Antibiotics for liver disease are linked to the emergence of antibiotic-resistant superbugs

An international team of researchers has found that an antibiotic called rifaximin, commonly prescribed to patients with liver disease, is preventing the global emergence of a nearly untreatable form of the antimicrobial-resistant superbug, vancomycin-resistant Enterococcus faecium (VRE). It was discovered that the disease caused severe symptoms. Infectious diseases in hospitalized patients.

This study demonstrated that rifaximin use promotes resistance to daptomycin, one of the last effective antibiotics for VRE infections.

Published today is nature, The study was led by researchers from the University of Melbourne's Peter Doherty Institute for Infection and Immunology (Doherty Institute) and Austin Health. This highlights the critical importance of a better understanding of the adverse effects of antibiotic use and emphasizes the importance of responsible antibiotic use in clinical practice.

Their findings reinforce the recent political declaration of the United Nations General Assembly High-Level Meeting on Antimicrobial Resistance (26 September 2024), in which world leaders announced that an estimated 4.95 million AMR-related He pledged decisive action against antimicrobial resistance, including reducing the number of human deaths by 10. percent by 2030.

The eight-year study drew on several disciplines, including molecular microbiology, bioinformatics, and clinical science. Using large-scale genomics (the study of an organism's DNA composition), scientists were able to identify changes in the DNA of daptomycin-resistant VRE that were not present in susceptible strains. Subsequent laboratory experiments and clinical studies showed that rifaximin use causes these changes, leading to the emergence of daptomycin-resistant VRE.

Dr Glenn Carter from the University of Melbourne, a senior research fellow at the Doherty Institute and lead author of the study, said the study challenges the long-held belief that rifaximin poses a “low risk”. said. antibiotic resistance.

We showed that rifaximin rendered VRE resistant to daptomycin in a previously unseen manner.

There is also concern that these daptomycin-resistant VREs could be transmitted to other patients in the hospital. This is the hypothesis we are currently investigating. ”

Dr. Glenn Carter, Senior Research Fellow, Doherty Institute

Dr Adrianna Turner from the University of Melbourne, a researcher at the Doherty Institute and lead author of the study, said rifaximin causes specific changes in an enzyme called RNA polymerase in bacteria. These changes “up-regulate” a previously unknown gene cluster (prdRAB), causing changes in the VRE cell membrane and causing cross-resistance to daptomycin.

“When bacteria become resistant to antibiotics, it's similar to gaining new abilities like super speed in a video game. However, when exposed to rifaximin, VRE bacteria receive more than just one boost. , gain multiple abilities such as super speed and super strength, allowing you to easily defeat even the final boss (in this case, the antibiotic daptomycin),” said Dr. Turner.

“In other words, rifaximin can make bacteria not only resistant to one antibiotic, but also resistant to other antibiotics, including important last-resort antibiotics like daptomycin. is.”

Associate Professor Jason Kwon, an infectious disease physician at Austin Health and principal investigator of the clinical study, highlighted two important implications of the study results.

“First, clinicians should use caution when treating VRE infections in patients who have been taking rifaximin since daptomycin administration. efficacy “Laboratory validation is required before use as it may be compromised,” said Associate Professor Kwon.

“Second, our findings highlight the importance for regulators to consider 'off-target and cross-class' effects when approving new drugs. In the case of antibiotics, this means that rifaximin It means understanding whether exposure to one drug can induce resistance to other antibiotics and even those antibiotics.

“Rifaximin remains a highly effective drug when used appropriately, and patients with advanced liver disease who currently take rifaximin should continue to take it. However, individual patient treatment and public health We need to understand the future impact from both perspectives.”

Dr Claire Gorey, senior bioinformatician at the Doherty Institute and co-senior author at the University of Melbourne, said: “By combining cutting-edge technology and multidisciplinary collaboration, this study shows how bacteria develop resistance to antibiotics.” “This highlights that it is possible to understand exactly how and why,” he said. People they have never encountered.

“These insights are important for developing smarter and more sustainable strategies for antibiotic use, especially as these lifesaving drugs become an increasingly valuable resource,” Dr. Gorey said. .

Professor Benjamin Howden, director of the Microbial Diagnostic Unit Public Health Laboratory at the Doherty Institute and an infectious disease physician at Austin Health, whose lab led the project, said the study showed that daptomycin was effective in treating severe VRE infections. This will help ensure that antibiotics remain effective in the treatment of cancer. Hospitals in Australia and around the world, especially our most vulnerable patients.

“Our findings highlight the critical need for effective genomics-based surveillance to detect emerging antimicrobial resistance and to protect important last-resort treatments like daptomycin. It also highlights the importance of judicious use of antibiotics,” Professor Howden concluded.

The team's main collaborators were the Bio21 Institute of Molecular Sciences and Biotechnology. University Medical Center, Regensburg, Germany. University of Queensland; Flinders University, Adelaide.