratrat, Melendhran Pillay, Deepak Chopra, Nizar A. Al-Shar’i, Wafa Hourani, Lina A. Dahabiyeh, Pobitra Borah, Rahul D. Nagdeve, Susanta K. Nayak, Basavaraj Padmashali, Mohamed A. Morsy, Bandar E. Aldhubiab, Mahesh Attimarad, Anroop B. Nair, Nagaraja Sreeharsha, Michelyne Haroun, Sheena Shashikanth, Viresh Mohanlall, Raghuprasad Mailavaram
Several therapeutics have been approved by the US Food and Drug Administration (US-FDA) to enhance the treatment of TB. Bedaquiline (approved in late 2012 under the FDA’s accelerated review program) (Figure 1) was found to exhibit favourable anti-TB effects and promising anti-TB action against MDR and XDR-TB when combined with first-line or second-line anti-TB drugs, resulting in a shorter duration of treatment. However, bedaquiline suffered from various adverse effects such as nausea, elongation of QT interval, and drug interaction with Cytochrome P3A4 inducers and inhibitors11. Delamanid (Figure 1) was the second anti-TB agent approved by European Medicine Agency in late 2013. Nevertheless, resistant MTB strains against both bedaquiline and delamanid have recently been reported, which acquired resistance as a result of prolonged duration of therapy12,13. Pretomanid was the last drug candidate from the TB drug pipeline to be approved by the FDA in 2019 for the treatment of MDR and XDR TB (Figure 1)14,15.