Antibiotic overuse is a key driver in the rise of antimicrobial resistance (AMR), a major global health crisis. Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) and Duke-NUS Medical School have provided compelling evidence that short-course antibiotic treatments can be a game-changer in tackling ventilator-associated pneumonia (VAP), a serious infection common in critically ill patients.
The findings from the landmark REGARD-VAP trial, published in Lancet Respiratory Medicine, and the accompanying economic analyses published in Lancet Global Health, highlight how prudent antibiotic use can curb resistance, effectively safeguarding patients as well as combatting the global threat of antimicrobial resistance while reducing healthcare costs.
Led by the NUS Medicine research team, the clinical trial examined over 450 patients across intensive care units (ICUs) in Singapore, Thailand, and Nepal. Results revealed that short-course antibiotics. carefully tailored to individual patients’ recovery, are just as effective as traditional longer treatments in preventing death and recurrence of pneumonia. “By shortening the duration of antibiotics, we can reduce the risks of side effects and resistance without compromising patient outcomes,” added Dr Mo Yin, Junior Academic Fellow at the Department of Medicine, NUS Medicine, and principal investigator of the clinical trial, and co-author of the economic analysis.
The economic analyses accompanying the trial were just published in the prestigious journal Lancet Global Health. They demonstrated that adopting short-course antibiotics offers significant value for healthcare systems. In Singapore, the strategy is cost-saving, reducing hospital expenditure while maintaining excellent outcomes for patients. In Thailand and Nepal, short-course antibiotics were highly cost-effective, with health gains outweighing the modest additional costs incurred. “Short-course antibiotics are a pragmatic solution that benefits patients and healthcare systems alike, particularly in resource-limited settings,” said Assistant Professor Yiying Cai, lead researcher from the Health Services and Systems Research Programme at Duke-NUS.
The REGARD-VAP study’s findings have practical implications for hospitals worldwide. Short-course antibiotics can streamline treatment in ICUs, where managing infections efficiently is vital. The approach is effective across high-income (Singapore), middle-income (Thailand), and low-income (Nepal) settings, making it a scalable solution for diverse healthcare systems. These results provide robust evidence including cost-effectiveness data for policymakers to adopt short-course antibiotics into national and institutional guidelines.
The team hopes to disseminate their findings globally to encourage the adoption of short-course antibiotics, particularly in regions with limited resources. They also advocate for integrating cost-effectiveness studies into future clinical trials to strengthen both clinical and economic decision-making processes. By reducing unnecessary antibiotic exposure, short-course treatments help preserve the effectiveness of existing drugs for future generations. Every additional day of antibiotic use increases the risk of drug resistance by 7%. Reducing treatment duration is a critical step in combating this silent epidemic. “Prudent antibiotic use is essential to combat antimicrobial resistance and optimise healthcare outcomes. Our findings make a strong case for adopting short-course antibiotics as the new standard of care,” concluded Dr Mo Yin.
Health campaigners have slammed a decision by the Competition Commission to end its investigation into Vertex Pharmaceuticals’ monopoly on life-saving medicines for people living with cystic fibrosis.
“We are concerned that the Commission has fallen victim to Vertex’s well-known and aggressive PR and legal strategy, designed to safeguard its global patent monopoly at all costs,” said a statement by nine organisations: the South African Cystic Fibrosis Association, Right to Breathe Campaign, Health Justice Initiative, Vertex Save Us, Just Treatment, SECTION27, Treatment Action Campaign, People’s Health Movement and Cancer Alliance.
The Commission, in a statement released on 11 December, said it had initiated the probe against Vertex based on allegations that it was engaging in exclusionary practices and excessive pricing in the provision of Kalydeco, Orkambi, Symdeko and Trikafta – medicines used to treat cystic fibrosis.
“Following the Commission’s investigation and various engagements with Vertex, Vertex gave formal undertakings to the Commission to continue to make Trikafta available in South Africa through Section 21 of the Medicines and Related Substances Act, which enables the sale of unregistered drugs within South Africa,” it said.
This undertaking, it said, had resulted in a “non referral” of all allegations against the company.
