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Streicher E.M.,Stellenbosch University | Maharaj K.,University of KwaZulu - Natal | York T.,Stellenbosch University | Van Heerden C.,Stellenbosch University | And 10 more authors.
Journal of Clinical Microbiology | Year: 2014

We developed a pyrazinamidase gene DNA-sequencing method to rapidly identify pyrazinamide resistance-causing mutations in GenoLyse-treated, smear-positive sputum specimens. The sensitivity and specificity were 90.9 and 100%, respectively, compared to those of MGIT drug susceptibility testing, after the exclusion of synonymous mutations and nonsynonymous mutations previously associated with susceptibility to pyrazinamide. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


PubMed | Statistical and Data Analysis Center, Médecins Sans Frontières, New York University, Baylor College of Medicine and 20 more.
Type: Journal Article | Journal: The Lancet. Infectious diseases | Year: 2015

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.


News Article | February 15, 2017
Site: www.sciencemag.org

A new treatment strategy has had as­tonishing success against extensively drug-resistant tuberculosis (XDR TB), which kills more than 70% of patients. XDR and other drug-resistant forms of TB are burgeoning among people with HIV, and current treatments are so pro­longed and toxic that many patients fail to adhere to them. But a small study now shows that a simpler, safer regimen can cure the disease. That “may represent an enormous breakthrough,” says Richard Chaisson, who directs the Johns Hopkins University Cen­ter for Tuberculosis Research in Baltimore, Maryland, and was not involved in the trial. Called Nix-TB, the trial has had 34 people in South Africa with XDR on three antibiotics that have never been combined before to treat TB: bedaquiline, pretomanid, and linezolid. Bedaquiline, which was designed for TB but has not been used much, came to market in 2012. Pretomanid is also designed for TB but is still experimental. Linezolid is mainly used for skin infections and pneumonia. After 6 months, the TB bacillus could not be cultured from anyone’s sputum, a sign that they had cleared the infection, Francesca Conradie of the University of the Witwa­tersrand in Johannesburg, South Africa, reported today at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington. More impressive, 20 people stopped taking the drugs at that point and just one relapsed. “I didn’t in my wild­est dreams expect the results to be this suc­cessful,” Conradie says. In 2015, the World Health Organization estimates, there were 480,000 new cases of multidrug-resistant (MDR) TB, and 7234 people were treated for XDR TB, which is even more drug resistant. Standard treat­ment takes up to 2.5 years, often requires hospitalization, and includes painful injec­tions. In addition, “The toxicities are al­most worse than the disease,” says Melvin Spigelman, who heads the TB Alliance, a nonprofit in New York City that sponsored the Nix-TB study. The drugs in Nix-TB are all pills, and they have been used sparingly for TB before, which minimizes the chance that people will be resistant to the combination. Though they also have toxicities, no one withdrew from the study. Early on, however, four people died from advanced TB. The Nix-TB protocol is tailored for XDR TB, but it could be used for MDR TB if future studies show that lower, less toxic doses of linezolid can work, Spigelman says. “This re­ally gives us a window on how to truly trans­form TB therapy.” Cost remains another big unknown. For example, Janssen Therapeutics of Titusville, New Jersey, which makes beda­quiline, has promised to donate 30,000 doses to poor countries, which also can buy it for $900 for a 6-month course. The same course sells for $30,000 in high-income countries. It’s unclear how quickly the treatment can be put into widespread use, as pretomanid has not yet been approved. “We’re discussing with regulatory authorities whether Nix-TB is sufficient for approval,” Spigelman says. Nesri Padayatchi, a TB doctor at the Cen­tre for the AIDS Programme of Research in South Africa in Durban, is enthusiastic about the new findings. But she cautions that be­cause many MDR and XDR TB patients are coinfected with HIV, studies must carefully evaluate interactions between antiretrovirals and the new TB drug combination.


