tag:theconversation.com,2011:/ca/topics/mdr-tb-26012/articlesMDR-TB – The Conversation2022-11-29T14:32:01Ztag:theconversation.com,2011:article/1919152022-11-29T14:32:01Z2022-11-29T14:32:01ZSouth Africa’s prisons are a breeding ground for the spread of TB. Our model shows how<figure><img src="https://images.theconversation.com/files/488556/original/file-20221006-24-3ly4qx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">People in prison are more at risk of TB than the general population.</span> <span class="attribution"><span class="source">Stephane de Sakutin/AFP via Getty Images</span></span></figcaption></figure><p>South African prisons are famously overcrowded. Prison populations are believed to exceed capacity by an overall 33%, although that number jumps to over 200% at some facilities, according to <a href="https://www.sabcnews.com/sabcnews/overcrowding-in-the-countrys-prisons-is-now-at-33-lamola/#:%7E:text=The%20Eastern%20Cape%2C%20the%20Western,and%20Mount%20Frere%20at%20243%25.">recent reports</a>.</p>
<p>The confined, often overcrowded conditions of prisons make them a <a href="https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(21)00025-6/fulltext">breeding ground</a> for disease. In particular, they are a high-risk environment for the spread of infectious diseases such as tuberculosis (TB) – a leading cause of death in South Africa. TB spreads in the air when a person with the disease coughs, speaks, or sings. </p>
<p>In South Africa’s general population TB prevalence is <a href="https://theconversation.com/first-ever-national-survey-shows-the-extent-of-south-africas-tb-problem-155153">737 per 100,000</a> people – one of the <a href="https://apps.who.int/iris/bitstream/handle/10665/341980/9789240029439-eng.pdf?sequence=1&isAllowed=y">highest</a> in the world. </p>
<p>A global <a href="https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(21)00025-6/fulltext">review</a> found that people in prison were more at risk of TB than the general population. But very little is known about the TB prevalence in South Africa’s prisons. A <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087262#:%7E:text=Studies%20from%20Sub%2DSaharan%20African,survey%20from%20Zambia%20%5B9%5D.">2010 study</a> of the country’s largest prison found that 38.6% of the study participants showed at least one symptom of TB. Only 1% of participants were receiving TB treatment. </p>
<p>In two <a href="https://www.hindawi.com/journals/jam/2018/3420528/">separate</a> <a href="https://www.naturalspublishing.com/files/published/p91le7563uyz2k.pdf">papers</a> we built models to better understand how TB is spread in a crowded environment, such as a prison. Our findings make it clear that as long as there is an influx of infected patients, TB cannot be eliminated. It will continue to spread through the influx of new carriers or new potential hosts. This in turn increases the risks of drug-resistant and multi-drug-resistant variants of TB developing.</p>
<p>Mathematical epidemiological modelling is a great tool for predicting the behaviour of a disease over a period of time. Models are not meant to treat the disease. But they inform public health decisions and policy. Models can be modified to suit a certain behaviour of the disease, specific lifestyle factors in the population and certain interventions by public health authorities. The accuracy of forward projections depends on the quality and quantity of the available (historical) data. </p>
<p>Mathematical models are able to inform us of the likelihood that, with or without control strategies such as screening and vaccination, the disease can be eliminated or will persist at a specified level of endemicity.</p>
<h2>Modelling in crowded environments</h2>
<p>Over the past few years, we and other researchers have been modelling the transmission of TB, using compartmental models. This is a modelling technique commonly applied in epidemiology to predict the spread of an infectious disease.</p>
<p>The technique derives its name from the fact that the population is divided into “compartments” according to the disease status of individuals: </p>
<ul>
<li><p>those who are susceptible </p></li>
<li><p>those who are infectious </p></li>
<li><p>those who have recovered. </p></li>
</ul>
<p>We then applied this technique to what is known as a crowded environment. This can be anything from an open-air concert to a mining population to a prison – any place where people could potentially gather <em>en masse</em> and in close proximity.</p>
<p>A key objective of the modelling study is what is known as the stability analysis of the disease-free equilibrium state, or the point where the disease is no longer found within that environment. This is because it is important to understand how the disease can possibly be eliminated from the population. There is a lot of maths involved. </p>
<p>In a <a href="https://www.hindawi.com/journals/jam/2018/3420528/">2018 paper</a> we looked at the inflow of infected patients into a prison, computing what the impact would be on the broader prison community. </p>
<p>In a <a href="https://www.naturalspublishing.com/files/published/p91le7563uyz2k.pdf">more recent paper</a> – in the interests of better accuracy – we added further complexity by developing a novel two-group model that mirrors the dynamics of TB in a prison system. </p>
<p>Our model, in addition to the compartmentalisation, further divides the prison population into two groups: sentenced individuals, and remanded individuals awaiting trial. </p>
<p>The model showed mathematically that when infected people continue to enter the system, the disease cannot be eliminated. It also showed that the average time inmates spend in prison could make a difference to TB dynamics – but this needs further study.</p>
<h2>Next steps</h2>
<p>There are a number of solutions.</p>
<p>The World Health Organization recommends early diagnosis, equitable access to health services, and the co-management of TB and HIV.</p>
<p>At the top of the list is the universal screening of those coming into the system. Research shows that this commonly <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907552/">proposed measure</a> can reduce the number of infectious individuals and help eliminate the disease.</p>
<p>Hand in hand with this should be a strategy to admit infected inmates to a prison facility which has an elimination plan in place, such as treatment for latent cases. </p>
<p>Providing comprehensive curative and preventive services for cases is vital if TB is to be eliminated in prisons.</p><img src="https://counter.theconversation.com/content/191915/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The overcrowded conditions of prisons make them a high-risk environment for the spread of infectious diseases such as TB.Sibaliwe Maku Vyambwera, Lecturer in Mathematics, University of the Western CapePeter Joseph Witbooi, Professor, University of the Western CapeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1884122022-08-16T14:41:17Z2022-08-16T14:41:17ZThe key to treating TB may be in a common carbohydrate. What we know so far<figure><img src="https://images.theconversation.com/files/479161/original/file-20220815-25-i854zg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">New remedies are needed as rates of multi-drug resistant TB rise.</span> <span class="attribution"><span class="source">Jarun Ontakrai/Shutterstock</span></span></figcaption></figure><p><a href="https://link.springer.com/article/10.1007/s00289-021-03860-1">Curdlan</a> is a popular carbohydrate in the food industry. Its name is derived from the word “curdle”, and as it suggests, it’s widely used as a thickener and stabiliser in everything from sausages to milk substitutes.</p>
<p>More recently, it has caught the eye of the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273257/">pharmaceutical industry</a>. That’s because curdlan, itself produced by bacteria, is able to trigger an antibacterial response in a range of environments and organisms. Among other uses, researchers are <a href="https://link.springer.com/article/10.1186/s13048-020-00626-7">looking at curdlan</a> as a possible treatment for cancers and <a href="https://www.sciencedirect.com/science/article/pii/S0144861714003828?casa_token=5A9L_uGxF5oAAAAA:56_9Q91nCk3cSJdLaXa0eZPp4iDXAs5b8XUUNQuwfhPdSl5Jg9w2wfxyjejHNCm7V8N5sH4iDrY">other diseases</a>.</p>