It said that Trikafta had broadly replaced the use of the other medicines. Previously patients with cystic fibrosis had to import it. To reduce the financial burden, Vertex had from April this year begun supplying it through a local distributor.
“This makes Trikafta available locally at prices that enable cystic fibrosis patients to access treatment. Separately, financial assistance is available through a patient assistance programme managed by a non-government organisation, and eligible cystic fibrosis patients who belong to certain medical schemes get Trikafta at no cost as they also receive some financial assistance from their medical aid schemes.”
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But health campaigners are not happy They say for the vast majority of cystic fibrosis patients (about 63%), nothing has changed.
“The real victims of this decision by the Commission are the most vulnerable South African children and young people who rely on the public health sector, who are not rich, and who have little or no medical scheme cover,” they said.
“These patients do not currently, and will not get access to this medication because of Vertex’s patents and secretive, limited access and excessive pricing strategies.”
Alarmingly, they said, the medicine remains unregistered in South Africa, forcing patients to either import it or rely on the “administratively burdensome” section 21 approval process.
“This is not a sustainable way to address a chronic treatment need,” they said.
The so-called patient assistance programme did not promote equity, was far from transparent, nor sustainable and the price was undisclosed.
They said they were seeking an urgent meeting with the Commission
“We cannot allow the manipulation of South Africa’s laws, regulations and health system to go unchecked in the name of one drug company’s self-interested monopoly greed.”
Vertex replies
Approached for comment, Vetex said more than 180 cystic fibrosis patients were accessing the medicine through the Section 21 pathway “which represents about 50% of the eligible population”.
“We took this pathway because we strongly believe that this is the fastest and most efficient route to sustainable access in South Africa, given that it does not require a regulatory filing, which can take many years.”
The company said even with regulatory approval, most novel, high value medicines were not included on the Prescribed Minimum Benefits list.
“There is therefore no obligation for funders [private and public health insurances] to reimburse the costs of these medicines, which effectively make them inaccessible to most patients. In our opinion, a license application would not speed up the process for broad access to our cystic fibrosis medicines.”
It said its triple combination therapy was currently funded by eleven healthcare providers, who cover most cystic fibrosis patients in the private sector in the country.
“We are continuing discussions with other health insurers and are in parallel exploring potential sustainable access opportunities in the public sector, which has been historically challenging for rare disease medicines in South Africa.”
It said “exact pricing” and details of its partnerships remained confidential.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
Multidrug-resistant tuberculosis (MDR-TB) poses a particular threat to global health. A study led by the Swiss Tropical and Public Health Institute (Swiss TPH) shows that resistance to the new MDR-TB treatment regimen recently recommended by the World Health Organization is already spreading between patients. The findings, published in NEJM, highlight the urgent need for better surveillance and infection control to counteract the rise in antimicrobial resistance.
The traditional treatment regimen for MDR-TB is lengthy, expensive, and comes with severe adverse event. In 2022, the World Health Organization (WHO) endorsed a new 6-month regimen, the BPaL(M), based on evidence of its improved safety and efficacy from numerous clinical studies, including TB-PRACTECAL.
Monitoring the implementation of a new treatment regimen
“While this new regimen is a game changer for patients suffering from MDR-TB, we knew that it will be difficult to outsmart Mycobacterium tuberculosis, the bacteria causing TB,” said Sébastien Gagneux, Head of the Department Medical Parasitology and Infection Biology at Swiss TPH and senior author of the study. “It was therefore crucial to study how the TB bacteria would react to the global roll-out of this new regimen.”
This new study led by Swiss TPH in collaboration with the National Centre for Tuberculosis and Lung Diseases in Tbilisi, Georgia, now examined in detail whether resistance to the drugs in the new regimen has already emerged since its introduction, and whether this resistance is transmitting between patients.
Over a quarter of resistant strains result from transmission between patients
The researchers analysed the genomes of close to 90 000 M. tuberculosis strains from Georgia and many other countries around the world. They identified a total of 514 strains that were resistant to TB drugs, including both the old and the new treatment regimens. These highly drug-resistant strains were found in 27 countries across four continents.
