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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
Surjit Singh, Pramod Kumar Sharma, Rimplejeet Kaur
No abstract text is available yet for this article.
July 2016: Indian Journal of Pharmacology
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
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
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
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
Martin Dedicoat
No abstract text is available yet for this article.
October 2016: International Journal of Tuberculosis and Lung Disease
Daniel L Priebbenow, Lisa Barbaro, Jonathan B Baell
Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered...
October 12, 2016: Organic & Biomolecular Chemistry
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...
2016: AIDS Research and Therapy
R Cariem, V Cox, V de Azevedo, J Hughes, E Mohr, L Triviño Durán, N Ndjeka, J Furin
Multidrug-resistant tuberculosis (MDR-TB) is a serious public health problem, but the new drugs bedaquiline (BDQ) and delamanid offer hope to improve outcomes and minimise toxicity. In Khayelitsha, South Africa, patients are routinely started on BDQ in the out-patient setting. This report from the field describes BDQ use in the out-patient setting at the Nolungile Clinic. The clinic staff overall report a positive experience using the drug. Challenges have been based largely on the logistics of drug supply and delivery...
September 2016: Public Health Action
Santiago Ramón-García, Rubén González Del Río, Angel Santos Villarejo, Gaye D Sweet, Fraser Cunningham, David Barros, Lluís Ballell, Alfonso Mendoza-Losana, Santiago Ferrer-Bazaga, Charles J Thompson
While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug...
September 28, 2016: Scientific Reports
Stewart T Cole
Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials...
November 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
T Maitre, A Aubry, V Jarlier, J Robert, N Veziris
The emergence of drug-resistant tuberculosis (TB) compromises global tuberculosis control. The incidence of multidrug-resistant strains (MDR) defined as resistant to the two main antituberculosis drugs, rifampicin and isoniazid, was raised in the 1990s. Ten percent of these strains have developed additional resistance to the main second-line antituberculosis drugs: fluoroquinolones and aminoglycosides. These strains are defined as extensively drug-resistant (XDR). The prognosis of MDR-TB and XDR-TB is poor due to limited therapeutic resources...
September 13, 2016: Médecine et Maladies Infectieuses
G K Raju, Karthik Gurumurthi, Reuben Domike
The analysis of benefit and risk is an important aspect of decision-making throughout the drug lifecycle. In this work, the use of a benefit-risk analysis approach to support decision-making was explored. The proposed approach builds on the qualitative FDA approach to include a more explicit analysis based on international standards and guidance that enables aggregation and comparison of benefit and risk on a common basis and a lifecycle focus. The approach is demonstrated on six decisions over the lifecycle (e...
September 14, 2016: Clinical Pharmacology and Therapeutics
Subhashri Kundu, Goran Biukovic, Gerhard Grüber, Thomas Dick
The tuberculosis drug Bedaquiline inhibits mycobacterial F-ATP synthase by binding to its c subunit. Using purified ϵ subunit of the synthase and spectroscopy we previously demonstrated that the drug interacts with this protein near its unique tryptophan residue. Here we show that replacement of ϵ's tryptophan with alanine resulted in Bedaquiline hyper susceptibility of the bacteria. Overexpression of wild type ϵ subunit caused resistance. These results suggest that the drug also targets the ϵ subunit.
September 12, 2016: Antimicrobial Agents and Chemotherapy
Eliza J R Peterson, Shuyi Ma, David R Sherman, Nitin S Baliga
The resilience of Mycobacterium tuberculosis (MTB) emerges from its ability to effectively counteract immunological, environmental and antitubercular challenges. Here, we demonstrate that MTB can tolerate drug treatment by adopting a tolerant state that can be deciphered through systems analysis of its transcriptional responses. Specifically, we demonstrate how treatment with the antitubercular drug bedaquiline activates a regulatory network that coordinates multiple resistance mechanisms to push MTB into a tolerant state...
2016: Nature Microbiology
Nesri Padayatchi, Sharana Mahomed, Marian Loveday, Kogieleum Naidoo
No abstract text is available yet for this article.
October 2016: Expert Opinion on Pharmacotherapy
Dirk A Lamprecht, Peter M Finin, Md Aejazur Rahman, Bridgette M Cumming, Shannon L Russell, Surendranadha R Jonnala, John H Adamson, Adrie J C Steyn
The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels...
2016: Nature Communications
Ji-Hye Byun, Jae-A Park, Hye-Rim Kang, Ju-Young Shin, Eui-Kyung Lee
BACKGROUND: No clear evidence on the comparative effectiveness of delamanid (DLM) and bedaquiline (BDQ) has been published. OBJECTIVE: This study aims to estimate the incremental effectiveness of DLM versus BDQ in patients with multidrug-resistant tuberculosis (MDR-TB). METHODS: We developed a Markov model based on a cohort with MDR-TB, which consisted of success, failure, loss to follow-up, and death. The cohort simulation was conducted assuming each patient was 36 years old and, lived until age 82, and that the cycle length was 1 year...
November 2016: Clinical Drug Investigation
H Simon Schaaf, Stephanie Thee, Louvina van der Laan, Anneke C Hesseling, Anthony J Garcia-Prats
INTRODUCTION: Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these are more toxic than first-line drugs. Little is known about the safety of new antituberculosis drugs in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes. AREAS COVERED: A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline...
October 2016: Expert Opinion on Drug Safety
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