A multinational study reveals that long-term use of the gut-selective antibiotic rifaximin in patients with cirrhosis and hepatic encephalopathy significantly increases the risk of antimicrobial resistance and infection-related complications, contrasting with earlier clinical focus on short-term microbial suppression and ammonia reduction.
Patients managing recurrent hepatic encephalopathy face a newly documented long-term risk regarding antimicrobial resistance. A large, multinational cohort study demonstrates that continuous use of rifaximin among individuals with cirrhosis and hepatic encephalopathy is associated with a heightened risk of antimicrobial resistance and infection-related complications over a one-year period. In this real-world analysis, investigators demonstrated an increased risk of antimicrobial resistance and infection-related complications in rifaximin users among patients with cirrhosis and hepatic encephalopathy. The risk was consistent across age, sex, etiology, and medication subgroups, particularly in those with prior antibiotic use. Furthermore, the escalated risk of infection-related adverse events and mortality in rifaximin users supports the concerns associated with long-term rifaximin use and highlights the need to re-evaluate current treatment strategies for recurrent hepatic encephalopathy and prophylaxis management.
Rifaximin and the Modulation of Gut Microbiota in Cirrhosis
Rifaximin is widely prescribed to manage recurrent hepatic encephalopathy by reducing ammonia production in the gut. In vitro investigations have demonstrated rifaximin’s broad antimicrobial activity against a range of common pathogens. In the short term, its activity appears to suppress orally derived, mucin-grading Streptococcus and Veillonella spp. in the intestine while promoting a TNF-alpha- and IL-17-mediated gut environment. This modulation reduces the likelihood of infection and improves overt hepatic encephalopathy within 30 days. However, given that rifaximin is a gut-selective antibiotic, there are growing concerns regarding its long-term impact on the gut microbiota. Changes in the gut microbiota, which progress with cirrhosis severity, are closely linked to complications such as hepatic encephalopathy and infection. Moreover, a recent study has pinpointed the role of the gut-liver-brain axis in hepatic encephalopathy development via the accumulation of phenylethylamine produced by Ruminococcus gnavus, challenging the traditional focus on ammonia. While short-term antimicrobial activity is evident, the long-term risks of rifaximin use in modulating the gut microbiome and its subsequent impact on hepatic encephalopathy and other complications warrant further investigation.
Cross-Resistance and Escalating Last-Line Antibiotic Use
A recent mechanistic study demonstrated that rifaximin exposure can induce antimicrobial resistance by promoting specific rpoB mutations in vancomycin-resistant Enterococcus faecium. These mutations led to cell membrane remodeling and conferred cross-resistance to daptomycin, even in the absence of daptomycin exposure. Similar mechanisms have been observed with rifampicin exposure, which induces cross-resistance to multiple antibiotics in Staphylococcus aureus. However, clinical evidence on whether rifaximin promotes antimicrobial resistance remains inconclusive. Antimicrobial resistance gene abundance is high in patients with cirrhosis and increases with disease severity. Although the study showed that antimicrobial resistance gene abundance appeared unaffected following rifaximin treatment, it is limited by recruiting only 19 patients. In contrast, our findings demonstrated an increased risk of antimicrobial resistance over a one-year period in rifaximin initiators. Additionally, the significant increase in the use of last-line antibiotics, including daptomycin and linezolid, among rifaximin initiators not only indicates emerging resistance to first-line antibiotics but also suggests a potentially escalated risk of daptomycin resistance.
Infection Risks and Prior Antibiotic Exposure
Intestinal colonization by multidrug-resistant bacteria in patients with cirrhosis has been linked to higher infection risk. Our findings support this evidence, as rifaximin use was associated not only with a higher risk of antimicrobial resistance but also with increased incidences of sepsis and spontaneous bacterial peritonitis. Moreover, patients who received other antibiotics within three months prior to rifaximin therapy exhibited an even greater risk of antimicrobial resistance, suggesting that concomitant antibiotic use may exacerbate microbial dysbiosis and promote the selection of multidrug-resistant microorganisms. These results were further supported by previous studies reporting increased frequencies of virulence factors and antimicrobial resistance genes, along with an overlap of oral and gut microbial communities, in patients with decompensated cirrhosis. This oral-gut microbial overlap likely results from the transit of oral bacteria to the gut following the depletion of resident microbiota after antibiotic treatment. Together, these findings are consistent with the effects of concomitant antibiotics we observed. There remains considerable debate regarding the benefits of rifaximin treatment in patients with cirrhosis. When prescribed with lactulose, rifaximin is widely used to manage recurrent hepatic encephalopathy. However, a recent meta-analysis has shown that although rifaximin likely prevents hepatic encephalopathy recurrence, it does not reduce mortality or the incidence of other adverse events. Limited evidence from a single-center study suggested improved short-term survival, yet no impact on 90- or 180-day mortality in critically ill patients with cirrhosis was observed.
Historical Context in Methicillin-Resistant Staphylococcus Aureus Models
Vancomycin is the standard treatment for methicillin-resistant Staphylococcus aureus infections, however nonsusceptibility and treatment failure underscore the need for more treatment options. Current methicillin-resistant Staphylococcus aureus treatment guidelines recommend daptomycin in combination with linezolid as an option in cases of persistent bacteremia or vancomycin treatment failure. No clinical data has been published on the activity using these combinations. Investigators including Kerry L. LaPlante of the Veterans Affairs Medical Center in Providence, RI, the University of Rhode Island College of Pharmacy in Kingston, RI, and the Warren Alpert Medical School of Brown University in Providence, RI, investigated the activity of daptomycin, linezolid, and vancomycin alone and in combination against methicillin-resistant Staphylococcus aureus in an in vitro pharmacodynamic model simulating bacteremia over 48 hours. This work was presented at the 53rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy in 2013.
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