Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and Conditions General InterestTags :

Interview: “The Only Good TB Bacillus is a Dead One”, Says UCT’s Prof Valerie Mizrahi

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By Biénne Huisman for Spotlight

Professor Valerie Mizrahi, a world-leading tuberculosis researcher and director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, is retiring at the end of the year. PHOTO: Nasief Manie/Spotlight

World-leading tuberculosis researcher Professor Valerie Mizrahi was 35 when her mother Etty started losing weight and coughing furiously. After healthcare professionals in Johannesburg failed to accurately diagnose her, it was a doctor in Plettenberg Bay who told Etty: “The good news is you don’t have lung cancer, the bad news is that you have tuberculosis (TB).”

At the time, Mizrahi’s two infant daughters – aged one and three years old – had been spending much time with their granny. And so Mizrahi found herself crushing TB prevention tablets into her children’s porridge with honey.

Etty was treated at the then-Rietfontein Hospital, the precursor to Sizwe Tropical Diseases Hospital in Johannesburg. “My mom got very ill,” recalls Mizrahi. “She almost died of TB. And then 10 years later, she had to have a lobe from one of her lungs removed because she was one of those unfortunate people who got post-TB fibrosis.”

This was the early 1990s. Mizrahi was then with the South African Institute for Medical Research (SAIMR) linked to the University of the Witwatersrand, where she established the Molecular Biology Unit. She had identified TB as a lurking problem in South Africa, particularly in mines and in hospitals, calling it “a worthy foe ripe with opportunity for scientific investigation” – a problem she felt not enough people were talking about. It had been a pivotal moment when TB entered her own home, one that she says galvanised her thinking.

“It was a dramatic eye-opener for me as a basic scientist,” she says. “It was traumatic because of the time it happened in my career. Our family suddenly being thrust into the world of TB control. We had all these questions like we didn’t know where my mum got it, was her TB drug-susceptible, and why it would take so long to find this out. I got to see first-hand how difficult it was to get answers…”

Born in 1958 to Etty and Morris in Harare, Zimbabwe, Mizrahi studied at the University of Cape Town (UCT), forging an unusual career path, veering from mathematics and chemistry to biochemistry, genetics, and microbiology. In a male-dominated field, she became one of the first in South Africa to interrogate TB at a basic science level – that is to say, research aimed at advancing our understanding of the basic science of how TB bacteria survive, replicate, and resist attempts to kill it.

‘the only good TB bacillus is a dead one’

Discussing TB, Mizrahi’s passion is effervescent, her every second sentence punctuated with “okay”. These underscore her statements – subtle pauses allowing for her preceding words to sink in.

Source: CC0

…there’s a reason why TB has persisted for so long. The bacillus is pretty hard to kill. It’s built like Fort Knox.

Prof Valerie Mizrahi

A particular interest for Mizrahi is developing antibiotics “that can kill this bacterium stone cold dead”.

“To me, the only good TB bacillus is a dead one,” she says. “But there’s a reason why TB has persisted for so long. The bacillus is pretty hard to kill. It’s built like Fort Knox. So it’s a monumental challenge. We don’t know where all the bacteria are residing. We know that TB in an infected lung is sitting in really difficult places, hard places for drugs to get to. This notion of going after the bacillus with drugs and just slamming it is a tough problem. Not insurmountable, but there’s a lot of research that needs to be done.”

TB can be cured, but treatment typically takes at least six months and involves taking at least four different antibiotics, with side effects ranging from minor to serious. In addition to research on new antibiotics, there are also several experimental TB vaccines currently in late-phase studies. The only TB vaccine we have was developed more than a century ago and only has some moderate efficacy in kids.

The IDM

Since 2011 Mizrahi has served as director of the Institute of Infectious Disease and Molecular Medicine (IDM) – the University of Cape Town’s (UCT) largest cross-faculty research unit with over 800 affiliated staff and grants running into hundreds of millions of rands.

Mizrahi’s glass-encased office looks directly onto Table Mountain and hospital bend – where, at the time of our interview, N2 traffic out of Cape Town is already at a standstill. Behind her desk, Mizrahi quips. “Yes, this is the most beautiful office at UCT, everyone agrees…” Below, students can be seen milling about on the health sciences campus.

