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Respiratory Infections
Published in Miriam Orcutt, Clare Shortall, Sarah Walpole, Aula Abbara, Sylvia Garry, Rita Issa, Alimuddin Zumla, Ibrahim Abubakar, Handbook of Refugee Health, 2021
Duration of TB treatment depends on the site of TB (6 months for pulmonary, lymphadenitis and gastrointestinal TB; 9 months for spinal TB; 12 months for CNS TB; and >18 months for drug-resistant TB, although 9-month MDR-TB regimens are available for specific cases (see ‘Bangladesh’ regimen).4 Adjunctive steroids should be used in CNS TB. The intensive phase consists of four drugs – rifampicin, isoniazid, pyrazinamide and ethambutol – and the continuation phase involves two drugs, usually rifampicin and isoniazid. If pyrazinamide is not used in the intensive phase (e.g. due to hepatotoxicity or side effects), the continuation phase is increased to 7 months (total treatment 9 months). An all oral 18–20-month treatment regimen for MDR-TB is now recommended by WHO for particular cases5 (reference: Frequently asked questions on the WHO Rapid Communication: key changes to the treatment of multidrug- and rifampicin – resistant TB. https://www.who.int/tb/publications/2018/MDR_RR-TB-TaskForce-FAQs-Updated-June2019.pdf). Recently, a new TB drug, pretomanid, has received approval in the United States of America (USA) in a combination regimen with bedaquiline and linezolid for people with XDR-TB or treatment-intolerant/non-responsive MDR-TB.
Treatment Guidelines for Active Drug-Susceptible and Drug-Resistant Pulmonary Tuberculosis, and Latent Tuberculosis Infection
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Lynn E. Sosa, Lloyd N. Friedman
Pretomanid was approved by the United States Food and Drug Administration as part of a three-drug regimen to treat highly resistant TB (predominantly XDR-TB but also MDR-TB that is nonresponsive or treatment intolerant). The regimen comprises bedaquiline, pretomanid, and linezolid for 6 months with an option to extend for a longer duration and is an all-oral regimen. Six months after completion of treatment, the regimen showed an efficacy of 90% which was defined as two consecutive negative cultures and no relapse in the subsequent 6 months. This is much better than the average historical control regimen efficacy of 14% for the treatment of XDR-TB.12
Delamanid and Pretomanid
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
Eric Nuermberger, Emily Kendall
Additional phase II and phase III trials are evaluating pretomanid as part of other tuberculosis drug combinations. The 8-week NC-005 study (clinical trial NCT02193776) is evaluating the bactericidal activity of the combination of pretomanid 200 mg daily with bedaquiline and pyrazinamide for drug-susceptible tuberculosis compared to standard regimen controls, and of pretomanid 200 mg daily with bedaquiline, pyrazinamide, and moxifloxacin for MDR-TB without a comparator arm. The phase III NiX-TB trial (clinicaltrials.gov NCT02333799) is evaluating 6 months of pretomanid 200 mg daily plus bedaquiline and linezolid for the treatment of XDR-TB or treatment-intolerant MDR-TB.
Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment
Published in Expert Review of Respiratory Medicine, 2021
James A Seddon, Sarah Johnson, Megan Palmer, Marieke M van der Zalm, Elisa Lopez-Varela, Jennifer Hughes, H Simon Schaaf
Pharmacokinetic studies (Janssen C211 and IMPAACT P1108) to establish optimal dosing and safety of bedaquiline in children began in 2016 and 2017, respectively [48,49], at least six years after bedaquiline was first made available under compassionate use for treatment of MDR-TB in adults [50]. Interim findings from these studies informed the 2019 WHO recommendations for optimal bedaquiline doses that can be used safely in children from the age of six years [37]; these studies are still ongoing to determine safety and dosing in younger children. Otsuka began Trials 232 and 233 to assess safety and tolerability of delamanid in children with RR/MDR-TB as early as 2013 [51,52], and findings from these trials led to the WHO recommendations for delamanid use in children as young as three years old [53]. While pretomanid was used in a handful of adolescents in the Nix-TB study, this and other novel anti-tuberculosis agents in the drug development pipeline, have not yet been studied in children.
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.
Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children
Published in Expert Review of Clinical Pharmacology, 2018
H. Simon Schaaf, Anthony J. Garcia-Prats, Lindsay McKenna, James A. Seddon
New anti-TB drugs to more safely and effectively treat MDR-TB are as much needed in children as in adults; however, children, and especially very young children who develop serious forms of disseminated TB, such as miliary TB and TB meningitis, are always last to gain access to these drugs. In the last decade, a number of new and repurposed drugs have entered adult MDR-TB trials from phase 1 to 3. Bedaquiline and delamanid have received accelerated or conditional approvals in different countries for use in MDR-TB treatment regimens, while clofazimine, linezolid, and the later-generation fluoroquinolones are used off-label for MDR-TB treatment in adults and children. Pretomanid has only been used in new trial regimens for both drug-susceptible (DS-TB) and DR-TB in adults and has not yet been registered.