News Article | October 26, 2016
Site: www.eurekalert.org

TUCSON, Ariz., October 25, 2016 - The Critical Path Institute's Critical Path to TB Drug Regimens (CPTR) initiative and the Global TB Programme of the World Health Organization (WHO) have partnered with researchers from the University of California, San Francisco (UCSF), to develop leading-edge quantitative analyses of data from the TB-Platform for Aggregation of Clinical TB Studies (TB-PACTS) database. This collaboration, called TB-ReFLECT, will extract from these analyses key lessons from the TB-PACTS platform, and then package such lessons as tools for future TB trial design. TB-PACTS, which is now available to researchers across the world, is an integrated and standardized patient-level database comprising data from three leading contemporary, Phase III studies (OFLOTUB, REMox, and RIFAQUIN trials) that were the first to evaluate the treatment-shortening potential of quinolone-containing regimens in a systematic and controlled way. TB-PACTS is hosted by C-Path, in partnership with the WHO Special Programme for Research and Training in Tropical Diseases (TDR), the TB Alliance, and St. George's, University of London. The database has been accessible since April 2016. So far, the TB-PACTS scientific committee has received 23 applications; 16 have been granted access within a mean of eight days. "TB-PACTS has already elicited a lot of interest; within the first six months of the database being available, 16 requests have been granted access to the data. And TB ReFLECT has already produced results, showing the value of data-sharing and maximizing the utility of shared trial data," says Piero Olliaro, head of Intervention and Implementation Research at TDR. TB-ReFLECT will evaluate endpoints of treatment outcome for the selection of new regimens to be tested in Phase III clinical trials, as well as optimizing statistical methods for comparing results between regimens. This will lead to an improved understanding of the factors responsible for the variability in a patient's response to treatment. As part of this effort, researchers will develop a framework with clinically relevant endpoints that links the response of the bacteria to treatment. "These Phase III trials represent over 4500 patients, decades of effort, and millions of dollars of investment," says Debra Hanna, PhD, Executive Director of CPTR. "The analysis of these aggregated data will provide critical new insights to the TB drug development community and help to shape increasingly informed TB clinical trial approaches." On October 27, CPTR and WHO will co-host a symposium at the 2016 Union World Conference on Lung Health in Liverpool, UK, to update the TB research community on the progress of the TB-ReFLECT partnership. Presentations and panel discussions will highlight initial results, publicly accessible tools, data standards, and the TB-PACTS data sharing platform. "The outcomes of this collaboration will provide vital guidance to the research and development community on their quest for shorter and optimal TB treatments," says Dr. Christian Lienhardt, Senior Research Adviser at the WHO Global TB Programme. "This will be crucial in saving lives, and easing the immense burden of suffering on the millions of people who combat TB each year." CPTR (Critical Path to TB Drug Regimens) is an initiative that aims to speed the development of new and markedly improved drug regimens for tuberculosis. This partnership brings together the world's leading pharmaceutical and other drug developers, global regulatory agencies, and civil society organizations to support advances in regulatory science, the development of infrastructure, and other progress needed to facilitate the development and availability of new TB drug treatments. Co-founded by the Bill & Melinda Gates Foundation, the Critical Path Institute, and the TB Alliance, and launched in March 2010, CPTR is working with stakeholders around the world to advance a new paradigm that dramatically speeds new TB drug regimens to patients. C-Path (Critical Path Institute) is an independent, nonprofit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the US Food and Drug Administration (FDA). C-Path's mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established 12 global, public-private partnerships that currently include over 1,450 scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona. For more information, visit http://www. The World Health Organization (WHO) Global TB Programme guides global action for a world free of TB by advancing universal access to TB prevention, care and control; framing the response to threats through norms, standards and strategy; technically supporting Member States; monitoring the burden and response; and promoting innovation. WHO is the directing and coordinating authority for health within the United Nations system.


PubMed | FIND., McGill University, World Health Organization, Bill and Melinda Gates Foundation and 7 more.
Type: | Journal: The Journal of infectious diseases | Year: 2015

Current phenotypic testing for drug resistance in patients with tuberculosis is inadequate primarily with respect to turnaround time. Molecular tests hold the promise of an improved time to diagnosis.A target product profile for a molecular drug-susceptibility test (DST) was developed on the basis of a collaborative effort that included opinions gathered from researchers, clinicians, policy makers, and test developers on optimal clinical and operational characteristics in settings of intended use. In addition, the current diagnostic ecosystem and the diagnostic development landscape were mapped.Molecular DSTs for detecting tuberculosis in microscopy centers should ideally evaluate for resistance to rifampin, fluoroquinolones, isoniazid, and pyrazinamide and enable the selection of the most appropriate treatment regimen. Performance characteristics of DSTs need to be optimized, but compromises can be made that depend on the trade-off between a false-positive result and a false-negative result. The operational requirements of a test will vary depending on the site of implementation. However, the most-important considerations pertain to quality control, maintenance and calibration, and the ability to export data.This target product profile defines the needs as perceived by the tuberculosis stakeholder community and attempts to provide a means of communication with test developers to ensure that fit-for-purpose DSTs are being developed.