<p>One of those diseases is tuberculosis (TB), the infection responsible for <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2017.02284/full">killing more people</a> than any other infectious disease in human history. <a href="https://www.nicd.ac.za/wp-content/uploads/2021/02/TB-Prevalence-survey-report_A4_SA_TPS-Short_Feb-2021.pdf">South Africa</a> has one of the world’s highest TB burdens – along with 29 other countries including India and China. These countries contribute 86% of the globe’s <a href="https://www.who.int/news-room/fact-sheets/detail/tuberculosis#:%7E:text=In%202020%2C%20the%2030%20high,Nigeria%2C%20Bangladesh%20and%20South%20Africa.">10 million annual TB cases</a>. South Africa’s combined burden of TB, TB/HIV and multi-drug resistant TB (MDR-TB), driven by socioeconomic factors and its high HIV <a href="https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&entity_type=%22country%22&lan=%22EN%22&iso2=%22ZA%22">numbers</a>, is especially worrying.</p>
<p>Existing remedies made up of cocktails of antibiotics are not effective against MDR-TB. This has sparked interest in finding alternative treatments. It’s why our research group at the School of Pharmacy at the University of the Western Cape, and others, are beginning to test the efficacy of curdlan as a potential drug candidate. </p>
<p>In a <a href="https://pubmed.ncbi.nlm.nih.gov/34534573/">recent paper</a>, for instance, we show very promising results for the potential treatment of TB using curdlan-based nanoparticles.</p>
<h2>How TB infects</h2>
<p>Our work centres on developing host-directed therapies using curdlan. Such treatments essentially let the human <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2017.02284/full">immune system</a> do the heavy lifting. This is done by activating its natural antibacterial mechanisms while controlling the inflammation that results from such activation. Inflammation is a signal that the immune system is working. But if inflammation is out of control it can cause major damage to human tissue, as seen in severe <a href="https://www.frontiersin.org/articles/10.3389/fimmu.2020.01446/full#:%7E:text=Accumulating%20evidence%20suggests%20that%20some,%2C%20TNF%2D%CE%B1%2C%20and%20VEGF">COVID-19 infections</a>.</p>
<p>Research has already shown that host-directed therapies hold <a href="https://www.frontiersin.org/articles/10.3389/fcimb.2020.618414/full">immense potential</a> for the <a href="https://link.springer.com/article/10.1007/s11095-018-2528-9">treatment of TB</a>.</p>
<p>To understand how these therapies work, it’s important to understand how TB infection unfolds in the human body.</p>
<p>Primary TB infection occurs when a person inhales aerosol droplets, released by contagious individuals, that contain <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>). This is the bacterium that causes TB. Once inhaled, <em>M.tb</em> quickly makes its way to the lung’s alveolar space, made up of tiny air sacs that sit at the end of the bronchioles, which are the air passages inside the lungs.</p>
<p>Here it is absorbed by what’s known as alveolar macrophages, the lung cells that are usually the first line of defence against pollutants and pathogenic organisms. Typically these macrophages would trigger an immune response in the body. But <em>M.tb</em> has evolved so cannily that it eludes or switches off this immune-triggering response in the macrophages. These alveolar macrophages become its infection headquarters; the bacterium remains concealed within these cells.</p>
<p>For any treatment to be successful, it has to navigate a <a href="https://www.frontiersin.org/articles/10.3389/fcimb.2020.618414/full">host of obstacles</a> to reach <em>M.tb</em>. It must make its way through complex lung lesions, then penetrate the cell membrane of macrophages and other host cells, and finally be taken up by the <em>M.tb</em> sitting within these cells.</p>
<p>That’s where nanoparticles enter the picture.</p>
<h2>Tiny ‘snipers’</h2>
<p>Nanoparticles are extremely small. They range from between one to 100 nanometres; for some perspective, there are a million nanometres in a single millimetre. In theory, and as is being shown in <a href="https://iopscience.iop.org/article/10.1088/1361-6528/ac7885/meta?casa_token=FjKJlNwJcFYAAAAA:CzLeHNZ_j9uFpGYgd9UnvJr-RBFnO8NoKhxymb8JcyrujuK0bISE6sP6vEIeYC8NvPcPJkLuIMA">laboratories</a> and existing treatments for other conditions like <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720743/">cancer</a>, nanotherapies allow drugs to target pathogens with sniper-like accuracy. They also have the potential to tackle patient non-compliance that can lead to drug resistant TB.</p>
<p>The <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449995/">reasons</a> for non-compliance are varied and complex, but the duration of the therapy itself is a factor. Existing treatments require that, depending on the severity and progress of the disease, patients take many drugs over as many as six months. The <a href="https://www.who.int/news-room/fact-sheets/detail/tuberculosis">course of treatment</a> for MDR-TB lasts up to 24 months. </p>
<p>This high pill load, together with sometimes toxic side effects, has been shown to overwhelm patients. Many do not return to clinics and hospitals for check-ups, especially when they feel better after a few weeks. Some stop taking their medication. This could be behind the rise of drug resistant strains. Such non-compliance is also believed to be the cause of South Africa’s comparatively <a href="https://www.copenhagenconsensus.com/publication/south-africa-perspective-tuberculosis#:%7E:text=TB%20is%20South%20Africa's%20leading,to%20bring%20it%20under%20control.">high TB mortality</a>.</p>
<p>Traditional drugs are taken orally or intravenously. They travel throughout the body via the blood circulatory system. Many drug molecules do not reach their targets, staying in the body where they cause several negative side effects. That’s where nanoparticle-based treatments have the <a href="https://www.tandfonline.com/doi/abs/10.1517/17425247.2014.846905">upper hand</a>: they are extremely targeted and their release into the system is very controlled. Smaller doses are required and there is less dispersion around the body, meaning fewer side effects.</p>
<h2>Promising findings</h2>
<p>All these factors suggest that nanoparticle-based treatments may be the right approach to take against TB. And two interesting findings from our study bolster the case.</p>
<p>One, we observed the production of what’s known as pro-inflammation cytokines, a signalling molecule that triggers an antibacterial effect in immune cells. This meant that the nanoparticles were doing what they were meant to do.</p>
<p>Secondly, we found that the <em>M.tb</em> bacteria in the immune cells were considerably reduced over a 72-hour period. </p>
<p>These results suggest that curdlan nanotherapeutics are an avenue worth exploring in treating TB. There is much more work to be done, but it’s an important step towards tackling TB – in South Africa and everywhere else.</p><img src="https://counter.theconversation.com/content/188412/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Admire Dube receives funding from the Fogarty International Center of the National Institutes of Health (K43TW010371) and the National Institute of Allergy and Infectious Diseases (5R01AI152109). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.</span></em></p>As antibiotics lose their power to treat some forms of TB, interest in the antibacterial powers of curdlan is rising.Admire Dube, Associate Professor, Pharmaceutical Sciences, University of the Western CapeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1141032019-03-27T13:30:50Z2019-03-27T13:30:50ZScientists are developing new, exciting strategies for the fight against TB<figure><img src="https://images.theconversation.com/files/266127/original/file-20190327-139361-27hj79.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chest x-ray showing TB infection in the lungs.</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Tuberculosis (TB) is a lung disease caused by the bacterium <em>Mycobacterium tuberculosis</em>. It’s transmitted through air droplets when an infectious person coughs or sneezes. The disease can be treated, but it’s a long process with the drugs that are currently available. It remains a major health problem: globally, about <a href="https://www.who.int/tb/publications/global_report/tb18_ExecSum_web_4Oct18.pdf?ua=1">1.6 million</a> died from it in 2017. </p>
<p>Most of these deaths occurred in the developing world. The African continent has a <a href="https://afro.who.int/health-topics/tuberculosis-tb">particularly severe</a> TB burden. This is worsened by the emergence of multidrug-resistant TB; patients with this form of the disease respond poorly to the usual first-line drugs. TB and HIV <a href="https://www.who.int/hiv/topics/tb/en/">co-infection</a> is also a big problem. </p>
<p>There are some glimmers of hope. Globally, TB related deaths dropped by <a href="https://www.who.int/tb/post2015_TBstrategy.pdf?ua=1">33%</a> between 2000 and 2017. There’s also a new push from the <a href="https://www.who.int/tb/post2015_TBstrategy.pdf?ua=1">World Health Organisation (WHO)</a> to reduce new TB cases by 90% by 2035. But for this to happen, new therapies and diagnostic tools are needed.</p>