Last year in its Best Global Universities 2022-2023 survey, online portal US News ranked UCT as 24th best university in the world for studying infectious diseases. Mizrahi is ambivalent about the IDM taking credit for this accolade. She notes that this success is founded on problems of a “confounding and overwhelming” scope, with many diseases being proxies for poverty and inequality in South Africa.

The IDM’s focus includes TB, HIV/AIDS, COVID-19, other infectious diseases like sexually transmitted infections, and non-communicable diseases such as preventable cancers, cardiovascular, and psychiatric disorders.

Reflecting on the IDM, she says they have accrued a “research ecosystem – a concentration of expertise, something resembling critical mass” – bringing together specialists across the basic, clinical, and public health sciences, in one place.

“We’ve got Groote Schuur Hospital across the road,” she says. “We have geneticists and biochemists, virologists, and immunologists. There’s a clinician across the corridor from me, bioinformaticians, and microscopists downstairs. If you are the kind of researcher who revels in asking questions and finding people who can answer them, then this is the place for you.”

Going forward, multi-disciplinary research is what excites her. “HIV and TB have been so dominant in the narrative of this country. But now when you look at the figures and the data, we are dealing with a huge burden of non-communicable disease on top of infectious diseases,” she says. “The key question moving forward is how not to think in silos.”

Polymaths and dilettantes

This, she says, takes humility.

“To do this, one has to be very humble. You need to know what you don’t know. People who work really well in interdisciplinary spaces are those who understand the limits of their own specialist knowledge, and the need to listen to where another person is coming from.”

She distinguishes between polymaths and dilettantes. “You have to be careful not to be a dilettante, who knows a little about a lot. Research can be very superficial in that way. So I have my antenna out all the time to distinguish between polymaths, who really are people who know a lot about a lot, and dilettantes who know a little about a lot. And well, in this institute we have a lot of polymaths, brilliant researchers who move across disciplines, very interesting people to work with.”

With a string of awards and an A1-rating from South Africa’s National Research Foundation, earlier this year, Mizrahi was elected a fellow of the Royal Society, the United Kingdom’s National Academy of Sciences. However, she recalls humbling moments along the way – like the time she flew to London seven months pregnant with her second child, for her first-ever interview with the Wellcome Trust committee to secure funding. “I was so confident, but I was ill-prepared,” she says. “They savaged me! I tried to frame it not as a failure but as a learning experience.”

Passing the baton

At the end of this year, Mizrahi will pass on the baton when she retires. Of her achievements, she is proudest of young scholars she has helped to shape. “Their legacies will last much longer than a few more citations of a publication,” she says.

Mizrahi notes more and more women leaders in her field. For example, recently, while delivering a talk at the Weizmann Institute in Israel, she noticed chemist and Nobel laureate Ada Yonath in the room. “Talk about a role model; I was almost in tears.”

Studying at UCT, Mizrahi’s own mentors had mostly been men – something she didn’t even notice, she says, as male professors treated her no different. What did cut her was racial segregation at the time, prompting a political awakening and stints leaving South Africa to work in the United States. First as a postdoctoral fellow at Pennsylvania State University and then at drug company, SmithKline & French in Philadelphia.

Her own background makes her sensitive to marginalised groups, she says. Her grandparents were Sephardi Jews who fled Rhodes Island, today part of Greece, ten years before World War II, to find refuge in Zimbabwe.

Having just read former UCT vice-chancellor Max Price’s book Statues and Storms: Leading a University Through Change, she says, “It took me back to some very difficult times. It’s harrowing and brave and made me realise that even though I was here in the midst of it [#feesmustfall and #rhodesmustfall protests], a senior person of the university, how little I really knew of what was going on. It really is a lesson in crisis leadership.”

 There’s no control experiment to life, you can’t go back and redo it.

Mizrahi lives in Sea Point with her one daughter. Her other daughter is based in Vancouver. Here, she likes to park her car at the end of the week, walking around – “either listening to a New York Times podcast or a beautiful piece of music and that’s when I think.”

She describes herself as an introvert who needs personal time to stay sane. She is deeply thoughtful about her roots, wondering about a sense of belonging. “As white people in Africa, I think this is part of the reckoning we go through. I truly identify as being African. Arriving at Johannesburg, just breathing in the air, it feels like home.”

Looking back, Mizrahi notes her mother as a major influence in her life. “Not a highly educated woman. But the wisest, smartest person I know.” Etty still lives in Johannesburg while Morris has passed away. To this day, Etty thinks of herself as a proud TB survivor, says Mizrahi.

