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https://www.readbyqxmd.com/read/27927925/the-emergence-of-mmpt5-variants-during-bedaquiline-treatment-of-mycobacterium-intracellulare-lung-disease
#1
David C Alexander, Ravikiran Vasireddy, Sruthi Vasireddy, Julie V Philley, Barbara A Brown-Elliott, Benjamin Perry, David E Griffith, Jeana L Benwill, Andrew D S Cameron, Richard J Wallace
Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for treatment of Mycobacterium tuberculosis (MTB) infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of thirteen patients with Mycobacterium intracellulare lung disease had an initial microbiological response, then relapsed. Whole genome comparison of pre-treatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5 Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in MTB...
December 7, 2016: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/27906009/current-trends-and-intricacies-in-the-management-of-hiv-associated-pulmonary-tuberculosis
#2
REVIEW
Narendran Gopalan, Padmapriyadarsini Chandrasekaran, Soumya Swaminathan, Srikanth Tripathy
Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary TB assumes utmost significance in the programmatic perspective as it is readily transmissible as well as easily diagnosable. HIV complicates every aspect of pulmonary tuberculosis from diagnosis to treatment, demanding a different approach to effectively tackle both the diseases. In order to control these converging epidemics, it is important to diagnose early, initiate appropriate therapy for both infections, prevent transmission and administer preventive therapy...
September 26, 2016: AIDS Research and Therapy
https://www.readbyqxmd.com/read/27878107/imaging-the-nadh-nad-homeostasis-for-understanding-the-metabolic-response-of-mycobacterium-to-physiologically-relevant-stresses
#3
Shabir A Bhat, Iram K Iqbal, Ashwani Kumar
The NADH:NAD(+) ratio is the primary indicator of the metabolic state of bacteria. NAD(H) homeostasis is critical for Mycobacterium tuberculosis (Mtb) survival and is thus considered an important drug target, but the spatio-temporal measurements of NAD(H) remain a challenge. Genetically encoded fluorescent biosensors of the NADH:NAD(+) ratios were recently described, paving the way for investigations of the metabolic state of pathogens during infection. Here we have adapted the genetically encoded biosensor Peredox for measurement of the metabolic state of Mtb in vitro and during infection of macrophage cells...
2016: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/27872065/in-vitro-susceptibility-testing-of-bedaquiline-against-mycobacterium-avium-complex
#4
Barbara A Brown-Elliott, Julie V Philley, David E Griffith, Foram Thakkar, Richard J Wallace
We performed bedaquiline broth microdilution susceptibilities using Clinical Laboratory Standards Institute (CLSI) guidelines on 103 respiratory isolates of Mycobacterium avium complex (MAC), including multidrug resistant isolates. Approximately 90% of isolates had bedaquiline minimal inhibitory concentrations (MICs) ≤0.008 μg/mL and 102/103 isolates had MICs ≤0.015 μg/mL. Bedaquiline has excellent potential for use in patients with MAC, although for reasons of its metabolism by the cytochrome P450 system, it should not be given with rifampin...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27865232/bedaquiline-introducing-a-new-drug-to-the-mdr-tb-armamentarium
#5
EDITORIAL
Chrispin Kambili
No abstract text is available yet for this article.