News Article | February 27, 2017
Site: www.sciencemag.org

You may never have heard of Acinetobacter baumannii, Pseudomonas aeruginosa, or the Enterobacteriaceae—but these three killers top a new list, drawn up by the World Health Organization (WHO) in Geneva, Switzerland, of bacteria for which new drugs are desperately needed. Unveiled today, the list contains 12 bacteria and bacterial families, with the top three making up the category “critical.” The list “is not meant to scare people about new superbugs, but to signal to researchers and pharmaceutical companies what their priorities should be,” Marie-Paule Kieny, WHO’s assistant director-general for health systems and innovation, told a press conference today. The crucial drugs are unlikely to be big moneymakers for companies that develop them, she notes, so governments and health agencies need to cooperate to boost the chances that they will be developed in time. Doctors, researchers, and health officials have been sounding the alarm for years about the rise of antibiotic resistance. The list, developed by researchers at the University of Tübingen in Germany, took into account the level of resistance each class of pathogen has already acquired, how deadly it can be, how widespread, and the burden it causes to health systems. The top three are all gram-negative bacteria that are resistant to multiple drugs. They aren’t widespread yet, but they do cause severe, frequently deadly infections in hospitals, especially in people who are already immune compromised—including transplant recipients, chemotherapy patients, and elderly people. Just last month, for instance, a woman in Nevada died of an infection with a so-called CRE, or carbapenem-resistant Enterobacteriaceae. These bacteria can cause deadly infections if they take up residence in the respiratory system or bloodstream. The most dangerous strains have recently acquired resistance to a class of antibiotics called carbapenems, the only group that still killed them effectively. Nine more pathogens round out the agency’s dirty dozen: Six are listed as high priority, including drug-resistant strains of Neisseria gonorrhoeae, which causes gonorrhea, and food-borne agents like Salmonella and Campylobacter. Bacteria in this category cause infections that are less deadly than those caused by the three critical-level bugs, but they are much more widespread. Three “medium” priority organisms all are susceptible to some drugs, but are increasingly becoming resistant. The list “sets priorities in the right direction,” says Petra Gastmeier, head of the Institute for Hygiene and Environmental Medicine at Charité University of Medicine Berlin, who wasn’t involved in the development of the list. In the current market, antibiotics aren’t an attractive investment, Kieny says. When used properly, the drugs are taken only for a short time, so they don’t bring in the high returns that drugs for chronic diseases do. “And rather than trying to maximize sales, we need to restrict usage,” Kieny says, to delay the inevitable emergence of resistance. Part of the solution will be finding new ways to reward companies for developing antibiotics, Kieny says. One idea is to agree to pay companies a big up-front fee, or “prize” as soon as a new drug comes on the market, with guidelines in place so that it would be used sparingly. But governments or other donors would have to agree to pay for the prize money. One drug-resistant bacterial pathogen is notably absent from the list: Mycobacterium tuberculosis. The problem of drug-resistant tuberculosis (TB) is "already a globally established priority," the report says; the goal was to increase attention to threats not yet widely recognized. But the TB Alliance, a nonprofit research and advocacy group based in New York City, calls on WHO to reconsider. "The absence of TB from this list is shocking,” the alliance's President and CEO Mel Spigelman said in a statement yesterday. "Every global effort to address the burgeoning AMR [antimicrobial resistance] emergency must include TB." In a response , WHO Director-General Margaret Chan emphasized that "[a]ddressing drug-resistant TB research is a top priority for WHO and for the world." WHO released its list ahead of a meeting of G20 health experts this week in Berlin, where the topic of antibiotic resistance is high on the agenda. The focus is appropriate, Gastmeier says. “This is not a problem that we can solve at a national level, and it is one in which low- and middle-income countries are linked to high-income ones.” A prime example: The woman who died in Nevada had spent time in India, where she most likely acquired the resistant strain. *Update, 1 March, 10:35 a.m.: This item has been updated to include a statement from the TB Alliance and additional comments from WHO.