On her retirement, the scholar says, “Now it’s about opening up opportunities for others, writing a few papers, and contributing to the TB drug discovery space.”

“I’ve done the best I can,” she says, “I don’t believe in having regrets…  There’s no control experiment to life, you can’t go back and redo it. But I don’t know that I could have done it any differently.”

Republished from Spotlight under a Creative Commons Licence.

Source: Spotlight

Categories : Diseases, Syndromes and Conditions PaediatricsTags :

Strong Results from Methotrexate Trial for Severe Atopic Dermatitis in Kids

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Atopic dermatitis in a young patient. Source: NIH

Positive results from a clinical trial comparing the safety and efficacy of ciclosporin with methotrexate in children and adolescents with severe dermatitis will likely change treatment paradigms for this debilitating skin condition, its researchers have said. The trial, published in the British Journal of Dermatology, also examined whether the severity of the disease changed or returned after treatment ended.

For children and young people with atopic dermatitis, the most common skin condition in children, the main first line conventional systemic treatments are methotrexate and ciclosporin, two immuno-modulatory drugs.

There have been no adequately powered randomised clinical trial evidence for safety and treatment success for paediatric patients with this condition, and with new therapies being introduced at a high cost, establishing a gold standard for treatment with the conventional systemic therapies like methotrexate and ciclosporin is needed.

The trial, led by King’s College London, assessed 103 children with severe atopic dermatitis age 2–16 years across 13 centres in the UK and Ireland. The patients were given oral doses of methotrexate or ciclosporin and assessed over nine months of treatment and six months after the therapy ended.

The study found that ciclosporin works faster and reduces disease severity more at 12 weeks but was more expensive, whereas methotrexate was significantly cheaper and led to better objective disease control after 12 weeks and off therapy, with fewer participant-reported flares of atopic dermatitis after treatment had stopped. There were also no concerning safety signals.

Based on the TREAT trial findings, methotrexate is a useful and safe treatment in paediatric patients with severe atopic dermatitis and a good alternative to ciclosporin, especially in settings where health care resources are limited.

Professor Carsten Flohr, Chair in Dermatology and Population Health Sciences at King’s College London, and consultant dermatologist at St John’s institute of dermatology, Guy’s and St Thomas’ NHS Foundation Trust, said:

“This is the largest paediatric trial using conventional immuno-modulatory treatments in severe atopic dermatitis and was conducted across 13 centres in the UK and Ireland and is likely to change our treatment paradigm around this condition, not just for patients in the UK but also internationally.”

Source: King’s College London

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Prescribed Oestrogen and Factor V Leiden Mutation More than Double Blood Clot Risk

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Source: Wikimedia CC0

New research from Queen Mary University of London, published in iScience, shows an increased risk of blood clots in women who have any combination of Factor V Leiden gene mutation, oestrogen use, or common medical conditions – specifically: obesity, high blood pressure, high cholesterol, and kidney disease.

Women with the Factor V Leiden (FVL) gene mutation who had been prescribed oestrogen had more than double the risk of blood clotting compared to women who did not have this mutation. And almost 20% of the women who carry FVL, were prescribed oestrogen and had two medical conditions suffered a blood clot. The presence of the FVL gene made a substantial difference to risk, with only around 5% of women taking oestrogen and having two conditions suffering a clotting event.

The study also found that a woman with obesity, hypertension, high cholesterol, and kidney disease (not uncommon in a clinical setting) had an 8 times greater chance of blood clotting compared to a woman with none of these conditions. This amounted to roughly one in every six women with the four conditions in the study suffering a blood clot. Three medical conditions meant a five times greater chance of blood clotting, and two medical conditions meant a two times greater chance.

One in three women who had the FVL gene mutation and three of the medical conditions examined also suffered a blood clotting event.

The researchers examined the health data of 20 048 British-Bangladeshi and British-Pakistani women from the Genes & Health project, a large community-based genetics study. While oestrogen use, FVL, and common medical conditions are all known risk factors of blood clots, studies have not looked at the combined risk of these factors together on blood clot prevalence.

Women are commonly prescribed oestrogen, both through oral contraception containing the hormone and as part of post-menopausal hormone replacement therapy.

Professor Sir Mark Caulfield, from Queen Mary University of London, said: “Our study gives a more complete picture of blood clotting in Bangladeshi and Pakistani communities who have previously been underrepresented in research.