<p>There are some promising therapies in the pipeline, particularly when it comes to host-directed therapies and biomarkers. The first refers to drugs that strengthen the immune system and reduce lung damage. Biomarkers are blood- or tissue-based indicators that tell clinicians about the presence of latent (or dormant) TB, the development of active TB and its progression.</p>
<p>Governments, global funding agencies, national research councils and the private sector now need to invest resources in developing these therapies to the point where they can be used widely. This is crucial if the WHO’s ambitious targets are to be met.</p>
<h2>Host-directed therapies</h2>
<p>In TB treatment, host-directed therapies have two major goals. One is to stimulate key components of the immune system to control TB infection. The other involves limiting damage to the lung tissue in a bid to slow down TB’s progression. </p>
<p>Host-directed therapies can also be combined with standard treatment regimens. This will likely shorten the current course of TB treatment, which at its shortest lasts for about six months.</p>
<p>Some of the host-directed therapies that are <a href="https://www.ncbi.nlm.nih.gov/pubmed/26184493">currently being investigated</a> include:</p>
<ul>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/21998409">Vitamin D</a>, which induces specific immune molecules that have protective effects against the TB bacteria.</p></li>
<li><p>Non-steroidal <a href="https://www.ncbi.nlm.nih.gov/pubmed/25986592">anti-inflammatory drugs</a> (ibuprofen, zileuton and aspirin). These work by suppressing excessive inflammation and tissue pathology and reduce bacterial burdens in the lung.</p></li>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/24133190">Statins</a> reduce cholesterol levels and limit bacterial growth in the body’s immune cells.</p></li>
<li><p><a href="https://www.thelancet.com/action/showPdf?pii=S1473-3099%2816%2900078-5">Angiogenesis inhibitor (Bevacizimub)</a> is a drug that works by blocking formation of new blood vessels (neovascularisation) in <a href="https://www.ncbi.nlm.nih.gov/pubmed/27043495">lung granulomas</a> (small areas of inflammation). It might improve anti-TB drug penetration into granulomas and increase air supply.</p></li>
</ul>
<h2>Diagnostics and biomarkers</h2>
<p>Treating TB is only one part of the puzzle. Proper, timely diagnosis and a good understanding of the disease’s progression in an individual patient are also important.</p>
<p>The disease is currently diagnosed in several ways. These include viewing a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705651/">sputum sample</a> under a microscope; through <a href="https://www.tbfacts.org/tb-tests/">a skin test</a>; or through <a href="https://www.tbfacts.org/tb-tests/">a blood test</a>.</p>
<p>But biomarkers could hold useful answers, too. About <a href="https://www.ncbi.nlm.nih.gov/pubmed/27822210">one-third </a>of the world’s population is infected with the bacterium that causes TB. Between 5% and 10% of these latently infected individuals will develop the active disease in their lifetime. Biomarkers could be used to reliably predict who these individuals are. The individuals could then be treated preemptively.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=191&fit=crop&dpr=1 600w, https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=191&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=191&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=240&fit=crop&dpr=1 754w, https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=240&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/266129/original/file-20190327-139361-1agnlps.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=240&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A representation different stages of TB.</span>
<span class="attribution"><span class="source">Pai et al, 2016</span></span>
</figcaption>
</figure>
<p>There have been exciting studies along these lines. These have identified the gene and protein signatures associated with the <a href="https://www.ncbi.nlm.nih.gov/pubmed/27017310">sub-clinical</a> stage of TB – that is, latently infected individuals on the brink of converting to active TB. Such signatures are evident in patients’ blood as early as 200 days before the onset of active TB. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Metabolite+changes+in+blood+predict+the+onset+of+tuberculosis">Metabolic biomarkers</a> associated with the pre-symptomatic stage of TB have also been identified. Again, these are detectable before the onset of the active disease.</p>
<p>However, the pipeline for biomarkers that can detect other forms of TB, among them the drug-resistant variety, is weak. More work remains to be done in this area.</p>
<h2>Investment needed</h2>
<p>Studies like these, and others, require <a href="https://www.ncbi.nlm.nih.gov/pubmed/27784885">increased investments</a> from a number of funders. These are crucial if scientists are to take their findings into the clinical trial stages and eventually develop tools that can be used in everyday TB diagnosis and treatment.</p>
<p>This is imperative if the world is to end TB.</p>
<p><em>Sephekana Samuel Mohapi, a Master’s student in the University of Cape Town’s Department of Pathology, contributed to this article.</em></p><img src="https://counter.theconversation.com/content/114103/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mohlopheni Jackson Marakalala receives funding from the Wellcome Trust, South African Medical Research Council and National Research Foundation. </span></em></p>The push to end TB requires significant investment into the research and development of new diagnostics and treatments.Mohlopheni Jackson Marakalala, Associate professor, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1008332018-07-31T13:31:11Z2018-07-31T13:31:11ZBongani Mayosi: South Africa’s giant of cardiology and a powerful mentor<figure><img src="https://images.theconversation.com/files/229976/original/file-20180731-136649-9sghil.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Professor Bongani Mayosi was a gifted researcher.</span> <span class="attribution"><span class="source">Michael Hammond/UCT</span></span></figcaption></figure><p><em>South Africa’s medical fraternity is mourning <a href="https://www.news24.com/SouthAfrica/News/family-devastated-by-death-of-professor-mayosi-who-struggled-with-depression-20180728">the death</a> of renowned academic and cardiologist Professor Bongani Mayosi. Mayosi, who was the Dean of the Faculty of Health Sciences at the University of Cape Town, was 51-years-old. He was a <a href="http://www.nrf.ac.za/content/professor-bongani-mayosi">National Research Foundation</a> A-rated scientist.</em></p>
<p><em>Mayosi’s family issued a statement after his death in which they described his <a href="https://www.sowetanlive.co.za/news/south-africa/2018-07-28-uct-health-dean-bongani-mayosi-took-his-own-life-says-devastated-family/">battle with depression</a> and called his death “a desperate decision to end his own life”. Tributes have poured in from many of his colleagues and former students: Mayosi was a committed mentor to many young medical students. Tolullah Oni, who previously worked with Mayosi at the University of Cape Town, spoke with Zolelwa Sifumba about Mayosi’s legacy as a mentor.</em></p>
<p><strong>Tell us a little bit about yourself and how you ended up meeting Professor Mayosi.</strong></p>
<p>My name is Dr Zolelwa Sifumba; I’m an intern working at Prince Mshiyeni Hospital in KwaZulu-Natal. I am originally from the Eastern Cape and completed my medical degree at the University of Cape Town (UCT) in 2017. </p>
<p>In my junior years at UCT medical school, as a young black person I was always so inspired by the black seniors and academics on campus. They always served as an encouragement that I could also reach the status of being a well-respected professional in the field of medicine. Professor Mayosi was top of that list.</p>
<p>I remember passing him in corridors with my friends and just staring, thinking, “Wow.” As I reached my senior years I started to understand and engage with <a href="https://www.researchgate.net/profile/Bongani_Mayosi">the research</a> he did and its relevance, his accomplishments and the difference his work was making; luckily I even managed to be on a few ward rounds and in cardiology tutorials with him. </p>
<p>We met properly in painful circumstances. In 2012 I <a href="http://www.tbproof.org/who-we-are/our-team/zolelwa-sifumba/">was diagnosed</a> with Multi Drug Resistant TB because I’d been exposed to it at work. The following year, I was <a href="http://blogs.msf.org/en/patients/authors/zolelwa-sifumba">struggling</a> with the treatment and its side effects. Professor Mayosi helped bridge the information gap between me and my family; they were far away at the time. He advised my parents that the insertion and use of a port to receive the injectable TB medication would be the best option to ensure my survival. </p>