Alarmingly, 28% of these strains were transmitted directly from one patient to another. “We already had anecdotal evidence of resistance emerging to the new regimen, but we did not know to what extent transmission was responsible for the spread of these highly drug-resistant strains,” said Galo A. Goig, postdoctoral collaborator at Swiss TPH and first author of the study.
“The good news is that the total number of these cases is still low. However, the fact that more than a quarter of these highly drug-resistant cases are due to patient-to-patient transmission, only two years after WHO endorsed the new regimen, is worrying,” added Goig.
Call for better surveillance and infection control
These findings have important implications for public health policy and interventions. “These new drugs have taken many years to develop, and to prevent drug resistance from emerging, it is essential to combine the deployment of these new regimens with robust diagnostics and surveillance systems,” said Chloé Loiseau, postdoctoral collaborator at Swiss TPH and co-author of the paper.
The authors emphasise the need for improved diagnostic tools, better infection control and robust surveillance systems to curb the spread of these highly drug-resistant strains, and to safeguard the efficacy of the new treatment regimen.
Tackling antimicrobial resistance
While there are already new TB drugs in the pipeline, experts worry that M. tuberculosis will continue to find ways to evade new drugs. “The example of these highly drug-resistant TB strains further illustrates that antimicrobial resistance is one of the most critical threats to global health today,” said Gagneux. “We must stay ahead in this constant race between drug development and bacterial resistance, and take proactive steps to prevent a ‘post-antibiotic era’ for TB and other diseases.”
Though several South African companies are producing HIV and TB medicines, the active ingredients that go into these medicines are usually imported from India or China. Now, a local company is planning to break new ground by making the active ingredients for two important TB medicines in Pretoria. We zoom in on the company’s efforts and outline some of the obstacles to getting such local production off the ground.
South Africa has a relatively robust pharmaceutical sector. Approximately 60% of the medicines sold in South Africa are locally produced, according to Dr Senelisiwe Ntsele, writing in an opinion piece for the Department of Trade, Industry and Competition (dtic).
But most of the time we are not producing these medicines from scratch. In fact, like most countries in the world, we mostly import the ingredients that make the medicines work – commonly referred to as active pharmaceutical ingredients, or APIs. In addition to APIs, medicines contain other inactive substances that maintain their form and structure and assist in their delivery: such as binders, stabilisers, and disintegrants.
Around 98% of the APIs used in locally formulated medicines are imported and South Africa spends around R15 billion a year importing APIs, according to Ntsele.
Government has tried to address South Africa’s dependence on imported APIs as part of its broader strategy to bolster the local pharmaceutical industry, which is identified as a priority sector for investment in the country’s Industrial Policy Action Plan. Several government departments provide support to the local pharmaceutical sector, including for local establishment of API manufacturing capacity. These departments include the dtic, the Department of Science and Innovation (DSI), the Technology Innovation Agency (TIA), and the Industrial Development Corporation (IDC) – South Africa’s development finance instrument.
In a bid to reduce the country’s reliance on imported APIs, Ketlaphela – a state-owned API manufacturing company – was announced in 2012. The plan was that Ketlaphela would produce APIs used in HIV medicines, but after multiple setbacks the initiative never got off the ground. Spotlight reported on the history of Ketlaphela in more detail here.
Turning to the private sector
Less well known than Ketlaphela, are government’s efforts to support API manufacturing capacity in the private sector. One private company that has received such government support and seem set to start delivering is Pretoria-based Chemical Process Technologies Pharma (CPT Pharma) that was established in 2014.
CPT Pharma is a subsidiary of Chemical Process Technologies, a company with many years of experience in chemical manufacturing and synthesis, including manufacturing of APIs for animal medicines. Human medicines, CPT Pharma’s core business, have stricter production management and quality control standards than those for animal medicines.
Dr Hannes Malan, Managing Director of CPT Pharma, told Spotlight that the company has 14 APIs in its pipeline, with a strong focus on TB medicines.