July 2016: Indian Journal of Tuberculosis
https://www.readbyqxmd.com/read/27863179/population-pharmacokinetics-of-bedaquiline-and-metabolite-m2-in-patients-with-drug-resistant-tuberculosis-the-effect-of-time-varying-weight-and-albumin
#6
E M Svensson, A-G Dosne, M O Karlsson
Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27861363/efficacy-safety-and-tolerability-of-a-24-month-treatment-regimen-including-delamanid-in-a-child-with-extensively-drug-resistant-tuberculosis-a-case-report-and-review-of-the-literature
#7
Susanna Esposito, Samantha Bosis, Marina Tadolini, Sonia Bianchini, Giovanni Battista Migliori, Nicola Principi
RATIONAL: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are emerging problems in several countries. These infections require long and expensive treatment regimens. Recently, 2 new drugs, bedaquiline and delamanid, have been approved in several countries for use in adults with severe, difficult-to-treat MDR-TB, and it has been suggested that they could also be administered to children with MDR-TB and limited treatment options. However, no study has been completed on their efficacy...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27854508/new-repurposed-drugs-for-pediatric-multidrug-resistant-tuberculosis-practice-based-recommendations
#8
Elizabeth P Harausz, Anthony J Garcia-Prats, James A Seddon, H Simon Schaaf, Anneke C Hesseling, Jay Achar, Jonathan Bernheimer, Andrea Cruz, Lia D'Ambrosio, Anne Detjen, Stephen M Graham, Jennifer Hughes, Sylvie Jonckheere, Ben J Marais, Giovanni Battista Migliori, Lindsay McKenna, Alena Skrahina, Marina Tadolini, Peyton Wilson, Jennifer Furin
It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents...
November 17, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27816662/applicability-of-the-shorter-bangladesh-regimen-in-high-mdr-tb-settings
#9
Giovanni Sotgiu, Simon Tiberi, Rosella Centis, Lia D'Ambrosio, Zhenia Fuentes, Alimuddin Zumla, Giovanni Battista Migliori
In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as Bangladesh regimen) proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high dose isoniazid and ethambutol followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol...
November 2, 2016: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/27798208/mechanisms-of-action-and-therapeutic-efficacies-of-the-lipophilic-antimycobacterial-agents-clofazimine-and-bedaquiline
#10
REVIEW
Moloko C Cholo, Maborwa T Mothiba, Bernard Fourie, Ronald Anderson
Drug-resistant (DR)-TB is the major challenge confronting the global TB control programme, necessitating treatment with second-line anti-TB drugs, often with limited therapeutic efficacy. This scenario has resulted in the inclusion of Group 5 antibiotics in various therapeutic regimens, two of which promise to impact significantly on the outcome of the therapy of DR-TB. These are the 're-purposed' riminophenazine, clofazimine, and the recently approved diarylquinoline, bedaquiline. Although they differ structurally, both of these lipophilic agents possess cationic amphiphilic properties that enable them to target and inactivate essential ion transporters in the outer membrane of Mycobacterium tuberculosis...
October 20, 2016: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/27797620/reply-call-for-regular-susceptibility-testing-of-bedaquiline-and-delamanid
#11
Harald Hoffmann, Sabine Hofmann-Thiel, Matthias Merker, Thomas A Kohl, Stefan Niemann
No abstract text is available yet for this article.
November 1, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27797614/preventing-acquired-resistance-to-bedaquiline-and-delamanid-in-multidrug-resistant-tuberculosis-treatment-requires-optimal-management
#12
Lorenzo Guglielmetti, Damien Le Dû, Mathilde Fréchet-Jachym, Carole Mitnick
No abstract text is available yet for this article.
November 1, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/27796146/new-antimycobacterial-agents-in-the-pre-clinical-phase-or-beyond-recent-advances-in-patent-literature-2001-2016
#13
Patricia Bento da Silva, Débora L Campos, Camila M Ribeiro, Isabel C Silva, Fernando Rogério Pavan
Tuberculosis, an infectious disease, has caused more deaths worldwide than any other single infectious disease, killing more than 1.5 million people each year; equating to 4,100 deaths a day. In the past 60 years, no new drugs have been added to the first line regimen, in spite of the fact that thousands of papers have been published on drugs against tuberculosis and hundreds of drugs have received patents as new potential products. Thus, there is undoubtedly an urgent need for the deployment of new effective drugs against tuberculosis...