<p>Later, he motivated for a much needed leave of absence from medical school. Honestly, that saved my life.</p>
<p>He managed to reassure my parents that taking time off to recover fully would not negatively affect my prospects of returning to complete my degree.</p>
<p><strong>How did he influence you as a medical student, and now as a medical intern?</strong></p>
<p>Through his example and great achievements, he taught me the importance of hard work and that even I could make a difference in the world.</p>
<p>In tutorials, he taught us not just the basics of cardiology but also to think critically when learning – not only to read but to try to understand. He taught us to also be human with patients. While watching him on ward rounds, he taught me a level of confidence, clinical knowledge and excellence to aspire to. </p>
<p><strong>I know that your experience has influenced your passion to work as an advocate for the health and well-being of health professionals. Can you speak to what lessons you’ll take from Professor Mayosi into this and other aspects of your work and life in future?</strong></p>
<p>Professor Mayosi encouraged the advocacy work I do around the health of health care professionals. We were also in conversation about how to increase awareness at medical school around issues of occupational exposure to TB. </p>
<p>I was especially looking forward to engaging with him on this, as I felt he understood my plight after having seen me suffer through TB; he would do all he could to ensure that I was able to assist our faculty in instituting a TB programme.</p>
<p>This support was not limited to his time as Dean. While he was Head of the Department of Medicine at Groote Schuur Hospital, he invited me to address senior management on matters regarding TB on campus, which was amazing for me. It showed that he not only understood my fight, but would fully support me. </p>
<p>After the meeting he gave me pointers to look at and tackle to reach the next level of seeing my dreams for the faculty becoming a reality, which was so encouraging. To have the Dean of a medical school who is an accomplished world renowned scientist agree with you, support you and allow you opportunities to make a difference was honestly incredible.</p>
<p>He showed me that my fight was relevant and that he supported it, which taught me to continue to fight and advocate for change.</p>
<p><strong>Clearly he was a powerful mentor. Why are good mentors so important in a field like medicine?</strong></p>
<p>The presence of good mentors serves as encouragement that it’s possible to reach heights you never knew existed. Their presence serves as a guide as to how to become what you want to become, also at times further stretching definitions of greatness. Their presence creates an environment that bolsters the strive for greatness within others. They serve to inspire, to educate, to show the way forward, to encourage, to work with, to lead and for us to follow.</p>
<p>Professor Mayosi was a great mentor to me. In losing him to mental illness, I am reminded that we are all human. This illness, which I and many others have suffered with, has nothing to do with being weak. It’s a part of the human condition for many of us and I pray that through this, many will begin to engage on the issue of mental well-being in health care workers.</p><img src="https://counter.theconversation.com/content/100833/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Tolullah Oni does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>South African Professor Bongani Mayosi was a great mentor to many. Losing him to mental illness is a reminder that we are all human.Tolullah Oni, Clinical Senior Research Associate, MRC Epidemiology Unit, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/781122017-06-01T14:01:51Z2017-06-01T14:01:51Z“Missing” TB cases are a huge problem. What Kenya needs to do to find them<figure><img src="https://images.theconversation.com/files/171321/original/file-20170529-25236-2a37ln.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Kenya needs to improve efforts to reach, treat and cure all TB patients.</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p><em>Tuberculosis (TB) is one of the <a href="http://www.who.int/mediacentre/factsheets/fs104/en/">top ten</a> causes of death worldwide. People with TB can infect up to <a href="https://www.cdc.gov/globalhivtb/who-we-are/resources/keyareafactsheets/finding-the-missing-4-million.pdf">10 to 15 </a> people annually if they are in close contact with them. Breaking the transmission cycle is key to fighting the disease. For that to happen diagnosis needs to be stepped up. The Conversation Africa’s Health Editor Joy Wanja Muraya spoke to Dr Jane Ong'ango on strategies to find the missing TB cases in Kenya.</em></p>
<p><strong>What is the burden of tuberculosis globally and in Kenya ?</strong></p>
<p>Great progress has been made to <a href="http://www.who.int/tb/en/">control and eliminate </a>TB. However it remains one of the top infectious diseases causing death. It disproportionately affects the <a href="http://www.who.int/bulletin/volumes/86/9/06-038737/en/">world’s poor</a> and is rated as one of the top 10 causes of death worldwide. In 2015 TB caused more deaths <a href="http://www.who.int/mediacentre/factsheets/fs310/en/">than HIV</a>. There were an estimated <a href="http://www.npr.org/sections/goatsandsoda/2015/10/28/452565249/tb-is-now-the-top-infectious-killer-even-though-deaths-are-down">10.4 million</a> cases across the world that year. </p>
<p>Global efforts to reduce illness and deaths from TB are part of the <a href="http://www.who.int/tb/End_TB_brochure.pdf?ua=1">sustainable development goals</a> and the World Health Organisation’s <a href="http://www.who.int/tb/post2015_strategy/en/">End TB Strategy</a>. The objectives of these two global efforts is to eliminate TB globally by <a href="https://sustainabledevelopment.un.org/?menu=1300">2030</a> through the reduction of TB deaths by 90% and the reduction of TB incidence by 80% compared with levels in 2015.</p>
<p>A tuberculosis prevalence <a href="http://nltp.co.ke/">survey</a> done in Kenya 2016 showed a prevalence rate of 558 tuberculosis cases per 100,000 population. This is double the 2015 WHO estimate of <a href="http://www.health.nsw.gov.au/Infectious/tuberculosis/Documents/countries-incidence.pdf">233</a> cases per 100,000 population. Tuberculosis is the <a href="http://hennet.or.ke/wp-content/uploads/2015/02/KENYA_HEALTH_POLICY_29-01-2014.pdf">fourth </a> biggest killer in Kenya after HIV/AIDS, maternal deaths and lower respiratory infections.</p>
<p>Based on the TB cases identified by the health system in 2015, the prevalence survey showed that every year about <a href="https://www.kma.co.ke/presentations/JaneRahediKMA%20meetingPP21042017jro.pdf">40%</a> of TB cases remain undetected in Kenya. This means that nearly half of the number of people with TB disease are undetected and not on treatment. They are considered as missing TB cases.</p>
<p><strong>Who constitutes the ‘missing’ TB cases?</strong></p>
<p>This is the gap between the estimated number of people who become ill with TB in a year and the number of people who were diagnosed and treated by the national TB programmes. </p>
<p>In 2015 the World Health Organisation estimated that there were about <a href="http://www.un.org/news/dh/pdf/english/2010/17052010.pdf">4.3</a> million people “missing across” the world. India, Indonesia and Nigeria accounting for almost half of them.</p>
<p>Finding the missing cases is critical to eliminating TB because they actively contribute to transmitting the disease to others.</p>
<p><strong>Where are the missing cases?</strong></p>
<p>A majority (<a href="http://nltp.co.ke">75%</a>) of individuals who have TB usually have TB related symptoms which could include any of the following; cough of any duration, night sweats, weight loss, fatigue, fever, and shortness of breath. Among these individuals the severity of the symptoms differ, despite this all should be screened for TB at the earliest possible time from when the symptoms develop. </p>
<p>In addition about a <a href="http://www.kma.co.ke/presentations/JaneRahediKMA%20meetingPP21042017jro.pdf">quarter</a> (25%) of individuals with TB do not have symptoms and will thus continue to spread the bacteria in the community. The missing TB cases may either have symptoms or not and could be found within three scenarios in the community which include;</p>
<ul>
<li>Individuals in the community with non severe symptoms, and therefore do not seek care.</li>
<li>Individuals at work, school, home or clinics are presumed not to have TB and hence not screened.</li>
