Medical Bulletin 08/ October/ 2024 - Video

Researchers have a new battle tactic to fight drug-resistant bacterial infections. Their strategy involves using collections of bacteriophages, viruses that naturally attack bacteria. In a new study, researchers at the University of Chicago Pritzker School of Molecular Engineering (PME) and UChicago Medicine have shown that a mixture of these phages can successfully treat antibiotic-resistant Klebsiella pneumoniae infections in mice.

At the same time, however, the team’s work revealed just how complex the interactions between phages and bacteria can be; the viruses predicted to be most effective in isolated culture dishes did not always work in animals. Moreover, both phages and bacteria can evolve over time – in some cases, phages evolved to be more efficient in killing bacteria while in other cases, Klebsiella evolved resistance to the phages.

“We still think phages are an incredibly promising approach to treating drug-resistant bacteria such as Klebsiella,” said Mark Mimee, assistant professor of molecular engineering and senior author of the new work, published in Cell Host & Microbe. “But phages are like a living, constantly changing antibiotic which gives them a lot of complexity.”

In the new research, Ella Rotman – a scientist in the Mimee Lab – screened wastewater to isolate phages that could effectively kill 27 different Klebsiella strains, including 14 that were newly isolated from University of Chicago patients. The team identified several dozen phages with the capability of killing at least some Klebsiella strains, Then, the researchers analyzed what genetic factors in the bacteria made them most prone to being killed or weakened by each of those phages.

Based on that analysis, Rotman and her colleagues developed a mixture of five phages that each targeted different components of the bacteria. In culture dishes as well as mice, this phage cocktail made antibiotic-resistant Klebsiella bacteria more likely to be attacked by the immune system and, in some cases, more susceptible to treatment with antibiotics. However, in other cases, the bacteria became more antibiotic resistant after treatment.

By exposing the phage mixture to a series of isolated Klebsiella bacteria, the researchers gave the phage the opportunity to evolve. This improved the ability of the cocktail to kill Klebsiella. In mice, the mixture effectively killed or weakened Klebsiella. The researchers observed co-evolution between the bacteria and phage in the mouse intestines, where the Klebsiella evolved to evade phage attack and the phage countered to better infect the altered bacteria.

Reference: “Rapid design of bacteriophage cocktails to suppress the burden and virulence of gutresident carbapenem-resistant Klebsiella pneumoniae,” Rotman et al, Cell Host & Microbe, October 4, 2024. DOI: https://doi.org/10.1016/j.chom.2024.09.004

A group of eight leading international scientists has developed a comprehensive framework that outlines the criteria for establishing prebiotic status, providing much-needed clarity in this evolving field. This new expert recommendation, published in Nature Reviews Gastroenterology and Hepatology, addresses the key challenges related to scientific substantiation of prebiotics and offers practical guidelines for accurately identifying prebiotics and assessing their health effects. The publication resulted from collaborations coordinated through the International Scientific Association for Probiotics and Prebiotics (ISAPP).

The authors detail a clear scientific pathway for demonstrating prebiotic effects, emphasizing that prebiotics must meet several essential criteria. First and foremost, a prebiotic must be a well-characterized substance that provides a measurable health benefit. In addition, it must be selectively utilized by host microorganisms, show measurable effects on microbiome composition or function, have a plausible mechanism linking the microbiome changes to the observed health benefit, and be safe for its intended use. Importantly, at least one study in the target host is required to demonstrate both microbiome modulation and a health benefit concurrently.

Two of the most important challenges addressed within the paper are validation of selective utilisation within the complexity of the microbial ecosystem’s response to a prebiotic intervention, as well as methods for delineating the mediation of health benefits via microbiome-based mechanisms.

The authors say that over time they hope regulatory and commercial approaches to prebiotics will increasingly align with the scientific criteria they specified.

Reference: Hutkins, R., Walter, J., Gibson, G.R. et al. Classifying compounds as prebiotics — scientific perspectives and recommendations. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00981-6

WHO announced that a fourth WHO-prequalified human papillomavirus (HPV) vaccine product, Cecolin® has been confirmed for use in a single-dose schedule. The decision is made based on new data on the product that fulfilled the criteria set out in the WHO’s 2022 recommendations for alternative, off-label use of HPV vaccines in single-dose schedules. This important milestone will contribute to improving sustainable supply of HPV vaccines—allowing more girls to be reached with the vaccines that prevent cervical cancer.