“Genetic testing of the FVL gene mutation could give a clearer sense of someone’s personalised risk of this potentially fatal complication if they were prescribed oestrogen.”

Source: Queen Mary University London

Categories : Diseases, Syndromes and Conditions HospitalsTags :

The Greater Clostridioides Difficile Threat may Come from Within

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Clostridioides difficile. Credit: CDC

Despite strenuous control efforts, hospital-acquired infections still occur – the most common of which is caused by the bacterium Clostridioides difficile, which creates lingering spores and resists alcohol-based hand sanitisers. Surprising findings from a new study in Nature Medicine suggest that the burden of C. diff infection may be less a matter of hospital transmission and more a result of characteristics associated with the patients themselves.

The study team, led by Evan Snitkin, PhD; Vincent Young, MD, PhD; and Mary Hayden, MD, leveraged ongoing epidemiological studies focused on hospital-acquired infections that enabled them to analyse daily faecal samples from every patient within the intensive care unit at Rush University Medical Center over a nine-month period.

Arianna Miles-Jay, a postdoctoral fellow in Dr Snitkin’s lab, analysed 1141 eligible patients, and found that a little over 9% were colonised with C. diff. Using whole genome sequencing at U-M of 425 C. difficile strains isolated from nearly 4000 faecal specimens, she compared the strains to each other to analyse spread. But she found that, based on the genomics, there was very little transmission.

Essentially, there was very little evidence that the strains of C. diff from one patient to the next were the same, which would imply in-hospital acquisition. In fact, there were only six genomically supported transmissions over the study period. Instead, people who were already colonised were at greater risk of transitioning to infection.

“Something happened to these patients that we still don’t understand to trigger the transition from C. diff hanging out in the gut to the organism causing diarrhoea and the other complications resulting from infection,” said Snitkin.

Hayden notes this doesn’t mean hospital infection prevention measures are not needed. In fact, the measures in place in the Rush ICU at the time of the study – high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms were likely responsible for the low transmission rate. The current study highlights, though that more steps are needed to identify patients who are colonised and try to prevent infection in them.

Where did the C. diff come from? “They are sort of all around us,” said Young. “C. diff creates spores, which are quite resistant to environmental stresses including exposure to oxygen and dehydration…for example, they are impervious to alcohol-based hand sanitiser.”

However, only about 5% of the population outside of a healthcare setting has C. diff in their gut – where it typically causes no issues.

“We need to figure out ways to prevent patients from developing an infection when we give them tube feedings, antibiotics, proton pump inhibitors – all things which predispose people to getting an actual infection with C. diff that causes damage to the intestines or worse,” said Young.

The team next hopes to build on work on AI prediction for patients at risk of C. diff infection to identify patients more likely to be colonised and who could benefit from more focused intervention.

Said Snitkin, “A lot of resources are put into gaining further improvements in preventing the spread of infections, when there is increasing support to redirect some of these resources to optimise the use of antibiotics and identify other triggers that lead patients harbouring C. diff and other healthcare pathogens to develop serious infections.”

Source: Michigan Medicine – University of Michigan

Categories : Diseases, Syndromes and ConditionsTags :

An Antibacterial for Livestock may be a Magic Bullet for Acne

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Photo by cottonbro studio

In a study published in the journal Nanoscale, researchers encased Narasin, a new antibacterial compound, in tiny, soft nanoparticles 1000 times smaller than a single strand of human hair and applied in a gel form to targeted acne sites. The University of South Australia (UniSA)-led research team found that the drug proved successful against drug-resistant acne bacteria and delivered via nanocarriers achieved a 100-fold increase in absorption than simply taken with water.

Lead author UniSA PhD student Fatima Abid says this is the first time that nano-micelle formulations of Narasin have been developed and trialled.

“Acne severely impacts approximately 9.4% of the world’s population, mainly adolescents, and causes distress, embarrassment, anxiety, low self-confidence and social isolation among sufferers,” Abid says.

“Although there are many oral medications prescribed for acne, they have a range of detrimental side effects, and many are poorly water soluble, which is why most patients and clinicians prefer topical treatments.”

Abid’s supervisor, pharmaceutical scientist Professor Sanjay Garg, says a combination of increasing antibiotic resistance and the ineffectiveness of many topical drugs to penetrate hair follicles in acne sites means there is a pressing need to develop new antibacterial therapies that are effective and safe.