<li>Individuals seek care for TB symptoms at health facilities, but do not get diagnosed.</li>
</ul>
<p><strong>What can we do to find the missing TB cases?</strong></p>
<p>There is need to provide<a href="https://www.standardmedia.co.ke/ureport/story/2000197762/i-suffered-out-of-ignorance-and-why-you-don-t-need-to"> public awareness</a> on Tuberculosis including having targeted messages for the vulnerable populations to encourage people to seek early intervention for any TB related symptom. </p>
<p>Health facilities should screen all persons with TB symptoms within their various departments to reduce possible chances of missing the cases. In addition to symptom screening there is need to expand use of Chest X-ray and avail GeneXpert as the first <a href="http://www.nation.co.ke/health/Advanced-diagnostic-tool-gives-hope-to-TB-patients/3476990-3876552-5t2bbjz/index.html">diagnostic</a> test for all presumed TB cases.</p><img src="https://counter.theconversation.com/content/78112/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jane Rahedi Ong'ang'o does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>About three million people globally are ‘missed’ each year for Tuberculosis diagnosis. Many of them will die, some will get better, others will continue to infect others.Jane Rahedi Ong'ang'o, Public Health Specialist, Senior Research Scientist, Kenya Medical Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/750102017-03-23T14:25:59Z2017-03-23T14:25:59ZLatest transmission patterns for drug resistant TB pose a new challenge<figure><img src="https://images.theconversation.com/files/162151/original/image-20170323-3535-3wutte.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The emergence of drug resistant tuberculosis has resulted in scientists taking a more aggressive and urgent approach to research into the development of the disease. </p>
<p>As the number of drug resistant TB cases has continued to rise, so has the need for rapid diagnosis, new treatment and new strategies that could help contain the disease. </p>
<p>Globally TB still kills <a href="https://www.newscientist.com/article/dn28405-tuberculosis-now-leading-cause-of-death-from-infectious-disease/">more people each year</a> than any other infectious disease, including HIV/AIDS. In 2014, an estimated <a href="http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf">1.4 million people</a> lost their lives to TB. In addition 500,000 people were diagnosed with multidrug-resistant tuberculosis (MDR-TB). </p>
<p>In South Africa, 20,000 MDR-TB cases were detected in 2014 though there were many more undetected cases. Of these 20,000 detected cases, 8% were thought to be extensively or totally drug resistant.</p>
<p>MDR-TB occurs when patients inappropriately or incorrectly use antimicrobial drugs or prematurely interrupt their treatment. Further resistance to the drugs used to treat MDR-TB results in extensively drug resistant TB (XDR-TB). When this happens the patient is resistant to at least four of the antibiotics that make up the first set of drugs used to treat TB, known as the first line regimen. </p>
<p>However, recent molecular and epidemiological <a href="http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30079-6/fulltext">studies</a> have challenged this belief. They suggest that in most regions of the world, drug-resistant TB is now predominantly caused by transmission. An estimated 95% of new MDR-TB strain cases are as a result of the drug resistant bacteria spreading from one person to the next.</p>
<p><a href="http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(17)30079-6/fulltext">New research</a> on the spread of MDR-TB has raised even more concerns. Until recently it was thought that drug-resistant strains of TB were less transmissible, that both MDR-TB and XDR-TB were only acquired by people as a result of poor compliance to treatment. </p>
<p>This means that the ease in which normal TB is commonly transmitted also applies to both MDR-TB and XDR-TB as well. This poses additional challenges to managing the disease.</p>
<h2>The challenge with transmission</h2>
<p>TB – under normal circumstances – is highly infectious. It’s commonly spread through the air from one person to another. The TB germs enter the air when a person with active TB coughs, sneezes or speaks. People nearby may breathe in these germs and become infected, and subsequently develop active disease.</p>
<p>At present, when patients with either XDR-TB or incurable TB who have failed treatment are discharged back into their communities, they pose a risk of infecting fellow community members. This inevitably increases the number of infections. </p>
<p>Patients are more likely to suffer psychologically, abandon treatment, and generally show very poor treatment outcomes as a result of being isolated in XDR-TB treatment hospitals, or at home, for a long period of time. Other <a href="https://www.pressreader.com/south-africa/citypress/20170226/281728384293476">studies</a> have shown that decentralising treatment may yield equivalent results to keeping them in hospital. </p>
<p>Taking into consideration both the patient’s well-being as well as that of the communities in which they live, means that public health specialists need to develop ingenious interventions that will be beneficial for all.</p>
<p>These strategies must include new detection and intervention technologies targeting transmission and voluntary long-term community based and palliative care facilities so that discharged patients can spend their last days with their families. </p>
<h2>Tackling the issue</h2>
<p>Although South Africa – which is often considered the TB capital of the world – has made some noticeable headway in managing TB – between 2000 and 2015, an estimated <a href="http://www.who.int/mediacentre/factsheets/fs104/en/">49 million lives</a> have been saved through TB diagnosis and treatment. But the rise of drug resistant TB threatens these significant gains. </p>
<p>Public health officials have found that despite drug-resistant TB comprising less than 5% of the total TB caseload in the country, it consumes around 40% of the total TB budget. And the very heart of the health system is further affected as TB continues to claim the lives of a large number of healthcare workers. </p>
<p>To tackle the problem, a dynamic change in discourse is needed. The focus must be on how to respond to the emerging complexities that TB presents.</p>
<p>Governments must also develop and roll out improved diagnostic technologies. This would result in governments actively finding cases, developing better drug dosing and administration strategies, and improving the healthcare system. They should also provide infection control solutions to healthcare workers, and make more effective treatment and newer drugs more widely available to the entire population. </p>
<p>This requires a multi-pronged approach that should include a reduction in poverty and overcrowding, and other drivers of TB like HIV and smoking. </p>
<p>Strategies that will develop new rapid diagnostic tools are just as important in the fight against the scourge of drug resistant TB. Although the government has made some efforts in containing the spread of drug-resistant-TB by means of rolling out new generation diagnostic technology, more needs to be done to develop and deploy more comprehensive diagnostic tools, and better TB drug development and education.</p><img src="https://counter.theconversation.com/content/75010/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Keertan Dheda receives funding from the South African Medical Research Council, the South African National Research Foundation, EDCTP, NIH and the Oppenheimer Foundation.</span></em></p>To tackle TB a dynamic change in discourse is needed. The focus must be on how to respond to emerging complexities the disease presents.Keertan Dheda, Head of the Division of Pulmonology, University of Cape TownLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/736092017-03-12T10:20:21Z2017-03-12T10:20:21ZWhy a test that tells when TB is cured is needed to help tackle resistance<figure><img src="https://images.theconversation.com/files/160322/original/image-20170310-3703-1clqol4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>-<em>Every day more than <a href="http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1">6 million people</a> across the world who have TB are subject to a standard treatment regime. This lasts at least six months. The medication must be taken diligently every day to prevent drug-resistance from developing. Shortening the treatment period has become a top priority within TB research. US and South African scientists are embarking on a clinical trial to try and find a solution. The Conversation Africa’s Health and Medicine Editor Candice Bailey asked Gerhard Walzl to explain the importance of the trial.</em></p>
