Meeting the Challenge of Antimicrobial Resistance in Cirrhosis: The Invisible Threat That Lies Within

See "Impact of antibiotic resistance genes in gut microbiome of patients with cirrhosis," by Shamsaddini A, Gillevet PM, Acharya C, et al on page 508. See "Impact of antibiotic resistance genes in gut microbiome of patients with cirrhosis," by Shamsaddini A, Gillevet PM, Acharya C, et al on page 508. The World Health Organisation describes antimicrobial resistance (AMR) as one of the greatest threats to global health, food security, and development.1World Health OrganizationGlobal action plan on antimicrobial resistance. World Health Organization, Geneva, Switzerland2015Google Scholar AMR infections cause approximately 700,000 deaths per year globally, predicted to increase to 10 million, costing $100 trillion by 2050 if no action is taken. The indiscriminate use of antimicrobials has driven the emergence of multidrug-resistant bacteria, resistant to 60% of antimicrobials in some countries.1World Health OrganizationGlobal action plan on antimicrobial resistance. World Health Organization, Geneva, Switzerland2015Google Scholar There is a very real threat that we will face a future in which antibiotics no longer work. Patients with cirrhosis are at high risk for AMR because they are frequently prescribed antibiotics (approximately 25% are on long-term antibiotics), frequently undergo invasive procedures such as large-volume paracentesis, and have recurrent hospitalisations2Fernandez J. Bert F. Nicolas-Chanoine M.H. The challenges of multi-drug-resistance in hepatology.J Hepatol. 2016; 65: 1043-1054Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 3Shallcross L. O'Brien A. Antimicrobial resistance in liver disease: better diagnostics are needed.Lancet Gastroenterol Hepatol. 2017; 2: 151-153Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 4Patel V.C. Williams R. Antimicrobial resistance in chronic liver disease.Hepatol Int. 2020; 14: 24-34Crossref PubMed Scopus (8) Google Scholar (decompensated cirrhotics have an approximately 37% readmission rate within 30 days).5Volk M.L. Tocco R.S. Bazick J. et al.Hospital readmissions among patients with decompensated cirrhosis.Am J Gastroenterol. 2012; 107: 247-252Crossref PubMed Scopus (272) Google Scholar The timely study by Shamsaddini et al6Shamsaddini A. Gillevet P.M. Acharya C. et al.Impact of antibiotic resistance genes in gut microbiome of patients with cirrhosis.Gastroenterology. 2021; 161: 508-521Abstract Full Text Full Text PDF Scopus (4) Google Scholar captures the incidence of AMR in patients with cirrhosis, with and without hepatic encephalopathy, as a marker of decompensation and poor prognosis. The authors show that in stable outpatients with cirrhosis, gut metagenomic antibiotic resistance gene (ARG) abundances increase with advancing cirrhosis and are associated with hospitalization and mortality. There was little influence of 8 weeks of treatment with the nonabsorbable antibiotic rifaximin in biobanked stool samples from a previously published open-label trial.7Bajaj J.S. Heuman D.M. Sanyal A.J. et al.Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.PLoS One. 2013; 8e60042Crossref PubMed Scopus (271) Google Scholar Moreover, rifaximin was associated with a greater abundance of potentially beneficial taxa and a decrease Klebsiella spp resistomes, as well as gram-negative ARG abundance. ARG abundance patterns in cirrhosis were distinct from healthy controls and those with inflammatory bowel disease, diabetes, and end-stage renal disease. It is important to bear in mind that these data demonstrate association but not causation of ARGs in cirrhosis progression. Because ARGs may not always be expressed, the presence of the gene does not accurately predict phenotypic AMR and future studies are required to characterize both gene and protein expression to provide phenotypes. Nevertheless, these data are novel, albeit limited by the small number of samples in the rifaximin cohort (the pre–post rifaximin analyses were done on just 19 patients) and they represent a snapshot taken at a single timepoint. Some patients in the cirrhosis cohorts were already on rifaximin when sampled, which does confound the analysis. Furthermore, 8 weeks of treatment with rifaximin may not have been sufficient to see the development of rifaximin resistance genes, although in a recent study 50% of patients prescribed rifaximin for encephalopathy developed rifaximin-resistant staphylococcal isolates after as little as 1–7 weeks of treatment.8Chang J.Y. Kim S.E. Kim T.H. et al.Emergence of rifampin-resistant staphylococci after rifaimin administration in cirrhotic patients.PLoS One. 2017; 12e0186120Crossref PubMed Scopus (11) Google Scholar It is unclear whether there is a temporal variation in carriage of ARGs and how this is influenced by interventions and hospitalization. Furthermore, could dietary changes, for example, fiber intake and consumption of fermented milk products, prebiotics (including lactulose) and probiotics, influence the ARGs identified? Infections caused by gram-positive bacteria and multidrug-resistant organisms (MDROs) constitute a prevalent and growing health care problem in patients with cirrhosis; 35% of patients with cirrhosis acquire nosocomial infections in hospital compared with 5% of patients without cirrhosis.9Fernandez J. Acevedo J. Castro M. et al.Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study.Hepatology. 