CCPT Pharma is a subsidiary of Chemical Process Technologies. (Photo: Supplied)
In 2023, the company secured a license from USAID to produce API for rifapentine, a drug widely used for TB prevention, and in 2022 they secured a licence from the Medicines Patent Pool to produce API for molnupiravir, a treatment for COVID-19. Malan pointed out that these two licenses were agreed with organisations aiming to expand the presence of API manufacturers in Africa – unlike typical arrangements driven by pharmaceutical companies looking to secure their own supply chains.
“For all the other APIs that we’re working on [beyond molnupiravir and rifapentine], we’re either working on technical packs [technical information about the API] that were available in the public domain or technologies that we’ve developed ourselves,” said Malan.
“Our approach has always been to look at the molecules, look at the market value, look at the technology, and then see if there’s an opportunity for us to develop technology that allows us to produce these compounds cost competitively,” he said.
“We really believe that to be competitive and independent, you have to have your own technology. Doing a technology transfer from Big Pharma does not make you independent,” Malan added.
How to fund it all?
In 2017, the company completed a pilot plant for making APIs. Then in 2020 it received approval from the South African Health Products Regulatory Authority (SAHPRA) to produce APIs for human use. The plant was built for R50 million, funded jointly by the IDC, TIA, and CPT Pharma.
Malan said that that the IDC and TIA also supported trial runs to test CPT Pharma’s manufacturing processes and technology. These tests included several APIs in development, such as isoniazid, a drug commonly used to prevent and treat TB.
The company has also secured funding from several international donors. The Gates Foundation provided support to develop manufacturing technology for the anti-malarial drug amodiaquine, as well as tuberculosis medicines bedaquiline and pretomanid. GIZ, a German development agency involved in a European Union project to boost vaccine and health product production in Africa, supported the company’s work on molnupiravir and dolutegravir – a widely used HIV medicine. USAID and the DSI are supporting the company’s work on developing rifapentine API manufacturing capacity.
Most of this financial support has been in the form of grants.
Still building new plants
While CPT Pharma has secured local and international funding to help construct a pilot plant and to develop its API manufacturing technology and processes, Malan said more investment is needed to support the construction of two commercial-scale manufacturing facilities: an isoniazid API manufacturing plant and a multiple API manufacturing facility.
Construction of the isoniazid manufacturing plant has already commenced using existing land and infrastructure with support from the IDC, but it is short of around R20 million to complete it, said Malan.
Although the plant is not yet operational, he said a company has already expressed interest in buying CPT Pharma’s locally produced isoniazid API. This company, said Malan, is contracted to supply isoniazid to government. The plan is to initially supply the company with isoniazid API produced at its pilot plant
Malan said the commercial plant, when built, will be able to manufacture enough isoniazid API to supply around 60% of local demand.
Things are less far down the road with plans for a plant to produce multiple different APIs at commercial scale, and more work is needed to understand the financing requirements for this type of facility, said Malan. “We want to do a bankable study and a concept design for such a plant,” he said. Based on CPT Pharma’s own experience, published data, and the required complexity and capacity of the plant, Malan said it is estimated that construction for the multi-API plant will cost around US$100 million or R1.8 billion.
Plans to commercialise
Meanwhile, the company is moving forward with plans to commercialise isoniazid and rifapentine API from its pilot plant. Isoniazid and rifapentine is increasingly used together as TB preventive therapy.
“For rifapentine, our pilot plant is seen as the commercial plant,” said Malan. “At this stage, we can use the pilot facility and the pilot reactor to produce enough rifapentine to get into the market and to grow the market.” But in the long term he said the company hopes to transfer rifapentine manufacturing to a larger commercial plant.
The company is also planning to apply for World Health Organization (WHO) pre-qualification status for its rifapetine API. The goal is to conduct demonstration runs in the pilot plant by June 2025 and validate the WHO pre-qualification application in September 2025.
If achieved, WHO pre-qualification of CPT Pharma’s rifapetine API would show that the company’s APIs meet high-quality standards. It would also allow CPT Pharma to supply rifapentine API to companies producing medicines for the broader African market, for which a significant proportion of medicines are procured by donors requiring WHO PQ approval.