Narasin is commonly used for bacterial infections in livestock but has never been previously investigated as a viable treatment for acne.

Abid, Prof Garg and researchers from UniSA, the University of Adelaide, and Aix-Marseille Université in France also investigated how well Narasin encased in nanoparticles penetrated various layers of skin, using pig’s ear skin as a model.

“The micelle formulation was effective in delivering Narasin to acne targets sites, as opposed to the compound solution which failed to permeate through skin layers,” Prof Garg says.

Source: University of South Australia

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Plant Compound could Prove to be a Potent Tool against Candida

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Photo by CDC on Unsplash

A new study published in the journal ACS Infectious Diseases has found that a natural compound found in many plants inhibits the growth of drug-resistant Candida fungi – including its most virulent species, Candida auris, an emerging global health threat.

Led by Emory University researchers, the study used in vitro experiments that showed that the natural compound, a water-soluble tannin known as PGG, blocks 90% of the growth in four different species of Candida fungi. The researchers also discovered the mechanism by which PGG inhibits the growth: It grabs up iron molecules, essentially starving the fungi of an essential nutrient.

By starving the fungi rather than attacking it, the PGG mechanism does not promote the development of further drug resistance, unlike existing antifungal medications. In vitro testing also showed minimal toxicity of PGG to human cells.

“Drug-resistant fungal infections are a growing healthcare problem but there are few new antifungals in the drug-development pipeline,” says Cassandra Quave, senior author of the study and assistant professor at Emory University. “Our findings open a new potential approach to deal with these infections, including those caused by deadly Candida auris.”

C. auris is often multidrug-resistant and has a high mortality rate, leading the Centers for Disease Control and Prevention (CDC) to label it a serious global health threat.

“It’s a really bad bug,” says Lewis Marquez, first author of the study and a graduate student in Emory’s molecular systems and pharmacology programme. “Between 30 to 60% of the people who get infected with C. auris end up dying.”

An emerging threat

Some species of Candida, a yeast commonly found on the skin or in the digestive tract, can cause infection, which can be invasive and life-threatening. Immunocompromised people, including many hospital patients, are most at risk for invasive Candida infections, which are rapidly evolving drug resistance.

In 2007, the new Candida species, C. auris, emerged in a hospital patient in Japan. Since then, C. auris has caused health care-associated outbreaks in more than a dozen countries around the world with more than 3000 clinical cases reported in the United States alone.

A ‘natural’ approach to drug discovery

Quave is an ethnobotanist, studying how traditional people have used plants for medicine to search for promising new candidates for modern-day drugs. Her lab curates the Quave Natural Product Library, which contains 2500 botanical and fungal natural products extracted from 750 species collected at sites around the world.

“We’re not taking a random approach to identify potential new antimicrobials,” Quave says. “Focusing on plants used in traditional medicines allows us to hone in quickly on bioactive molecules.”

Previously, the Quave lab had found that the berries of the Brazilian peppertree, a plant used by traditional healers in the Amazon for centuries to treat skin infections and some other ailments, contains a flavone-rich compound that disarms drug-resistant staph bacteria. They had also found that the leaves of the Brazilian peppertree contain PGG, a compound that has shown antibacterial, anticancer and antiviral activities in previous research.

A 2020 study by the Quave lab, for instance, found that PGG inhibited growth of Carbapenem-resistant Acinetobacter baumannii, a bacterium that infects humans and is categorised as one of five urgent threats by the CDC.

The Brazilian peppertree is a member of the poison ivy family. “PGG has popped up repeatedly in our laboratory screens of plant compounds from members of this plant family,” Quave says. “It makes sense that these plants, which thrive in really wet environments, would contain molecules to fight a range of pathogens.”

Experimental results

The Quave lab decided to test whether PGG would show antifungal activity against Candida.

In vitro experiments demonstrated that PGG blocked around 90% of the growth in 12 strains from four species of Candida: C. albicans, multidrug-resistant C. auris and two other multidrug-resistant non-albicans Candida species.

PGG is a large molecule known for its iron-binding properties. The researchers tested the role of this characteristic in the antifungal activity.

“Each PGG molecule can bind up to five iron molecules,” Marquez explains. “When we added more iron to a dish, beyond the sequestering capacity of the PGG molecules, the fungi once again grew normally.”

Dish experiments also showed that PGG was well-tolerated by human kidney, liver and epithelial cells.

