After an eight-year study, scientists recently made a surprising finding in the first recorded instance of one antibiotic causing resistance to another in a different class – resulting in the rise of a nearly untreatable superbug, they said.
The Australian-led research found that rifaximin, used to treat liver disease, causes resistance to another antibiotic, daptomycin, reports The Guardian.
Daptomycin is one of the few treatments effective against vancomycin-resistant enterococcus (VRE), a contagious bacterial infection that can cause serious reactions in hospitalised patients.
The University of Melbourne’s Dr Adrianna Turner, the study’s lead author, said it was a “really surprising” finding, and that it was previously thought that the risk of antibiotic resistance only applied to the one antibiotic.
The findings, published in Nature, also overturned the widely held idea that rifaximin was a low-risk antibiotic.
Last month international leaders committed to decisive action on antimicrobial resistance – the development of bacteria to resist treatment. This included the aim of reducing the estimated global 4.95m deaths associated with antimicrobial resistance annually by 10 percentage points by 2030.
Turner said when bacteria became resistant to an antibiotic, “it’s a bit like gaining a new ability in a video game”.
“But when exposed to rifaximin, the VRE bacteria don’t just get one boost. They gain multiple abilities, like super-speed and super-strength, allowing them to easily defeat even the final boss, which in this case is the antibiotic daptomycin.”
Rifaximin use triggers changes in an enzyme within the bacteria, which then leads to changes in the VRE’s cell membrane, causing cross-resistance, researchers from the Doherty Institute and Austin Health found.
Turner did not rule out the possibility that other antibiotics could create resistance to antibiotics in different classes.
Researchers are now investigating whether daptomycin-resistant strains of VRE may be transmitted to other patients within the hospital.
The eight-year study involved genomic analyses of isolates from patients from Australia and Germany, and used animal models to support the hypotheses.
Turner said the findings highlighted the need for surveillance and investigation into how bacteria become antibiotic-resistant, allowing researchers to create diagnostic tests and genomic surveillance to understand the prevalence of such bacteria.
Professor Jason Kwong, from Austin Health, said rifaximin was still effective when used appropriately and those taking it to treat advanced liver disease should continue to do so.
“But we need to understand the implications both when treating individual patients and from a public health perspective,” he said.
He advised clinicians treating patients with VRE who have taken rifaximin to confirm that daptomycin is working via a lab test, as its efficacy may be affected.
He also emphasised the importance of drug regulators considering whether the use of one drug makes another less effective when approving new drugs.
Professor Martina Sanderson-Smith, a molecular bacteriologist at the University of Wollongong, said the finding that antibiotic resistance can affect different types of antibiotics was “really concerning and interesting”.
She said the findings highlighted the difficulties in the responsible use and prescription of antibiotics, and the need to balance safety with clinical need.
“We need to better understand the possible sort of consequences of prescribing all classes of antibiotics on this idea of shared resistance across antibiotic classes, so that clinicians can make more informed decisions,” she said.
Study details
Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin
Adrianna Turner, Lucy Li, Ian Monk, Jean Lee et al.
Published in Nature on 23 October 2024
Abstract
Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action, but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered ‘low risk’ for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.
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