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.
An injection given during some asthma and COPD attacks was shown to be more effective than the current treatment of steroid tablets, reducing the need for further treatment by 30%. The findings, published in The Lancet Respiratory Medicine, could be “game-changing” for millions of people with asthma and COPD around the world, scientists say.
The type of symptom flare-up the injection treats are called ‘eosinophilic exacerbations’ and involve symptoms such as wheezing, coughing and chest tightness due to inflammation resulting from high amounts of eosinophils, a type of white blood cell. Eosinophilic exacerbations make up to 30% of COPD flare-ups and almost 50% of asthma attacks. They can become more frequent as the disease progresses, leading to irreversible lung damage in some cases.
Treatment at the point of an exacerbation for this type of asthma has barely changed for over fifty years, with steroid drugs being the mainstay of medication. Steroids such as prednisolone can reduce inflammation in the lungs but have severe side-effects such as diabetes and osteoporosis. Furthermore, many patients ‘fail’ treatment and need repeated courses of steroids, re-hospitalisation or die within 90 days.
Results from the phase two clinical trial ABRA study, led by scientists from King’s College London and sponsored by the University of Oxford, show a drug already available can be re-purposed in emergency settings to reduce the need for further treatment and hospitalisations. The multi-centre trial was conducted at Oxford University Hospitals NHS Foundation Trust and Guy’s and St Thomas’ NHS Foundation Trust.
Benralizamab is a monoclonal antibody which targets eosinophils to reduce lung inflammation. It is currently used for the treatment of severe asthma. The ABRA trial has found a single dose can be more effective when injected at the point of exacerbation compared to steroid tablets.
The study investigators randomised people at high risk of an asthma or COPD attack into three groups, one receiving benralizumab injection and dummy tablets, one receiving standard of care (prednisolone 30mg daily for five days) and dummy injection and the third group receiving both benralizumab injection and standard of care. As a double-blind, double-dummy, active-comparator placebo-controlled trial, neither the people in the study, or the study investigators knew which study arm or treatment they were given.
After 28 days, respiratory symptoms of cough, wheeze, breathlessness and sputum were found to be better with benralizumab. After 90 days, there were four times fewer people in the benralizumab group that failed treatment compared to standard of care with prednisolone.
Treatment with the benralizumab injection took longer to fail, meaning fewer episodes to see a doctor or go to hospital. Quality of life also improved for people with asthma and COPD.
This could be a game-changer for people with asthma and COPD. Treatment for asthma and COPD exacerbations have not changed in fifty years despite causing 3.8 million deaths worldwide a year combined.
– Lead investigator of the trial Professor Mona Bafadhel from King’s Centre for Lung Health
She added: “Benralizumab is a safe and effective drug already used to manage severe asthma. We’ve used the drug in a different way – at the point of an exacerbation – to show that it’s more effective than steroid tablets which is the only treatment currently available. The big advance in the ABRA study is the finding that targeted therapy works in asthma and COPD attacks. Instead of giving everyone the same treatment, we found targeting the highest risk patients with very targeted treatment, with the right level of inflammation was much better than guessing what treatment they needed.”
The benralizumab injection was administered by healthcare professionals in the study but can be potentially administered in the GP practice or in the Emergency Department. Benralizumab was safe in the study and similar in safety to many past studies.
Professor Mona Bafadhel said, “We hope these pivotal studies will change how asthma and COPD exacerbations are treated for the future, ultimately improving the health for over a billion people living with asthma and COPD across the world.”
Creative artwork featuring 3D renderings of respiratory syncytial virus (RSV)—a common contagious virus that infects the human respiratory tract – colourised as follows: (the viral envelope is purple, G- glycoproteins are light blue, and F-glycoproteins are orange). F-glycoproteins allow the virus to fuse with and infect human cells. Credit: NIAID/NIH
Since their introduction last year, researchers have been monitoring the real-world impact of the new respiratory syncytial virus (RSV) vaccines. In a recent commentary in The Lancet, Angela Branche, MD, an infectious diseases researcher at the University of Rochester Medical Center (URMC), details what has been learned during the vaccine’s first season.
