Letter: Association between terlipressin and multidrug-resistant organism rectal colonization: Authors' reply

Abstract

We read with great interest the letter to the editors by Tan et al.¹ discussing our study² and their own findings concerning the impact of terlipressin on colonization of multidrug-resistant bacteria (MDRO) in patients with decompensated liver cirrhosis. In our study, apart from the well-known risk factor of antibiotic therapy, terlipressin administered in the previous 14 days was the only independent pharmaceutical agent associated with MDRO colonization. Similarly, Tan et al. observed a significant association of terlipressin therapy with the detection of MDRO colonization in univariate analysis. However, in multivariate analysis, when considering other risk factors, such as prior detection of (the same) MDRO in the last 365 days before liver transplantation, terlipressin was only borderline significant associated with vancomycin-resistant Enterococcus spp. (HR 2.0, p = 0.06) and not significant with MDR Gram-negative (GN) bacteria (HR 2.2, p = 0.09) colonization. More surprisingly, in the multivariate analysis also the antibiotic therapy was not associated with MDRO colonization. This raises doubts about the selection of the population in this study. Indeed, this was a highly selected patient collective of 594 liver transplant recipients. Being on the waiting list for liver transplant implies that patients had an intensive health care contact (clinical decompensations, diagnostic/therapeutic procedures). By contrast, our data are based in ‘all comers’ in an acute decompensation from a training cohort, validation cohort and international external cohort with in total almost 656 patients.

We agree with the authors, for patients with advanced liver disease and previous health care exposure such as antibiotic therapy, hospitalization or ICU admission constitute important risk factors to favour MDRO colonization. In our study, these commonly accepted risk factors equally distributed among both the groups with and without terlipressin treatment in all three cohorts. Additionally, we carefully considered all risk factors in our analyses and even matched cohorts according to disease severity and antibiotic therapy as well as other potential confounders while matching was not performed in the cohort of Tan et al.

In their cohort prior colonization with (the same) MDRO was the strongest independent risk factor in multivariate analysis. Because of that, the authors proposed to focus on patients' history and MDRO risk factors. Indeed, MDRO risk factors, including prior MDRO colonization, were extensively considered in our study and consecutive analyses. Only patients with a new MDRO isolation resulting from rectal MDRO screening were considered as (de novo) colonized patients. Thus, all patients with previous known and similar MDRO were not considered as (de novo) colonized. Accordingly, previous MDRO colonization with the same/a similar MDRO could neither be a confounder nor a risk factor in our analyses.

Taken together, the data by Tan et al. rather support our findings that terlipressin seems to be associated with MDRO colonization, which is a relevant problem in patients with liver cirrhosis. Multiple risk factors for MDRO acquisition should be considered. Further studies—preferably randomized controlled trials—are necessary to unravel the role and the mutual influence of each of these risk factors, including terlipressin use.

Marcus M. Mücke: Conceptualization; investigation; writing – original draft; writing – review and editing. Wenyi Gu: Writing – review and editing. Javier Fernandez: Conceptualization; writing – original draft; writing – review and editing; supervision. Jonel Trebicka: Supervision; conceptualization; investigation; writing – original draft; writing – review and editing.

Jonel Trebicka was supported by the German Research Foundation (DFG) project ID 403224013—SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875) and IHMCSA (project ID 964590) projects have received funding from the European Union's Horizon 2020 research and innovation programme. The manuscript reflects only the authors' views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish or preparation of the manuscript.

This article is linked to Mücke et al papers. To view these articles, visit https://doi.org/10.1111/apt.17899 and https://doi.org/10.1111/apt.18200