“Unlike most other cancers, we have the ability to eliminate cervical cancer, along with its painful inequities,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “By adding another option for a one-dose HPV vaccination schedule, we have taken another step closer to consigning cervical cancer to history.”

More than 95% of the 660 000 cervical cancer cases occurring globally each year are caused by HPV. Every two minutes, a woman dies from this preventable disease globally, and 90% of these deaths occur in low- and middle-income countries. Of the 20 hardest hit countries by cervical cancer 19 are in Africa.

HPV vaccine introductions have been hampered by global supply shortages since 2018 and production challenges encountered by one of the manufacturers earlier this year led to further shortfalls, potentially impacting millions of girls in need of HPV vaccines in Africa and Asia.

“Having 90% of girls fully vaccinated with the HPV vaccine by 15 years of age is the target for the first pillar of the WHO global strategy for cervical cancer elimination,” said Dr Kate O'Brien, Director of the Department of Immunization, Vaccines and Biologicals at WHO. “Given the continuing supply challenges, this addition of single-dose vaccine product means countries will have greater choice of vaccines to reach more girls.”

A growing number of vaccine products initially prequalified for use in a 2-dose schedule can now be used in a single-dose schedule. The single-dose use indication for this additional vaccine, Cecolin®, is incorporated into the second edition of WHO’s technical document on considerations for HPV vaccine product choice. Like for other medications and vaccines, when there is data to support modified use, guided by a clear public health benefit, public health advisory bodies can recommend "off-label” use, until a manufacturer adds this modified use to their label.

A further piece of good news is the WHO prequalification on 2 August 2024, of an additional HPV vaccine, Walrinvax®, making it the fifth product available on the global market. This will contribute to a more sustainable supply of HPV vaccines, enabling more girls to receive the vaccine. Walrinvax® is prequalified with a two-dose schedule. Further data will be needed to assess if this vaccine can be recommended for single-dose schedule in the future.

To keep weight in check, it is not only important to consider what we eat, but also the times at which we eat. According to a study published in the International Journal of Behavioral Nutrition and Physical Activity, there are two specific habits that are associated with a lower body mass index (BMI) in the long term: keeping a longer overnight fast and eating breakfast early. This research was led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the "la Caixa" Foundation.

The study involved more than 7,000 volunteers aged 40-65 from the GCAT | Genomes for Life cohort, a project led by the Germans Trias i Pujol Research Institute (IGTP). In 2018, participants answered questionnaires about their weight and height, eating habits including meal times, other lifestyle habits and socioeconomic status. In 2023, after five years, more than 3,000 participants made a follow-up visit to the research team, where their measures were registered again and new questionnaires were completed.

"Our results, in line with other recent studies, suggest that extending the overnight fast could help maintain a healthy weight if accompanied by an early dinner and an early breakfast. We think this may be because eating earlier in the day is more in line with circadian rhythms and allows for better calorie burning and appetite regulation, which can help maintain a healthy weight. However, it is too soon to draw definitive conclusions, so recommendations will have to wait for more robust evidence," explains Luciana Pons-Muzzo, researcher at ISGlobal at the time of the study and currently at IESE Business School.

Analysis of the data by gender showed that, compared to men, women generally showed lower BMI, higher adherence to the Mediterranean diet, lower propensity to consume alcohol, poorer mental health, and were more likely to be responsible for household or family supervision.

The team used a statistical technique called 'cluster analysis' to group individuals with similar characteristics. From the results of this analysis, the authors were struck by a small group of men whose first meal of the day was after 2PM and who, on average, fasted for 17 hours. Compared to the rest, this group of men tended to have less healthy lifestyles (more likely to smoke, drink alcohol, less physical activity, less adherence to the Mediterranean diet), and had lower levels of educational attainment and were more likely to be unemployed. These patterns were not observed in any group of women.

"There are different ways of practising what is known as 'intermittent fasting' and our study relates to one of them, which is overnight fasting. What we observed in a subgroup of men who do intermittent fasting by skipping breakfast is that this practice has no effect on body weight. Other intervention studies in participants with obesity have shown that this tactic is no more effective than reducing calorie intake in reducing body weight in the long term," says Camille Lassale, ISGlobal researcher and senior co-author of the study.

Reference: Pons-Muzzo, L., de Cid, R., Obón-Santacana, M. et al. Sex-specific chrono-nutritional patterns and association with body weight in a general population in Spain (GCAT study). Int J Behav Nutr Phys Act 21, 102 (2024). https://doi.org/10.1186/s12966-024-01639-x