“Iron in human cells is generally not free iron,” Marquez says. “It is usually bound to a protein or is sequestered inside enzymes.”

A potential topical treatment

Previous animal studies on PGG have found that the molecule is metabolised quickly and removed from the body. Instead of an internal therapy, the researchers are investigating its potential efficacy as a topical antifungal.

“If a Candida infection breaks out on the skin of a patient where a catheter or other medical instrument is implanted, a topical antifungal might prevent the infection from spreading and entering into the body,” Marquez says.

The researchers will bext test PGG as a topical treatment for fungal skin infections in mice.

Meanwhile, Quave and Marquez have applied for a provisional patent for the use of PGG for the mitigation of fungal infections.

“These are still early days in the research, but another idea that we’re interested in pursuing is the potential use of PGG as a broad-spectrum microbial,” Quave says. “Many infections from acute injuries, such as battlefield wounds, tend to be polymicrobial so PGG could perhaps make a useful topical treatment in these cases.”

Source: Emory University

Categories : Diseases, Syndromes and ConditionsTags :

RSV Easier to Inactivate than Many Other Viruses

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Photo by Andrea Piacquadio on Unsplash

Every year, respiratory syncytial viruses (RSV) cause countless respiratory infections worldwide. For infants, young children and people with pre-existing conditions, the virus can be life-threatening and so clinicians are always on the look-out for ways to reduce infections. New research published in the Journal of Hospital Infection shows that, when used correctly, alcohol-based hand sanitisers and commercially available surface disinfectants provide good protection against transmission of the virus via surfaces.

Some viruses are known to remain infectious for a long time on surfaces. To determine this period for RSV, the Ruhr-University Bochum virology team examined how long the virus persists on stainless steel plates at room temperature. “Even though the amount of infectious virus decreased over time, we still detected infectious viral particles after seven days,” says Dr Toni Luise Meister. “In hospitals and medical practices in particular, it is therefore essential to disinfect surfaces on a regular basis.” Five surface disinfectants containing alcohol, aldehyde and hydrogen peroxide were tested and found to effectively inactivate the virus on surfaces.

RSV is easier to inactivate than some other viruses

Hand sanitisers recommended by the WHO also showed the desired effect. “An alcohol content of 30 percent was sufficient: we no longer detected any infectious virus after hand disinfection,” said Toni Luise Meister. RSV is thus easier to render harmless than some other viruses, such as mpox (formerly monkeypox) virus or hepatitis B virus.

Still, most infections with RSV are transmitted from one person to another, via airborne droplets. The risk of contracting the virus from an infected person decreases if that person rinses their mouth for 30 seconds with a commercial mouthwash. The lab tests showed that three mouthwashes for adults and three of four mouthwashes designed specifically for children reduced the amount of virus in the sample to below detectable levels.

“If we assume that these results from the lab can be transferred to everyday life, we are not at the mercy of seasonal flu and common cold, but can actively prevent infection,” concludes Toni Luise Meister. “In addition to disinfection, people should wash their hands regularly, maintain a proper sneezing and coughing etiquette, and keep their distance from others when they’re experiencing any symptoms.”

Source: Ruhr-University Bochum

Categories : Diseases, Syndromes and ConditionsTags :

Opinion: A UN Meeting on TB is at Best a Means to More Important Ends

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Tuberculosis bacteria. Credit: CDC

By Marcus Low for Sporlight

In 2018 the first findings from a landmark tuberculosis (TB) vaccine trial were published in the New England Journal of Medicine. The experimental vaccine, called M72, was found to be roughly 50% effective in preventing pulmonary TB disease. It was the most promising finding for a new TB vaccine since the development of the BCG vaccine a century ago.

Since the study reported in the NEJM was only a phase 2B study, the results have to be confirmed in a phase 3 study before the vaccine can be considered for wider use. For a while, it seemed that the phase 3 study would never happen – that is, until a few months ago, two philanthropies, Wellcome and the Bill and Melinda Gates Foundation, announced that they would put up $550 million to get it done.

Meanwhile, on September 22, ministers, heads of state, and other officials from around the world will gather in New York for the second United Nations High-Level Meeting on TB. A draft declaration can be read here. The declaration is full of the kind of lofty rhetoric one would expect.

Yet, it is hard to avoid a sense that, for the most part, the emperor is wearing no clothes. After all, as one government representative after another read their speeches in New York, everyone in the room will know that it was not governments but two philanthropies who stepped up to ensure that arguably the most important TB trial of the decade goes ahead. When most needed, the groundswell of new government investment in TB research just wasn’t there.

