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https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-in-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistances
#1
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28887015/bedaquiline-or-delamanid-for-rifampin-resistant-tuberculosis
#2
Erica Lessem, Vivian Cox, Jennifer Furin
No abstract text is available yet for this article.
September 5, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28840010/delamanid-and-bedaquiline-to-treat-multidrug-resistant-and-extensively-drug-resistant-tuberculosis-in-children-a-systematic-review
#3
REVIEW
Lia D'Ambrosio, Rosella Centis, Simon Tiberi, Marina Tadolini, Margareth Dalcolmo, Adrian Rendon, Susanna Esposito, Giovanni Battista Migliori
The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB...
July 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28826448/clinical-significance-of-qt-prolonging-drug-use-in-patients-with-mdr-tb-or-ntm-disease
#4
H-Y Yoon, K-W Jo, G B Nam, T S Shim
SETTING: Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus. OBJECTIVE: To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease. METHODS: We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin)...
September 1, 2017: International Journal of Tuberculosis and Lung Disease
https://www.readbyqxmd.com/read/28821804/nos2-deficient-mice-with-hypoxic-necrotizing-lung-lesions-predict-outcomes-of-tuberculosis-chemotherapy-in-humans
#5
Martin Gengenbacher, Maria A Duque-Correa, Peggy Kaiser, Stefanie Schuerer, Doris Lazar, Ulrike Zedler, Stephen T Reece, Amit Nayyar, Stewart T Cole, Vadim Makarov, Clifton E Barry Iii, Véronique Dartois, Stefan H E Kaufmann
During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 (-/-) mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 (-/-) mice with TB to monotherapy before or after establishment of human-like pathology...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28767036/six-month-response-to-delamanid-treatment-in-mdr-tb-patients
#6
Cathy Hewison, Gabriella Ferlazzo, Zaza Avaliani, Armen Hayrapetyan, Sylvie Jonckheere, Zarema Khaidarkhanova, Erika Mohr, Animesh Sinha, Alena Skrahina, Debrah Vambe, Irina Vasilyeva, Nathalie Lachenal, Francis Varaine
Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.
October 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/28758888/bedaquiline-and-delamanid-combination-treatment-of-5-patients-with-pulmonary-extensively-drug-resistant-tuberculosis
#7
Andrey Maryandyshev, Emanuele Pontali, Simon Tiberi, Onno Akkerman, Shashank Ganatra, Tsetan Dorji Sadutshang, Jan-Willem Alffenaar, Rohit Amale, Jai Mullerpattan, Sonam Topgyal, Zarir Farokh Udwadia, Rosella Centis, Lia D'Ambrosio, Giovanni Sotgiu, Giovanni Battista Migliori
We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.
October 15, 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/28739779/in-vitro-drug-susceptibility-of-bedaquiline-delamanid-linezolid-clofazimine-moxifloxacin-and-gatifloxacin-against-extensively-drug-resistant-tuberculosis-from-beijing-china
#8
Yu Pang, Zhaojing Zong, Fengmin Huo, Wei Jing, Yifeng Ma, Lingling Dong, Yunxu Li, Liping Zhao, Yuhong Fu, Hairong Huang
Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore in vitro drug susceptibility of bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MXF), and gatifloxacin (GAT) against 90 XDR-TB strains isolated from patients in China. We also described the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD and BDQ was found in 82 (91...
July 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28709481/extensively-drug-resistant-tuberculosis-xdr-tb-a-daunting-challenge-to-the-current-end-tb-strategy-and-policy-recommendations
#9
REVIEW
Md Arifur Rahman, Atanu Sarkar
Extensively Drug-resistant Tuberculosis (XDR-TB) has emerged as one of the most formidable challenges to the End TB Strategy that has targeted a 95% reduction in TB deaths and 90% reduction in cases by 2035. Globally, there were an estimated 55,100 new XDR-TB cases in 2015 in 117 countries. However, only one in 30 XDR-TB cases had been reported so far. Drug susceptibility test (DST) is the mainstay for diagnosing XDR-TB, but the lack of laboratory facilities in the resource-limited endemic countries limit its uses...