2012; 55: 1551-1561Crossref PubMed Scopus (383) Google Scholar In data collected data from >1300 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers worldwide, the prevalence of MDROs was estimated to be 34%. Independent risk factors for MDRO infections included antibiotic prescription and health care interventions/exposure.10Piano S. Singh V. Caraceni P. et al.Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.Gastroenterology. 2019; 156: 1368-1380 e10Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Indeed, the prescription of long-term quinolones for the prophylaxis of spontaneous bacterial peritonitis has been associated with the carriage of MDROs with rates approaching 40% with the inherent risk of breakthrough bacterial peritonitis.4Patel V.C. Williams R. Antimicrobial resistance in chronic liver disease.Hepatol Int. 2020; 14: 24-34Crossref PubMed Scopus (8) Google Scholar The CANONIC Study group recently reported a concerning increase of culture-positive MDRO infections in patients with cirrhosis from 29% in 2011 to 38% in 2017 and 2018 in Europe.11Fernandez J. Prado V. Trebicka J. et al.Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe.J Hepatol. 2019; 70: 398-411Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar In a prospective cohort study of liver transplant recipients evaluating 998 stool samples and 119 rectal swabs from 128 patients, MDRO colonization was detected in 67% of patients at least once and was significantly associated with subsequent MDRO infection. High rates of carriage with Enterobacterales resistant to third-generation cephalosporins, carbapenem-resistant Enterobacterales and vancomycin-resistant Enterococci were observed.12Macesic N. Gomez-Simmonds A. Sullivan S.B. et al.Genomic surveillance reveals diversity of multidrug-resistant organism colonization and infection: a prospective cohort study in liver transplant recipients.Clin Infect Dis. 2018; 67: 905-912Crossref PubMed Scopus (27) Google Scholar Surprisingly, no carbapenem-resistant Enterobacterales were detected in these cohorts, which could be due to enhanced susceptibility of the gram-negative cell wall to disruption and in turn degradation of the DNA over time. However, methicillin-resistant Staphylococcus aureus, one of the most important causes of hospital infections worldwide and highly prevalent in US health care settings, was also not detected. The gut microbiome of patients with cirrhosis is dysbiotic (characterized by a decrease in diversity) with an overabundance of pathogenic species. The gut microbiome has prime importance in the pathogenesis of cirrhosis with an evolution from health to dysbiosis associated with progression to chronic liver failure.13Bajaj J.S. Heuman D.M. Hylemon P.B. et al.Altered profile of human gut microbiome is associated with cirrhosis and its complications.J Hepatol. 2014; 60: 940-947Abstract Full Text Full Text PDF PubMed Scopus (529) Google Scholar Dysbiosis and bacterial translocation culminate in systemic inflammation, endotoxemia and innate immune dysfunction, referred to as cirrhosis-associated immune dysfunction, which predisposes to infection resulting in hospitalization and worsening liver function and is associated with a high mortality rate.14Albillos A. Lario M. Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.J Hepatol. 2014; 61: 1385-1396Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar,15Cirera I. Bauer T.M. Navasa M. et al.Bacterial translocation of enteric organisms in patients with cirrhosis.J Hepatol. 2001; 34: 32-37Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar The gut microbiota are by far the largest reservoir of MDROs. Collectively, the AMR genes contained within the microbiome are known as the resistome. Antibiotics decrease colonization resistance, enabling MDROs to establish. Intestinal inflammation and barrier damage have been shown to increase AMR carriage and transmission.16Stecher B. Denzler R. Maier L. et al.Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae.Proc Natl Acad Sci U S A. 2012; 109: 1269-1274Crossref PubMed Scopus (250) Google Scholar,17Diard M. Bakkeren E. Cornuault J.K. et al.Inflammation boosts bacteriophage transfer between Salmonella spp.Science. 2017; 355: 1211-1215Crossref PubMed Scopus (92) Google Scholar Bacterial adherence to mucosal surfaces and barrier damage plays a pivotal role in cirrhosis progression, making them potential targets in the development of novel antimicrobial therapeutics (Figure 1).18Tranah TH, Edwards LA, Schnabl B, et al. Targeting the gut-liver-immune axis to treat cirrhosis. Gut 2020l70:982–994.Google Scholar Not only can gastrointestinal colonization facilitate horizontal gene transfer, but it can also serve as a reservoir for the spread of AMR organisms into the environment by contamination.19Huddleston J.R. Horizontal gene transfer in the human gastrointestinal tract: potential spread of antibiotic resistance genes.Infect Drug Resist. 2014; 7: 167-176Crossref PubMed Scopus (263) Google Scholar Targeting the gut microbiome to prevent and decrease AMR in patients with cirrhosis could make a significant impact on individual patient outcomes, as well as decrease environmental contamination with MDROs. The development of therapies that can favorably manipulate the gut microbiome have the potential to have a huge real-world impact on the millions of people who suffer from cirrhosis and whose outcomes are adversely impacted by MDRO infections. This finding represents a paradigm change in the therapeutic landscape, which might conceivably influence clinical guidelines within the decade and lead to greater rationalization of antibiotics. Such strategies might include fecal microbial transplantation or the use of bacteriophage therapies.