<p><strong>What are the current challenges around TB treatment?</strong></p>
<p>In 2015 there were an estimated <a href="http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1">10.4 million new TB cases</a> worldwide. Six countries accounted for 60% of them: India, Indonesia, China, Nigeria, Pakistan and South Africa. </p>
<p>TB treatment is long and complicated to administer. It also has severe side effects. </p>
<p>To prevent the disease from reoccurring after treatment patients must take a combination of different antibiotics for at least six months. But the side effects linked to this antibiotic combination often include mild but annoying symptoms. In rarer cases the side effects can be severe and can include jaundice due to drug-induced liver disease. </p>
<p>The milder side effects include a general feeling of unwellness with nausea or loss of appetite, dizziness, skin rashes, sensations like pins and needles in the limbs or around the mouth, or flu-like symptoms. This often leads people, particularly in the later stages of the treatment period, to stop taking the medication. The problem is that this can result in multi-drug-resistant TB (MDR-TB) developing. </p>
<p>In 2015 there were an estimated <a href="http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1">480 000 new cases of multidrug-resistant TB</a> (MDR-TB). </p>
<p>To treat drug-resistant TB can take up to two years – and is even more complex, expensive and toxic. There’s also a staggering cost attached to this treatment, which poses a significant challenge to governments, health systems and other payers. </p>
<p>In addition many patients are unable to even access treatment. Among those who do receive treatment for MDR TB, only 50% survive.</p>
<p><strong>Can this lengthy process be shortened?</strong></p>
<p>Shortening of standard treatment has become a top priority within TB research. </p>
<p>According to the studies, 95% of TB patients are cured with six-month courses while only 80% to 85% of patients are cured with shorter courses. </p>
<p>What this means is that most patients are cured after four months. The challenge is that scientists are unable to tell beforehand which patients belong to which group.</p>
<p>If it were possible to identify the patients who only require four-month therapy we would be able to reduce treatment duration in the vast majority of patients. </p>
<p><strong>How have scientists tried to reduce treatment time and why has it not worked? How can this be changed?</strong></p>
<p><a href="http://www.sciencedirect.com/science/article/pii/000709718190022X">Previous</a> <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1407426">studies</a> into the viability of shortening treatments to four months have been unsuccessful. New drugs were used in <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1314210#t=article">four-month treatment regimens</a> in the hope that they could replace the longer treatments. But the rates at which the infection recurred were unacceptably high. Our hypothesis is that not all patients are suitable for shortened treatment regimens, regardless of the effectiveness of the new drugs and that a more individualised approach might be required.</p>
<p>Over the next five years the Predict-TB consortium, which includes five TB research groups in Cape Town, five in China and three institutions in Europe will address the problem. </p>
<p>The project will develop a smart set of treatment stopping criteria that are based on special lung scans (PET/CT imaging) as well as a point-of-care device which can measure the immunological markers that contribute to the decision on whether or not to stop treatment. These are proteins in the blood, whose levels are affected by inflammation and their levels will be measured by strip tests, similar to finger stick tests used to measure blood sugar levels. </p>
<p>These parameters will answer two key questions: is it possible to identify patients who are cured during a shorter treatment duration, and what combination of parameters can best identify these patients?</p>
<p><strong>If treatment could be shortened, what would that mean for the treatment of TB?</strong></p>
<p>This new method –if successful -– could be a true game changer. It will advance treatment standards from the current practice of “one size fits all” to precision-guided individualised therapy. This will allow for shortened treatment in a significant proportion of drug sensitive TB patients.</p>
<p>The benefits would extend beyond patients, who would receive treatment for shorter periods and with better completion rates. Reducing the TB burden will also have an effect on the economic situation in many developing countries and less drug resistance will benefit public health on a global scale.</p><img src="https://counter.theconversation.com/content/73609/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gerhard Walzl works for Stellenbosch University. He receives funding from the Bill and Melinda Gates Foundation, the EDCTP, the NIH, the South African National Research Foundation and the Medical Research Foundation. He contributes to the National TB Think Tank. </span></em></p>Shortening the treatment period has become a top priority within TB research but studies to date have been unsuccessful.Gerhard Walzl, Head of the Immunology Research Group at the Division of Molecular Biology & Human Genetics, Department of Biomedical Sciences, Faculty of Medicine & Health Sciences, Stellenbosch UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/631312016-10-10T17:39:36Z2016-10-10T17:39:36ZFresh effort in quest to find a drug that cracks resistant TB<figure><img src="https://images.theconversation.com/files/140910/original/image-20161007-21430-1nmm9yf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Reuters/Mike Hutchings</span></span></figcaption></figure><p>A significant amount of tuberculosis research in recent years has been focused on combating the bacterial lung disease by treating it with drugs that are used to treat other diseases and conditions. There is still no cure and more drugs are urgently needed to meet the acute demand of the disease. </p>
<p>The problem has been exacerbated by the discovery of drug-resistant tuberculosis in 2006. It is now an escalating global threat. Each year more than 9 million people are infected with TB and another 1.5 million die. At least 4% of people diagnosed for the first time and up to 20% of those treated for the disease have “<a href="http://www.who.int/tb/challenges/mdr/MDR_TB_FactSheet.pdf">multiple-drug-resistant TB</a>”. About 9.7% of these also have “<a href="http://www.tbfacts.org/xdr/#sthash.k20TRGTx.dpuf">extensively-drug-resistant TB</a>”.</p>
<p>Most TB treatments target bacteria that actively grow in the body. Four major classes of strong antibiotics are used: isoniazid, rifampin, fluoroquinolones, and aminoglycosides. But for patients who do not respond to these key treatments the outlook is grim. </p>
<p>New drugs are being developed but they need to go through rigorous and lengthy safety, efficacy and compatibility tests. This affects how fast they come onto the market.</p>
<p>Re-purposing antibiotics or combining commercially available products which are not earmarked for TB with the current and new anti-TB regimens could, however, solve this problem. </p>
<p><a href="http://www.nejm.org/doi/full/10.1056/NEJMc1513236">Our study</a> found that if re-purposed antibiotics were administered in the first 14 days of treatment they had the same effect as both established TB drugs and new drugs. Our study focused on the first 14 days of treatment because in that period it is still safe to give only one drug and to be able to measure its effect. </p>
<p>If these re-purposed antibiotics prove effective beyond the first two weeks, they could be added to the much needed arsenal of drugs to fight the deadly disease. </p>
<h2>Understanding antibiotics</h2>
<p>Various classes of antibiotics have a spectrum of micro-organisms that they can kill. </p>
<p>In the last two decades of TB research, researchers have investigated the viability of various antibiotics which were not originally meant to treat TB. <a href="http://www.webmd.com/brain/news/20130826/fda-strengthens-fluoroquinolone-warning">Fluoroquinolones</a> are a good example. They are a class of antibiotics that are administered to treat urinary tract infections. <a href="http://www.atsjournals.org/doi/full/10.1164/rccm.201308-1446ED#.V_eHouB97IU">Studies</a> have shown that some fluoroquinolones work well for TB if they are taken over several months.</p>