The bigger picture

It is estimated that globally just over $1 billion was invested in TB research in 2021. In the preceding three years, the figure was hovering between $900 million and $1 billion. Astonishingly, $416 million (over 40%) of the $1 billion in 2021 was from the United States government. The second largest funder of TB research in the world is the Gates Foundation – which with its $113 million in 2021 invested more in TB research than any government except for the US. Together, these two entities account for more than half of all investment in TB research in 2021.

BRICS partners India and South Africa respectively invested $23.4 and $4.8 million in TB research in 2021. Both are classified as high TB burden countries.

At the 2018 UN High-Level Meeting on TB world leaders committed to provide $2 billion per year for TB research by the end of 2022. Figures for 2022 aren’t out yet, but given that the 2021 figure was only half the target, we are clearly not on track.

In addition, the target should probably be much higher if we are to have a good chance of getting the breakthrough diagnostics, treatments, and vaccines we will need to end TB. The Stop TB Partnership recently estimated that around $5 billion is needed for TB research per year from 2023 to 2030 – in other words, five times as much as the actual investment in 2021. This level of investment in TB research is needed because modelling suggests that with the currently available tools, we will at best see a relatively slow decline in TB rates in the coming years.

Why then a High-Level Meeting?

One may well ask what the point is of UN High-Level Meetings if key commitments made at these meetings are not kept and if the further development of critical new tools like M72 remains dependent on support from philanthropists. But that would be to mistake these meetings for an end in themselves rather than merely a means to an end.

A meeting of this nature will always just be one small part of a larger puzzle in the fight against TB. The bigger question is how the momentum and political potential created by the High-Level Meeting can be leveraged to get more done in other arenas, especially back in people’s home countries.

Governments are accountable to the people who elected them. There are, of course, some international pressures and some issues of international law, but on something like TB, the most important accountability levers are all domestic. Ultimately, political parties, trade unions, and domestic civil society have much more power over what a government actually does or does not do than some politely expressed peer pressure in New York or Geneva.

Unfortunately, at least here in South Africa, political parties and trade unions have generally failed to hold government to account when it comes to TB – although our Department of Health has nevertheless made some good policy calls and our investment in TB research is decent given the size of our economy.

All of this is not to say that the UN High-Level Meeting on TB is not important – it most certainly is. It is just that it should not be mistaken for an end in itself. Governments, and especially those in countries where many people get TB and die of TB, must invest more in TB. We shouldn’t let leaders of these governments get away with saying they’ll put up the money in New York, but then forgetting all about it once they go back home.

NOTE: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation. Spotlight is editorially independent, an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.

Republished from GroundUp under a Creative Commons Licence.

Source: Spotlight

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Multidrug-resistant Hypervirulent K. Pneumoniae Still Vulnerable to Immune Defences

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A human neutrophil interacting with Klebsiella pneumoniae (pink), a multidrug–resistant bacterium that causes severe hospital infections. Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

New “hypervirulent” strains of the bacterium Klebsiella pneumoniae have emerged in healthy people in community settings, prompting researchers to investigate how the human immune system defends against infection by it. After exposing the strains to components of the human immune system in vitro, they found that some strains were more likely to survive in blood and serum than others, and that neutrophils are more likely to ingest and kill some strains than others. The study, published in mBio, was led by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

“This important study is among the first to investigate interaction of these emergent Klebsiella pneumoniae strains with components of human host defence,” Acting NIAID Director Hugh Auchincloss, MD, said. “The work reflects the strength of NIAID’s Intramural Research Program. Having stable research teams with established collaborations allows investigators to draw on prior work and quickly inform peers about new, highly relevant public health topics.”

K. pneumoniae was identified over a hundred years ago as a cause of serious, often fatal, human infections, mostly in already ill or immunocompromised patients and especially if hospitalised. Over decades, some strains developed resistance to multiple antibiotics. Often called classical Klebsiella pneumoniae (cKp), this bacterium ranks as the third most common pathogen isolated from hospital bloodstream infections. Certain other Klebsiella pneumoniae strains cause severe infections in healthy people in community settings (outside of hospitals) even though they are not multidrug-resistant. They are known as hypervirulent Klebsiella pneumoniae, or hvKp. More recently, strains with both multidrug resistance and hypervirulence characteristics, so-called MDR hvKp, have emerged in both settings.