July 2017: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/28651480/news-on-therapeutic-management-of-mdr-tuberculosis-a-literature-review
#10
Lucie Barthod, Jean-Guillaume Lopez, Christophe Curti, Charléric Bornet, Manon Roche, Marc Montana, Patrice Vanelle
In 2015, the World Health Organization registered 10.4 million people who developed tuberculosis worldwide and 480,000 new cases of multidrug-resistant tuberculosis were identified. The care of multi and extensively drug-resistant tuberculosis is based on a combination of pyrazinamide and second-line drugs. These regimens are lengthy, partially effective and poorly tolerated. The challenge is to re-evaluate the use of existing molecules and to develop new agents more effective against resistant strains with shorter treatment duration...
June 26, 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/28625141/bedaquiline-a-new-hope-for-shorter-and-better-anti-tuberculosis-regimens
#11
Niccolò Riccardi, Filippo Del Puente, Federica Magnè, Lucia Taramasso, Antonio Di Biagio
Background: In 2014, an estimated 1.8 million people died from Mycobacterium tuberculosis (MTB); moreover, 680,000 people developed multidrug-resistant TB (MDR-TB). Methods: Currently available anti-MDR and XDR regimens are long-lasting and expensive, need high adherence and are undermined by a high frequency of adverse drug events, thus leading to a low success rate; moreover, in the last 50 years only two new molecules, bedaquiline (BDQ) and delamanid, have been approved and released for treatment of MDR-TB...
June 19, 2017: Recent Patents on Anti-infective Drug Discovery
https://www.readbyqxmd.com/read/28584788/clinical-implications-of-new-drugs-and-regimens-for-the-treatment-of-drug-resistant-tuberculosis
#12
REVIEW
Yong-Soo Kwon
The emergence of drug-resistant tuberculosis (TB) is a growing problem worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. Therefore, new TB drugs able to bolster the current TB treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multi-drug-resistant (MDR)-TB...
May 2017: Chonnam Medical Journal
https://www.readbyqxmd.com/read/28462832/6-nitro-2-3-dihydroimidazo-2-1-b-1-3-thiazoles-facile-synthesis-and-comparative-appraisal-against-tuberculosis-and-neglected-tropical-diseases
#13
Andrew M Thompson, Adrian Blaser, Brian D Palmer, Robert F Anderson, Sujata S Shinde, Delphine Launay, Eric Chatelain, Louis Maes, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, William A Denny
As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis...
June 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28459575/7-substituted-2-nitro-5-6-dihydroimidazo-2-1-b-1-3-oxazines-novel-antitubercular-agents-lead-to-a-new-preclinical-candidate-for-visceral-leishmaniasis
#14
Andrew M Thompson, Patrick D O'Connor, Andrew J Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, Christopher B Cooper, William A Denny
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28373190/delamanid-kills-dormant-mycobacteria-in-vitro-and-in-a-guinea-pig-model-of-tuberculosis
#15
Xiuhao Chen, Hiroyuki Hashizume, Tatsuo Tomishige, Izuru Nakamura, Miki Matsuba, Mamoru Fujiwara, Ryuki Kitamoto, Erina Hanaki, Yoshio Ohba, Makoto Matsumoto
Tuberculosis (TB) treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug susceptibilities. Drugs with broad activity are urgently needed. This study aimed to evaluate delamanid's activity against growing or dormant bacilli in vitro as well as in vivo Cultures of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic conditions were used to study the activity of delamanid against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above concentrations of 0...