<p>But some antiobiotics, such as those derived from pencillin such as beta-lactams, have been shown to be ineffective. Two clinical trials have been done – one in 1997 and 2001 – with a commonly used antibiotic called amoxcillin/clavulanic acid and also known as amoxiclav or augmentine. One took place in the <a href="http://www.jstor.org/stable/4481488?seq=1#page_scan_tab_contents">US and Turkey</a> and the other in <a href="http://www.tandfonline.com/doi/abs/10.1080/00365540152029954">South Africa</a>. Both found that the bacteria that causes TB overpowered the beta-lactams. </p>
<p>But we retested more beta-lactams in the laboratory. Our results show that more modern beta-lactams could perhaps overcome the TB bacteria’s defences.</p>
<h2>The tests</h2>
<p><a href="task.org.za">Our laboratory</a> does clinical trials to find better TB treatments. For this particular study we wanted to establish whether a new beta-lactam, which is commercially available and safe, could be used for TB treatment.</p>
<p>We randomly allocated two groups of 15 patients who had TB with either a combination of re-purposed antibiotics or existing TB treatments. We limited the trial to 14 days. We tested three beta-lactams: one, meropenem, we administered intravenously, and two we administered orally, amoxicillin–clavulanic acid and faropenem. The sputum samples of patients was analysed.</p>
<p>We <a href="http://www.nejm.org/doi/full/10.1056/NEJMc1513236">found</a> that when combined two specific beta-lactams – meropenem and amoxicillin–clavulanic acid – were able to break through the bacteria’s defence. As a combination, meropenem, which is commonly used for severe infections, combined with amoxicillin/clavulanic acid was as active over the first 14 days of treatment as the established drugs (rifampicin and pyrazinamide) and the novel drugs (bedaquiline and delamanid). </p>
<p>Intravenous meropenem treatment was as active as the most successful drugs on the market for TB treatment. The more practical oral treatment (faropenem) was not active because not enough of the drug was taken up into the body. But both treatments were well tolerated. </p>
<h2>Next steps</h2>
<p>Our study only looked at the effectiveness of the two drugs in the first two weeks of treatment. </p>
<p>The effectiveness of the antibiotics do not guarantee a relapse-free cure for TB. Longer trials are now needed to determine how beta-lactams can contribute to the treatment of TB. </p>
<p>But based on these results, an intensive search for an orally active beta-lactam for TB treatment has begun. The next oral beta-lactam test will be done in 2017 and the results should be available towards the end of that year. Once a drug has been found that can be taken orally and has the same effect as the treatment given intravenously larger studies in combination with other drugs will follow. It might nevertheless be several years before beta-lactams become part of standard treatment.</p><img src="https://counter.theconversation.com/content/63131/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andreas Henri Deacon received a grant from the European and Developing Countries Clinical Trials Partnership.</span></em></p>Antibiotics that were not originally earmarked to treat TB have shown the first signs of effectiveness and could be added to the much-needed arsenal of drugs to fight the deadly disease.Andreas Henri Diacon, Scientist with the Division of Molecular Biology and Human Genetics and Director of TASK Applied Science, Stellenbosch UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/583432016-05-15T14:17:54Z2016-05-15T14:17:54ZAfrican scientists make headway in grasping persistent TB bacteria<figure><img src="https://images.theconversation.com/files/122143/original/image-20160511-18165-1f3bukt.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>The arrival of drug-resistant tuberculosis has significantly complicated global efforts to decrease the scourge of the disease. </p>
<p>Each year more than nine million people are infected with TB and another 1.5 million die. But the latest figures show that at least 20% of people diagnosed with the disease have “multiple-drug-resistant” TB. And <a href="http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf?ua=1">about 9.7%</a> of these also have “extensively-drug-resistant TB”. </p>
<p>TB is caused by bacteria that attacks the lungs. Most TB treatments target bacteria that actively grow in the body. But a very important subset of bacteria is able to survive treatment. These are known as persistent bacteria. </p>
<p>Though these persistent bacteria only represent a very small proportion of the bacteria that causes TB, failing to get rid of them can have devastating consequences. They are responsible for lengthy drug treatment, and could contribute to drug resistance. They therefore should also be the target of TB therapies. </p>
<p>The challenge with these persistent bacteria is that they are very difficult to isolate. This makes it difficult to study them and therefore difficult to develop drugs to kill them.</p>
<p>As a team of scientists at Stellenbosch University in South Africa, together with colleagues at Imperial College London, we found a new way to identify, isolate and target persistent bacteria. <a href="http://mic.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.000288#tab2">Our technique</a>, which has never before been applied in TB research, will help scientists understand why some bacteria respond to treatment and others become resistant.</p>
<h2>How this bacteria works</h2>
<p>Persistent bacteria plays a particularly important role in latent TB – when bacteria that can cause TB hibernate in the body. Someone with latent TB will not have any clinical symptoms and will therefore not know that he or she has the disease. Latent TB can survive in the body for decades and only flare up when someone’s immune system is compromised. </p>
<p>Latent TB can therefore progress to full-blown disease in people who have compromised immune systems. These are often people who have HIV/AIDS, suffer from malnutrition, are ageing or have a substance-abuse problem. About one-third of the world’s population carries latent TB. </p>
<p>Conventional thinking has held that persistent bacteria are also present in people who have latent TB. These bacteria are thought to either stop growing or are slowly growing, although they still survive in the body. </p>
<p>But <a href="http://www.cell.com/trends/microbiology/abstract/S0966-842X(14)00070-5?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0966842X14000705%3Fshowall%3Dtrue">emerging research</a> has started to question this assumption on two fronts: </p>
<ul>
<li><p>Some research shows that proportions of the bacteria continue to grow while others die.</p></li>
<li><p>Other research argues that the bacteria do not grow.</p></li>
</ul>
<p>Understanding the bacteria present in latent TB is important to choose the best TB treatments. This is especially important because of the difficulties associated with treating persistent bacteria that can survive treatment.</p>
<p>For this reason <a href="http://mic.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.000288#tab2">our research</a> is focused on finding ways to study and target persistent bacteria. We used specific bacteria-associated labels and sophisticated laser-based methods to identify and isolate this bacteria. </p>
<h2>A new method to study persistent bacteria</h2>
<p>The technique, known as fluorescence dilution, uses two fluorescent proteins to label the bacteria. One protein tracks live bacteria and the other measures its growth. It is applied to identify and isolate individual bacteria to study it. </p>
<p>The technique can best be described as using “micro-tweezers” to physically pick out the slow-growing bacteria from the rest. This enables us to find the hard-to-identify persistent bacteria. </p>
<p>We were able to do this by applying the same approach that’s been used to isolate the bacteria that causes food poisoning, Salmonella. This involves subjecting the bacteria to conditions that come closest to those found in the body as opposed to conditions in the laboratory.</p>
<p>Using this technique, we found that when bacteria entered a specific type of white blood cell, a population of non- or slowly-growing persistent bacteria appeared. White blood cells play a critical role in defending the body against invading bacteria. In the laboratory we use them to mimic the environment found in the body.</p>
<p>This finding is important because it shows that the numbers of persistent bacteria increase by being inside white blood cells. This means that the host’s own defences can help the bacteria to survive TB treatment.</p>
<h2>Hope for the future</h2>
<p>These are only the first steps, but this technique offers unique opportunities to deepen scientists’ understanding of why and how the body’s response to TB treatment results in drug resistance.</p>