NIAID scientists have studied this general phenomenon before. In the early 2000s they observed and investigated virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) bacteria that had emerged in US community settings and caused widespread infections in otherwise healthy people.

Now, the same NIAID research group at Rocky Mountain Laboratories in Hamilton, Montana, is investigating similar questions about the new Klebsiella strains, such as whether the microbes can evade human immune system defenses. Their findings were unexpected: the hvKp strains were more likely to survive in blood and serum than MDR hvKp strains. And neutrophils had ingested less than 5% of the hvKp strains, but more than 67% of the MDR hvKp strains – most of which were killed.

The researchers also developed an antibody serum specifically designed to help neutrophils ingest and kill two selected hvKp and two selected MDR hvKp strains. The antiserum worked, though not uniformly in the hvKp strains. These findings suggest that a vaccine approach for prevention/treatment of infections is feasible.

Based on the findings, the researchers suggest that the potential severity of infection caused by MDR hvKp likely falls in between the classical and hypervirulent forms. The work also suggests that the widely used classification of K. pneumoniae into cKp or hvKp should be reconsidered.

The researchers also are exploring why MDR hvKp are more susceptible to human immune defences than hvKp: Is this due to a change in surface structure caused by genetic mutation? Or perhaps because combining components of hypervirulence and antibiotic resistance reduces the bacterium’s ability to replicate and survive in a competitive environment.

As a next step, the research team will use mouse models to determine the factors involved in MDR hvKp susceptibility to immune defences. Ultimately, this knowledge could inform treatment strategies to prevent or decrease disease severity.

Source: NIH/National Institute of Allergy and Infectious Diseases

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An ‘Epidemic’ of Sepsis in Southern Sweden

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Photo by Camilo Jimenez on Unsplash

A research team in Sweden has found that more than 4% of all hospital admissions in southern Sweden, also known as Skåne, are associated with sepsis. The results, published in JAMA Network Open, suggest that is a significantly under-diagnosed condition that can be likened to an epidemic.

In 2016, the researchers conducted an initial study where they revealed that sepsis is much more common than previously believed. The incidence turned out to be 750 adults per 100 000 individuals. In the latest study in the same region, the results showed that more than 4% of all hospitalisations involved the patient suffering from sepsis, and 20% of all sepsis patients died within three months.

“This makes sepsis as common as cancer with similar negative long-term consequences, and as deadly as an acute myocardial infarction. Among sepsis survivors, three-quarters also experience long-term complications such as heart attacks, kidney problems, and cognitive difficulties,” says Adam Linder, sepsis researcher and associate professor at the Departmentof infection medicine at Lund University, as well as a senior physician at Skåne University Hospital.

The European Sepsis Alliance has assigned the researchers with assessing how common sepsis is in the rest of Europe. Given the differing healthcare systems across countries, it wasn’t immediately clear how they should proceed to obtain accurate figures. Consequently, the researchers conducted a pilot study southern Sweden to determine if their methods were applicable to other European hospitals.

“Doctors classify patients using diagnostic codes. Since sepsis is a secondary diagnosis resulting from an infection, the condition is significantly underdiagnosed, as the primary disease often dictates the diagnostic code. This makes it challenging to find a way to accurately determine the number of sepsis cases,” says Lisa Mellhammar, sepsis researcher at Lund University and assistant senior physician at Skåne University Hospital.

The research showed that 7500 patients in southern Sweden were associated with sepsis in 2019, and the incidence increased to 6% during the COVID pandemic. However, even in the absence of COVID, the researchers believe that sepsis should be viewed as an epidemic.

The aim is to use the publication to influence the EU to establish a common surveillance system for sepsis. The team are in contact with authorities and researchers from around thirty European countries and hope that the research project can secure sufficient funding to start soon. There is no indication that the number of sepsis cases would be lower in other parts of Europe than in Sweden. In Swedish hospitals, only two percent of all sepsis patients are antibiotic-resistant, and the researchers speculate that the proportion of resistant cases is higher in many other European countries.

“Although sepsis care has improved in recent years, we need to enhance our diagnostic methods to identify patients earlier and develop alternative treatment methods beyond antibiotics to avoid resistance. Increasing awareness about sepsis among the public and decision-makers is crucial to ensure that resources are allocated appropriately,” concludes Adam Linder.

Source: Lund University