“The evidence is clear; individuals should get vaccinated if they have conditions that place them at risk for severe disease. For older adults and those with chronic conditions, RSV should be considered as serious as the flu, and they should get vaccinated,” said Branche.
RSV is a significant cause of severe respiratory illness among older adults, especially those with underlying health conditions. Worldwide, RSV causes millions of infections, hundreds of thousands of hospitalisations, and tens of thousands of deaths annually in adults aged 60 and older. Older people with RSV are at higher risk of severe illness compared to those with influenza or COVID.
In 2023, the FDA approved three RSV vaccines for older adults. Studies have shown these vaccines to be effective, with the Pfizer, GSK, and Moderna vaccines preventing RSV pneumonia and bronchitis in more than 80% of participants.
A recent study published in The Lancet assessed the effectiveness of RSV vaccines using data from a large electronic health record network involving the Centers for Disease Control and Prevention (CDC) and multiple US healthcare systems. The study found that RSV vaccines were 80% effective in preventing hospitalisation, ICU admission, and death among adults aged 60 and older. Vaccine effectiveness was consistent across age groups, including those 75 and older, and among immunocompromised individuals. The study did not find evidence of waning vaccine protection within the season.
The uptake of the RSV vaccine in the 2023-2024 winter season was low, however. An estimated 24% of US adults aged 60 years and older received the vaccine, compared to influenza vaccination rates, which approach 50% each year for the same group. “Providers were not sure how to apply the shared clinical decision-making recommendations in the first season, and there remains a general lack of knowledge among the medical community and the public on what constitutes a risk for severe disease and who needs to be protected,” said Branche.
Based on these findings, the US Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that advises the CDC, updated guidelines in June 2024 to recommend RSV vaccination for all adults aged 75 and older, those 60 and older in long-term care facilities or with chronic and high-risk health conditions.
“This new data enabled the ACIP to make more definitive recommendations, which will build public confidence in the effectiveness of these vaccines and make implementation a lot easier for providers and pharmacies,” said Branche.
New research shows that vaccines that target multiple strains of the RSV virus, called bivalent vaccines, may provide longer protection. URMC infectious disease experts helped lead an international study of a bivalent RSV vaccine developed by Pfizer, the results of which were recently detailed in the New England Journal of Medicine. The vaccine effectively prevented severe RSV-related lower respiratory tract illnesses over two RSV seasons, with > 80% overall efficacy. The experimental vaccine was particularly effective in individuals aged 60-79.
Scientists from the University of Leicester have discovered that tuberculosis disrupts glucose metabolism in the body. The findings, which have now been published in PLoSPathogens complement the understanding that diabetes worsens the symptoms of tuberculosis. Importantly, they now say, undiagnosed tuberculosis could be pushing vulnerable patients towards metabolic disease such as diabetes.
Tuberculosis (TB) remains one of the most devastating infectious diseases worldwide, killing over 4,000 people every day. Prevention through the development of improved vaccines remains a priority for the World Health Organisation. Currently only one vaccine exists for TB and this is predominantly given to infants and young children to help protect them from severe forms of infection.
Scientists at the University are researching tuberculosis in the hope of creating improved vaccines and are specifically looking at ways in which undiagnosed and subclinical infection can impact health. This new discovery, they say, could pave the way to define the molecular pathways by which the immune response changes liver metabolism, thereby allowing for the creation of targeted interventions.
She said: “Our paper changes the focus from diabetes making TB worse to the possibility that late diagnosis of TB can contribute to disruption of glucose metabolism, insulin resistance and therefore can promote progress towards diabetes in those that are susceptible.
“As diabetes compromises drug treatment, our paper also supports the idea that metabolic screening should be involved in any drug or vaccine trials.”
The study first used laboratory models of pulmonary TB to examine the changes happening within the liver during the early stages of infection. It found that an immune response was triggered within the liver cells and glucose metabolism was altered.
First author Dr Mrinal Das then reanalysed published metabolic data from humans, where he found that liver glucose metabolism was also disrupted when people progressed to TB from latent infection.