<p>We can now, for example, begin to study what drives bacteria into a latent state. Once we understand this better it will be possible to begin designing drugs that better manage latent TB. Importantly, this could help decrease the amount of time it takes to treat TB as well as minimise drug resistance.</p><img src="https://counter.theconversation.com/content/58343/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jomien Mouton receives funding from the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa that was awarded to Samantha Sampson, award number UID 86539 and the NRF Scarce Skills Postdoctoral fellowship, award number 96831. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NRF.</span></em></p><p class="fine-print"><em><span>Samantha Sampson receives funding from the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa, award number UID 86539. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NRF.</span></em></p>South African scientists have found a way to single out the problematic parts of the bacteria causing TB that results in drug resistance.Jomien Mouton, Postdoctoral research fellow in the MRC Centre for Tuberculosis Research, Stellenbosch UniversitySamantha Sampson, Associate Professor, SARChI Research Chair in Mycobactomics, Stellenbosch UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/566952016-03-23T04:04:16Z2016-03-23T04:04:16ZThe fight against TB shifts to fixing the immune system, not only bacteria<figure><img src="https://images.theconversation.com/files/116045/original/image-20160322-32320-bavjy6.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A pair of lungs infected with TB. </span> <span class="attribution"><span class="source">shutterstock</span></span></figcaption></figure><p>Tuberculosis (TB) has managed to remain a major global health problem, despite 100 years of research and more than 50 years of treatment being available. It still claims up to 1.5 million lives each year.</p>
<p>Although there have been ongoing efforts that provide some hope in the fight against the disease, the TB drug pipeline remains thin and vaccine development slow as resistance grows. </p>
<p>More than 9.6 million new TB cases were recorded in 2014. This prompted the Stop TB Partnership and the World Health Assembly to set a target of reducing TB-related deaths by 95% and cases by 90% by <a href="http://stm.sciencemag.org/content/7/276/276fs8.full">2035</a>. But new therapeutic and diagnostic interventions – including an effective vaccine – are urgently needed if these goals are to be achieved. </p>
<p>Recently there has been an increasing focus on alternative treatment strategies known as <a href="https://www.ncbi.nlm.nih.gov/pubmed/26184493">host-directed therapies</a>. These are mostly drugs and therapies that have been developed to treat other diseases and conditions such as diabetes or inflammation and then re-purposed to tackle TB.</p>
<p>What makes these therapies unique and important is that after 60 years of targeting the bacteria that kills TB, these treatments open a new door in the fight against infection. They focus on fixing the body rather than the bacteria. </p>
<p>If successful, these alternative treatments will add huge value by addressing the clinical demands around treating TB. </p>
<h2>Alternative approaches</h2>
<p>Host-directed therapies work differently from TB drug treatments. TB treatment drugs target the bacteria that causes TB. Host-directed therapies focus on areas in the lung that encourage the TB infection. They have two major goals: </p>
<ul>
<li><p>to improve the state of the immune system, which must be intact to fight off TB; and</p></li>
<li><p>to limit lung tissue destruction.</p></li>
</ul>
<p>Limiting tissue destruction is important because it prevents the disease from progressing. Tissue destruction can be the result of an overwhelming inflammation that destroys important cells in the immune system where the infection occurs. This may lead to cavities forming in the lung. The bacteria that causes TB is then able to disseminate throughout the lung and is coughed out through the airway. </p>
<p>A number of host-directed therapies currently being investigated could potentially be used for <a href="https://www.ncbi.nlm.nih.gov/pubmed/26184493">adjunctive TB therapy</a>. These include:</p>
<ul>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/21998409">vitamin D</a>, which induces specific immune molecules that have protective effects against the TB bacteria;</p></li>
<li><p>the diabetes drug, <a href="https://www.ncbi.nlm.nih.gov/pubmed/25411472">metformin</a>, which has been shown to enhance the body’s immune responses and decrease the TB bacterial loads in the lung;</p></li>
<li><p>non-steroidal <a href="https://www.ncbi.nlm.nih.gov/pubmed/25986592">anti-inflammatory drugs</a> that limit inflammation and tissue pathology. Inflammation leads to lung damage and progression of the disease; and</p></li>
<li><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/24133190">statins</a> that reduce cholesterol levels and limit bacterial growth in the body’s immune cells. Cholesterol is known to encourage the growth of bacteria. </p></li>
</ul>
<p>When these therapies are used in combination with standard treatment regimens that target the bacteria, they are likely to shorten the current course of treatment. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/1mRTm6qPu1c?wmode=transparent&start=110" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Mohlopheni Marakalala speaks about host directed therapies at the Next Einstein Forum.</span></figcaption>
</figure>
<h2>Why we need alternatives</h2>
<p>There are several challenges that affect TB eradication. </p>
<p>First, the TB burden has been aggravated by HIV co-infection. HIV compromises the immune response required to protect a person against TB. This increases vulnerability to the disease. The World Health Organisation’s most recent <a href="http://www.who.int/tb/publications/global_report/gtbr2015_executive_summary.pdf">global TB report</a> shows that of the TB-related deaths in 2014, just under 27% of patients were HIV-positive. This is a slight increase <a href="http://apps.who.int/iris/bitstream/10665/91355/1/9789241564656_eng.pdf">from 2012</a>.</p>
<p>A second challenge is drug resistance. </p>
<p>First-line drug regimens have saved millions of lives but have been marred by non compliance and inconsistent use. TB patients who fail to adhere to their drug regimens often develop drug resistant TB. This means they have to go onto second-line drugs which are more expensive and may take even longer to complete.</p>
<p>Further resistance to second-line drugs leads to extensively drug-resistant TB (XDR-TB). This is more difficult to treat. </p>
<p>Drug resistance has led to a number of patients not responding to current treatment protocols, which is why there is a dire need for more treatment options.</p>
<p>The third challenge is that there is no adequate vaccine for adults.</p>
<p>The only approved TB vaccine, Bacille Calmette-Guérin, introduced 95 years ago, reduces the risk of TB in children. But it does not help adults with lung TB. An efficacious vaccine that provides a reliable protection against pulmonary TB is essential to eradicate TB. </p>
<p>In the past ten years, there has been some progress in developing a vaccine. A new candidate, <a href="https://www.ncbi.nlm.nih.gov/pubmed/23391465">MVA85A</a>, reached a phase 2b clinical trial. </p>
<p>Although MVA85A failed the clinical end point trial due to limited efficacy, several lessons were gained from the study. These will be highly beneficial in guiding future vaccine development efforts. </p>
<p>Currently over a dozen preventive vaccine candidates are progressing through the <a href="https://www.ncbi.nlm.nih.gov/pubmed/21798463">development pipeline</a>, providing some hope in achieving the 2035 targets.</p>
<h2>Other interventions that could help</h2>
<p>There are several other areas that need to be looked at to help eradicate TB. </p>
<p>First, the rapid diagnostic tools that can detect latent TB, drug-susceptible TB and drug-resistant TB need to be improved to detect the disease earlier. </p>
<p>Second, patients that do not respond to current treatments due to drug resistance do not have any other alternatives. A new strategy is needed here. </p>
<p>Finally, combination therapy hasn’t been cracked. This would shorten treatment protocols, thus improving adherence.</p><img src="https://counter.theconversation.com/content/56695/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mohlopheni Marakalala has previously received funding from the South African National Research Foundation and the Medical Research Council. </span></em></p>There is an increasing focus on alternative treatment strategies, developed to treat other diseases and conditions but re-purposed to tackle TB.Mohlopheni Jackson Marakalala, Senior Lecturer and Group Leader in the Division of Immunology, University of Cape TownLicensed as Creative Commons – attribution, no derivatives.