News Article | February 15, 2017
Site: www.newscientist.com

Tuberculosis, the world’s leading infectious killer, may have finally met its match. Two new drug therapies may be able to cure all forms of tuberculosis – even the ones most difficult to treat. “We will have something to offer every single patient,” says Mel Spigelman, president of the TB Alliance, the organisation coordinating trials of the two treatments. “We are on the brink of turning TB around.” It presently takes six months of drug treatment to cure ordinary TB, and two years to cure people whose infections are resistant to drugs. People may need to take up to 20 tablets a day, plus injections. Together, the new treatments, called BPaMZ and BPaL, could make treating TB much simpler and more effective. BPaMZ involves taking four drugs once a day. Trials carried out in 240 people across 10 countries in Africa suggest that it cures almost all cases of ordinary TB in four months, and most people with drug-resistant TB in about six months. In the majority of cases, the TB bacterium had disappeared from sputum within two months. “The alliance has never before seen such rapid action against TB bacteria,” says Spigelman. Meanwhile, BPaL, a therapy that involves taking three drugs once a day, has so far cured 40 of 69 patients with “extremely-drug-resistant TB” – the most difficult form to treat. What’s more, it achieved this within six months. The 29 remaining participants in this trial are still to be assessed. The TB Alliance says that BPaMZ has the potential to treat 99 per cent of people who catch TB each year, while BPaL could treat the remainder. Researchers presented results from both sets of trials at the Conference on Retroviruses and Opportunistic Infections in Seattle this week. The arrival of new drugs is long-awaited, says Spigelman, because the existing treatment for TB is now 50 years old. According to the latest figures from the World Health Organization, there were 10.4 million new cases of TB in 2015, but only 20 per cent of those with resistant TB were treated, and of those only half were cured. Once mass produced, BPaMZ could cost just a tenth of the $3000 it now costs to treat drug-resistant TB. Spigelman cautions, however, that larger trials are needed to confirm the effectiveness of both therapies and for them to be approved for global use. At best, this would take at least three years for BPaMZ, he says, although the therapy for extremely-drug-resistant TB may be available sooner. “The results are exciting and encouraging, but we must be cautious saying we can treat everyone with these regimes,” says David Moore at the London School of Hygiene and Tropical Medicine. “These are only preliminary data, so there’s a danger of jumping the gun.”


News Article | October 28, 2016
Site: www.rdmag.com

One of the world’s largest food and beverage companies is launching a new initiative to help children all over the world. Pepsi is teaming up with the nonprofit TB alliance to engineer new flavors to counteract the bitter taste found in tuberculosis drugs. The company will, “apply proprietary flavor and sensory expertise,” to help develop strategies that can hopefully solve the bitter taste issue. Pepsi won’t receive any financial payments for these efforts whereas the TB Alliance will have free access to the results of this program applying it to its drug development efforts, according to the announcement. “At PepsiCo, we saw a unique opportunity to leverage our R&D talent and flavor expertise to help improve the palatability of certain TB medicines,” said Pepsi’s Dr. Mehmood Khan, the vice chairman and chief scientific officer of Global Research and Development. “In collaboration with the TB Alliance team and others, we are hopeful that we can identify formulation changes that will make it easier for caregivers to administer TB medicines to children. Our work together has the potential to significantly improve the care and well-being of many TB patients and move us one step closer to the goal of eradicating TB in children,” Khan added. The formulation process for tuberculosis drugs is intended for adults, making them difficult to swallow and unpleasant for kids, wrote The New York Times. Parents are recommended to try to crush the pills and mix them into applesauce to disguise the taste, but it has the adverse effect of turning kids off from these treats. Tuberculosis is the leading infectious cause of death worldwide with 1 million children getting diagnosed with TB each year and 210,000 children succumb to it, according to statistics from The World Health Organization, emphasizing how important it is in seeking a solution to boost adherence with this medication.


Gillespie S.H.,University of St. Andrews | Crook A.M.,University College London | McHugh T.D.,University College London | Mendel C.M.,TB Alliance | And 5 more authors.
New England Journal of Medicine | Year: 2014

Background Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.Results Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-totreat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.Conclusions The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.). Copyright © 2014 Massachusetts Medical Society. All rights reserved.

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