October 31, 2016: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27792278/structural-simplification-of-bedaquiline-the-discovery-of-3-4-n-n-dimethylaminomethyl-phenyl-quinoline-derived-antitubercular-lead-compounds
#14
Chunxian He, Laura Preiss, Bin Wang, Lei Fu, Hui Wen, Xiang Zhang, Huaqing Cui, Thomas Meier, Dali Yin
Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead...
October 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27762157/individualizing-management-of-extensively-drug-resistant-tuberculosis-diagnostics-treatment-and-biomarkers
#15
Jan-Willem Alffenaar, Onno W Akkerman, Richard Anthony, Simon Tiberi, Scott Heysell, M P Grobusch, Frank Cobelens, Dick van Soolingen
Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M...
October 20, 2016: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/27756966/bedaquiline-versus-placebo-for-management-of-multidrug-resistant-tuberculosis-a-systematic-review
#16
Surjit Singh, Pramod Kumar Sharma, Rimplejeet Kaur
No abstract text is available yet for this article.
July 2016: Indian Journal of Pharmacology
https://www.readbyqxmd.com/read/27756712/clinical-management-of-adults-and-children-with-mdr-and-xdr-tb
#17
REVIEW
Keertan Dheda, Kwok Chiu Chang, Lorenzo Guglielmetti, Jennifer Furin, H Simon Schaaf, Dumitru Chesov, Aliasgar Esmail, Christoph Lange
Globally there is a burgeoning epidemic of drug mono-resistant tuberculosis (TB), multi-drug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB). Almost 20% of all TB strains worldwide are resistant to at least 1 major TB drug including isoniazid. In several parts of the world there is an increasing incidence of MDR-TB, and alarmingly almost a third of MDR-TB cases globally are resistant to either a fluoroquinolone or aminoglycocide. This trend cannot be ignored because DR-TB is associated with greater morbidity compared to drug-sensitive TB, it accounts for almost 25% of global TB mortality, is extremely costly to treat, consuming substantial portions of budgets allocated to national TB programmes in TB endemic countries, and is a major threat to healthcare workers who are already in short supply in resource-poor settings...
October 15, 2016: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/27755552/sterilizing-activity-of-fully-oral-intermittent-regimens-against-mycobacterium-ulcerans-infection-in-mice
#18
Aurélie Chauffour, Jérôme Robert, Nicolas Veziris, Alexandra Aubry, Vincent Jarlier
BACKGROUND: The treatment of Buruli ulcer (BU) that is caused by Mycobacterium ulcerans, is currently based on a daily administration of rifampin and streptomycin (RIF-STR). A fully oral intermittent regimen would greatly simplify its treatment on the field. METHODOLOGY/PRINCIPAL FINDINGS: The objective of this study was to assess the bactericidal and sterilizing activities of intermittent oral regimens in a murine model of established M. ulcerans infection. Regimens combining rifapentine (RFP 20 mg/kg) with either moxifloxacin (MXF 200 mg/kg), clarithromycin (CLR 100 mg/kg) or bedaquiline (BDQ 25 mg/kg) were administrated twice (2/7) or three (only for RFP-CLR 3/7) times weekly during 8 weeks...
October 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/27727274/tradeoffs-in-introduction-policies-for-the-anti-tuberculosis-drug-bedaquiline-a-model-based-analysis
#19
Amber Kunkel, Frank G Cobelens, Ted Cohen
BACKGROUND: New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients' resistance patterns. METHODS AND FINDINGS: We created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies...
October 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27726797/mouse-and-guinea-pig-models-of-tuberculosis
#20
Ian M Orme, Diane J Ordway
This article describes the nature of the host response to Mycobacterium tuberculosis in the mouse and guinea pig models of infection. It describes the great wealth of information obtained from the mouse model, reflecting the general availability of immunological reagents, as well as genetic manipulations of the mouse strains themselves. This has led to a good understanding of the nature of the T-cell response to the infection, as well as an appreciation of the complexity of the response involving multiple cytokine- and chemokine-mediated systems...
August 2016: Microbiology Spectrum
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