June 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28361737/therapy-of-multidrug-resistant-and-extensively-drug-resistant-tuberculosis
#16
REVIEW
Barbara J Seaworth, David E Griffith
The global epidemic of multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampin was recently reported as larger than previously estimated, with at least 580,000 new cases reported in 2015. Extensively drug-resistant tuberculosis (XDR-TB), MDR-TB with additional resistance to a second-line fluoroquinolone and injectable, continues to account for nearly 10% of MDR cases globally. Cases in India, China, and the Russian Federation account for >45% of the cases of MDR-TB...
March 2017: Microbiology Spectrum
https://www.readbyqxmd.com/read/28344011/the-epidemiology-pathogenesis-transmission-diagnosis-and-management-of-multidrug-resistant-extensively-drug-resistant-and-incurable-tuberculosis
#17
REVIEW
Keertan Dheda, Tawanda Gumbo, Gary Maartens, Kelly E Dooley, Ruth McNerney, Megan Murray, Jennifer Furin, Edward A Nardell, Leslie London, Erica Lessem, Grant Theron, Paul van Helden, Stefan Niemann, Matthias Merker, David Dowdy, Annelies Van Rie, Gilman K H Siu, Jotam G Pasipanodya, Camilla Rodrigues, Taane G Clark, Frik A Sirgel, Aliasgar Esmail, Hsien-Ho Lin, Sachin R Atre, H Simon Schaaf, Kwok Chiu Chang, Christoph Lange, Payam Nahid, Zarir F Udwadia, C Robert Horsburgh, Gavin J Churchyard, Dick Menzies, Anneke C Hesseling, Eric Nuermberger, Helen McIlleron, Kevin P Fennelly, Eric Goemaere, Ernesto Jaramillo, Marcus Low, Carolina Morán Jara, Nesri Padayatchi, Robin M Warren
Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis)...
March 15, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28331043/world-health-organization-treatment-guidelines-for-drug-resistant-tuberculosis-2016-update
#18
Dennis Falzon, Holger J Schünemann, Elizabeth Harausz, Licé González-Angulo, Christian Lienhardt, Ernesto Jaramillo, Karin Weyer
Antimicrobial resistance is a major global concern. Tuberculosis (TB) strains resistant to rifampicin and other TB medicines challenge patient survival and public health. The World Health Organization (WHO) has published treatment guidelines for drug-resistant TB since 1997 and last updated them in 2016 based on reviews of aggregated and individual patient data from published and unpublished studies. An international expert panel formulated recommendations following the GRADE approach. The new WHO guidelines recommend a standardised 9-12 months shorter treatment regimen as first choice in patients with multidrug- or rifampicin-resistant TB (MDR/RR-TB) strains not resistant to fluoroquinolones or second-line injectable agents; resistance to these two classes of core second-line medicines is rapidly detectable with molecular diagnostics also approved by WHO in 2016...
March 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28270207/cost-effectiveness-of-adding-novel-or-group-5-interventions-to-a-background-regimen-for-the-treatment-of-multidrug-resistant-tuberculosis-in-germany
#19
Daniel Wirth, Ramesh Dass, Robert Hettle
BACKGROUND: Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective...
March 8, 2017: BMC Health Services Research
https://www.readbyqxmd.com/read/28256383/the-challenge-of-the-new-tuberculosis-drugs
#20
REVIEW
Simon Tiberi, Ruaridh Buchanan, José A Caminero, Rosella Centis, Marcos Abdo Arbex, Miguel Salazar, Jessica Potter, Giovanni Battista Migliori
Tuberculosis (TB) continues to cause more deaths worldwide than any other single infectious disease. Even though tuberculosis appears to be decreasing in incidence globally for some time, the proportion of drug resistance is increasing, contributing to greater complexity, morbidity and mortality as well as cost. Since the advent of rifampicin in the 1960s, and the implementation of standard quadruple anti-tuberculosis regimen in the late 1970s, no new drugs have been changed the first line regimen. This regimen is effective however it is pill burden, and duration has not received investment and innovation...
March 2017: La Presse Médicale
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