Professor Cooper added: “Our future aim is to define the molecular pathways by which the immune response is changing liver metabolism, allowing us to potentially create targeted interventions.
“We will also be investigating how latent TB (which is infection with the bacterial agent of TB without significant symptoms) might be impacting metabolic health in humans.”
Respiratory syncytial virus (RSV) is the leading cause of hospitalisation in young children due to respiratory complications such as bronchiolitis and pneumonia. Yet little is understood about why some children develop only mild symptoms while others develop severe disease.
To better understand what happens in these cases, clinician-scientists from Brigham and Women’s Hospital, and Boston Children’s Hospital analysed samples from patients’ airways and blood, finding distinct changes in children with severe cases of RSV, including an increase in the number of natural killer (NK) cells in their airways.
The descriptive study, which focuses on understanding the underpinnings of severe disease, may help to lay groundwork for identifying new targets for future treatments. Results are published in Science Translational Medicine.
“As a physician, I help to care for children who have the most severe symptoms, and as a researcher, I’m driven to understand why they become so sick,” said corresponding author Melody G. Duvall, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital (BWH) and the Division of Critical Care Medicine at Boston Children’s Hospital. “NK cells are important first responders during viral infection – but they can also contribute to lung inflammation. Interestingly, our findings fit with data from some studies in COVID-19, which reported that patients with the most severe symptoms also had increased NK cells in their airways. Together with previous studies, our data link NK cells with serious viral illness, suggesting that these cellular pathways merit additional investigation.”
Duvall and colleagues, including lead author Roisin B. Reilly of the Division of Pulmonary and Critical Care Medicine at BWH, looked at samples from 47 children critically ill with RSV, analysing immune cells found in their airways and peripheral blood. Compared to uninfected children, those with severe illness had elevated levels of NK cells in their airways and decreased NK cells in their blood. In addition, they found that the cells themselves were altered, both in appearance and in their ability to perform their immunological function of killing diseased cells.
Duvall and co-authors have previously described a post-pandemic surge in paediatric RSV infections. While clinicians can only provide supportive care to the most severely sick children, vaccines to prevent RSV are now available for children 19 months and younger, adults 60 years and over, and people who are pregnant.
A therapy showing promise to help control tuberculosis (TB) does not interfere with combined antiretroviral therapy (cART), according to research by Texas Biomedical Research Institute (Texas Biomed) which was recently published in JCI Insight.
“This is an important hurdle that this host-directed therapy had to clear in order to help patients battling both HIV and TB,” said study leader Professor Smriti Mehra, PhD of Texas Biomed.
TB is responsible for more than 1.3 million deaths worldwide every year. Dr. Mehra and her team have been investigating a therapy currently used in cancer as a potential treatment for patients with drug-resistant TB and/or comorbid HIV. While many cases of TB can be controlled with months of antibiotics, the infection can return in people who are immunocompromised as a result of HIV. Now that cART is so effective at controlling HIV, a resurging TB infection can often be deadly to those individuals.
Dr Mehra is studying a host-directed therapy that blocks or inhibits an immune system protein naturally found in the body. The protein, called IDO (short for Indoleamine-2,3-dioxygenase), normally suppresses the immune system, preventing it from causing excessive inflammation and organ damage. Inhibiting IDO for short intervals of time has led to more successful cancer treatments. Dr. Mehra’s team has previously shown the same approach improves control of TB in conjunction with antibiotics.
This current study in nonhuman primates with both TB and simian immunodeficiency virus, the nonhuman primate version of HIV, showed the IDO inhibitor does not interfere with cART.
Researchers compare the impacts of cART by itself versus cART plus the IDO inhibitor in lung tissue of nonhuman primates with both TB and SIV. Left: Following just cART, significantly more IDO is detected in pink. Right: With the IDO inhibitor and cART, immune cells recruited to fight bacteria are observed inside the granuloma, a hallmark structure of TB. Specifically, CD4+ T cells are in green and CD68 proteins expressed by macrophages are in red.
