PREBIOTIC INULIN TO LIMIT ANTIMICROBIAL-RESISTANT INFECTIONS DURING CRITICAL ILLNESS: A PHASE II CLINICAL TRIAL

Background: Antibiotic resistance is a problem of the human gastrointestinal microbiome, which is the reservoir for the bacteria and plasmids that encode antibiotic resistance genes. Normal gut bacteria prevent colonization and subsequent infection with MDR organisms (MDROs) through competition for resources and other mechanisms. During critical illness, this function of the microbiome is lost, and there are no current treatments to restore it. Preliminary data indicates that the prebiotic fiber inulin may alter the gastrointestinal microbiome to improve gut barrier function, decrease colonization with MDROs, and reduce downstream risk for intensive care unit (ICU)-acquired MDR infections. Inulin is safe and well-tolerated, and it has beneficial effects in healthy volunteers. However, the impact of inulin during critical illness is unknown. This grant application proposes a double-blind, randomized clinical trial of inulin for the prevention of antibiotic-resistant infections in the ICU.Relevance to Topic Area: The proposed trial directly addresses the Topic Area of Antimicrobial Resistance by contributing towards novel therapies directed at MDR infections that will benefit critically ill military personnel and Veterans.Hypothesis/Objectives: The proposed trial hypothesizes that inulin maintains short-chain fatty acid (SCFA)-producing colonic anaerobes and that these bacteria are protective against MDRO colonization and subsequent MDR infection. Inulin, a vegetable-derived non-digestible polysaccharide is well established as the key nutrient source for SCFA-producing bacteria. Previous human studies have shown that (1) inulin increases levels of SCFA producers and SCFAs and (2) that this increase correlates with improved colonic mucosal integrity and resistance to MDR pathogens. In animal studies, inulin improves survival after pathogen challenge or injection with lipopolysaccharide. The short-term objective of the trial is to obtain feasibility and safety data and effect size estimates in the ICU setting in support of a definitive trial appropriately powered for a relevant clinical primary outcome (i.e., MDR infection). The long-term objective is to determine the efficacy of inulin for the prevention of MDR infections in ICU patients.Specific Aims: The overall aim is to determine whether inulin improves gut colonization resistance against antibiotic-resistant pathogens and therefore prevents antibiotic-resistant infections in the setting of critical illness. To accomplish this, 90 critically ill adults who are receiving broad-spectrum antibiotics will be blindly randomized 1:1:1 to receive placebo, inulin 8 g twice daily, or inulin 16 g twice daily for a minimum of 7 days, with bedside follow-up extending to 30 days or hospital discharge. The specific aims are: 1: To determine the feasibility, tolerability, and safety of inulin in the intensive care unit. 2: To determine the impact of inulin on gut colonization with antibiotic-resistant pathogens.2A/exploratory: To determine the impact of inulin on ICU-acquired antibiotic-resistant infections.Study Design: This will be a randomized, double-blind trial of adults newly admitted to a medical ICU who meet Sepsis-3 criteria and are receiving broad-spectrum antibiotics. The primary outcomes will be feasibility (Aim 1), which will be evaluated in terms of enrollment rate, protocol adherence, and intervention fidelity, and rates of gut colonization with antibiotic-resistant pathogens (Aim 2), which will be evaluated from rectal swabs taken on study Day 7 by selective and non-selective culture and also by multiplex qPCR of antibiotic resistance genes. An exploratory outcome (Aim 2A) will be a composite of 30-day rates of death or ICU-acquired antibiotic-resistant infections, conducted among subjects who receive one or more doses of the assigned intervention.Clinical Impact: Inulin is a novel yet simple and apparently safe therapy that may reduce the spread of antimicrobial resistance and prevent infections with MDROs in at-risk patients.Military Relevance: Active military personnel are susceptible to MDR infections due to the nature of open trauma-related infections, deployment in regions with high prevalence of MDRO colonization, and the impossibility of practicing infection control in combat situations. For example, up to 75% of E. coli isolates from traumatic wounds in Iraq or Afghanistan 2009-2012 were positive for ESBL bacteria. By the time Soldiers return home, it is often too late to prevent downstream complications. Even after evacuation to the U.S., post-hospital discharge superinfection and complications are common. The problem requires a solution that is preventive rather than reactive, safe, and easily implemented even in field settings. Inulin has these characteristics and therefore the potential to decrease the burden of antibiotic-resistant infections among military personnel at home and abroad.