In a groundbreaking study published in Nature, researchers have challenged the long-standing belief that rifaximin, an antibiotic frequently prescribed for patients with liver disease, carries a low risk of contributing to antibiotic resistance. This research, spearheaded by a team from the University of Melbourne at the Peter Doherty Institute for Infection and Immunity and Austin Health, reveals a concerning link between rifaximin and the rise of vancomycin-resistant Enterococcus faecium (VRE), a superbug that poses a significant threat to public health.
Understanding the Risks of Rifaximin
Rifaximin has been widely regarded as a safe option for treating gastrointestinal issues, particularly in patients with liver disease. However, the findings from this eight-year study indicate that the antibiotic may inadvertently contribute to the emergence of an almost untreatable form of VRE. This superbug is notorious for causing severe infections, particularly in hospitalized patients, underscoring the urgent need for responsible antibiotic use in clinical settings.
The researchers emphasize that the implications of this study align with the recent political declaration made during the UN General Assembly High-Level Meeting on Antimicrobial Resistance. World leaders have committed to taking decisive action against antimicrobial resistance, aiming to reduce the estimated 4.95 million AMR-associated human deaths annually by 10% by 2030. This study serves as a critical reminder of the challenges that lie ahead in combating antibiotic resistance.
Innovative Research Methods
The research team employed a multidisciplinary approach, integrating molecular microbiology, bioinformatics, and clinical science to investigate the mechanisms behind rifaximin’s effects on VRE. By utilizing large-scale genomics, the scientists were able to identify specific changes in the DNA of daptomycin-resistant VRE strains that were absent in susceptible strains. Their laboratory experiments and clinical studies demonstrated that the use of rifaximin led to these genetic changes, facilitating the emergence of daptomycin-resistant VRE.
Dr. Glen Carter, a Senior Research Fellow at the Doherty Institute and senior author of the study, expressed concern over the implications of their findings. “We’ve shown that rifaximin makes VRE resistant to daptomycin in a way that has not been seen before,” he stated. This revelation raises alarms about the potential for these resistant strains to spread among patients in hospital settings, a hypothesis that the researchers are currently exploring.
The Mechanism of Resistance
Dr. Adrianna Turner, the first author of the study, elaborated on the specific changes triggered by rifaximin. The antibiotic induces alterations in an enzyme called RNA Polymerase within the bacteria, leading to the upregulation of a previously unknown gene cluster (prdRAB). This process results in modifications to the VRE cell membrane, ultimately causing cross-resistance to daptomycin.
To illustrate the complexity of this resistance, Turner likened it to a video game scenario where bacteria gain multiple abilities instead of just one. “When exposed to rifaximin, the VRE bacteria don’t just get one boost — they gain multiple abilities, allowing them to easily defeat even the final boss, which in this case is the antibiotic daptomycin,” she explained. This analogy highlights the multifaceted nature of antibiotic resistance and the challenges it presents in clinical treatment.
Implications for Clinical Practice
Associate Professor Jason Kwong, an Infectious Diseases Physician at Austin Health and lead investigator of the clinical studies, emphasized two critical implications stemming from the research. First, he urged clinicians to exercise caution when treating VRE infections in patients who have been prescribed rifaximin, as the efficacy of daptomycin may be compromised. This necessitates laboratory verification before administering treatment.
Secondly, Kwong pointed out the importance of regulatory bodies considering “off-target and cross-class” effects when approving new drugs. Understanding how exposure to one antibiotic, like rifaximin, could induce resistance against others is vital for safeguarding public health. While rifaximin remains an effective medication when used appropriately, the researchers stress the need for a comprehensive understanding of its implications for both individual patients and broader public health strategies.
Advancements in Genomics-Based Surveillance
Dr. Claire Gorrie, a senior bioinformatician from the Doherty Institute and co-senior author of the study, highlighted the role of cutting-edge technologies in uncovering the mechanisms behind antibiotic resistance. The research underscores the importance of interdisciplinary collaboration in developing smarter, more sustainable strategies for antibiotic use, especially as these life-saving drugs become increasingly precious resources.
Professor Benjamin Howden, Director of the Microbiological Diagnostic Unit Public Health Laboratory at the Doherty Institute, emphasized the need for effective genomics-based surveillance to detect emerging antimicrobial resistance. He concluded that the findings of this study will help ensure that daptomycin remains an effective treatment option for severe VRE infections in hospitals, particularly for the most vulnerable patients.
The collaborative efforts of the research team, which included partners from the Bio21 Molecular Science and Biotechnology Institute, University Medical Center in Regensburg, Germany, The University of Queensland, and Flinders University in Adelaide, reflect a concerted effort to address the pressing issue of antibiotic resistance.