“There was no increase in viral load in animals given cART and the IDO inhibitor, compared with animals only given cART, proving the inhibitor is safe to give to patients with HIV,” Dr. Mehra said.
Now that the researchers have shown the inhibitor works well in conjunction with TB antibiotics and with cART separately, they plan to study how it performs when given in conjunction with both antibiotics and cART together. This treatment regimen is standard for patients with both HIV and active TB. Dr. Mehra said that longer-term studies are also needed to confirm there are no unintended side effects.
The IDO inhibitor is already FDA-approved for use in patients with cancer, which shortens the path to potential approval for patients with TB/HIV when compared with developing a brand-new drug.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
A compound found in African wormwood – a plant used medicinally for thousands of years to treat many types of illness – could be effective against tuberculosis, according to a new study available online in the Journal of Ethnopharmacology.
The team, co-led by Penn State researchers, found that the chemical compound, an O-methylflavone, can kill Mycobacterium tuberculosis, or Mtb, that causes tuberculosis in both its active state and its slower, hypoxic state, which the mycobacteria enters when it is stressed.
Bacteria in this state are much harder to destroy and make infections more difficult to clear, according to co-corresponding author Joshua Kellogg, assistant professor of veterinary and biomedical sciences in the College of Agricultural Sciences.
While the findings are preliminary, Kellogg said the work is a promising first step in finding new therapies against tuberculosis.
“Now that we’ve isolated this compound, we can move forward with examining and experimenting with its structure to see if we can improve its activity and make it even more effective against tuberculosis,” he said. “We’re also still studying the plant itself to see if we can identify additional molecules that might be able to kill this mycobacterium.”
Tuberculosis is one of the world’s leading killers among infectious diseases, according to the Centers for Disease Control and Prevention. There are about 10 million cases a year globally, with approximately 1.5 million of those being fatal.
While effective therapies exist for TB, the researchers said there are several factors that make the disease difficult to treat. A standard course of antibiotics lasts six months, and if a patient contracts a drug-resistant strain of the bacteria, it stretches to two years, making treatment costly and time consuming.
Additionally, the bacteria can take two forms in the body, including one that is significantly harder to kill.
“There’s a ‘normal’ microbial bacterial form, in which it’s replicating and growing, but when it gets stressed – when drugs or the immune system is attacking it – it goes into a pseudo-hibernation state, where it shuts down a lot of its cellular processes until it perceives that the threat has passed,” Kellogg said. “This makes it really hard to kill those hibernating cells, so we were really keen to look at potential new chemicals or molecules that are capable of attacking this hibernation state.”
Multiple species of the Artemisia plant have been used in traditional medicine for centuries, the researchers said, including African wormwood, which has been used to treat cough and fever. Recent studies in Africa have suggested that the plant also has clinical benefits in treating TB.
“When we look at the raw plant extract that has hundreds of molecules in it, it’s pretty good at killing TB,” Kellogg said. “Our question was: There seems to be something in the plant that’s really effective – what is it?”
For their study, the researchers took raw extract of the African wormwood plant and separated it into “fractions” – versions of the extract that have been separated into simpler chemical profiles. They then tested each of the fractions against Mtb, noting whether they were effective or ineffective against the bacteria. At the same time, they created a chemical profile of all of the tested fractions.
“We also used machine learning to model how the changes in chemistry correlated with the changes in activity that we saw,” Kellogg said. “This allowed us to narrow our focus to two fractions that were really active.”
From these, the researchers identified and tested a compound that effectively killed the bacteria in the pathogen’s active and inactive states, which the researchers said is significant and rare to see in TB treatments. Further testing in a human cell model showed that it had minimal toxicity.
Kellogg said the findings have the potential to open new avenues for developing new, improved therapeutics.
“While the potency of this compound is too low to use directly as an anti-Mtb treatment, it may still be able to serve as the foundation for designing more potent drugs,” he said. “Furthermore, there appear to be other, similar chemicals in African wormwood that may also have the same type of properties.”
The researchers said that in the future, more studies are needed to continue exploring the potential for using African wormwood for treating TB.
