Prebiotic Inulin to Limit Antimicrobial-Resistant Infections During Critical Illness: A Phase II Clinical Trial

Antibiotic resistance is an emerging healthcare crisis. Critically ill patients (typically in intensive care units or ICUs) are among the hardest hit; over half of all infections in ICU patients are due to multidrug-resistant (MDR) bacteria, and widespread infection (sepsis) with these bacteria significantly increases risk of death. Active military personnel are particularly susceptible to acquisition of MDR organisms due to trauma-related infections, increased spread of MDR organisms in deployed medical treatment facilities, and working in regions where the prevalence of antimicrobial resistance is extremely high. Veterans Affairs (VA) healthcare facilities also face significant rates of MDR infections. There are currently no available therapies aimed at limiting the spread of antibiotic resistance in critically ill patients.

Antibiotic resistance in critical illness is a problem of the human microbiome, a term that describes the bacteria (both beneficial and harmful) that inhabit the human host. The gut microbiome is the key reservoir for the bacteria that have the ability to resist multiple antibiotics. Our own research and other studies show that serious infections that arise in the ICU frequently come from the patient's own gut. The normal gut microbiome has protective bacteria that prevent MDR bacteria from gaining a foothold, proliferating, and ultimately causing life-threatening infections. These protective bacteria include species that produce compounds called short chain fatty acids (SCFAs), which help protect against invasion and infection by MDR bacteria. Our group has found that during critical illness, proliferation of MDR organisms occurs when these key SCFA-producing bacteria are lost, and this process puts patients at risk for developing infections from bacteria with a high degree of antimicrobial resistance.

The proposed research hypothesizes that treatments aimed at preserving SCFA-producing bacteria will limit the proliferation of antimicrobial resistance and ultimately prevent life-threatening infections with MDR bacteria. Specifically, we propose a clinical trial testing inulin, a prebiotic fiber made from root vegetables, because inulin is the preferred nutrient source for SCFA-producing bacteria. Previous human studies show that inulin is safe, has the expected effect on these bacteria, and confers the desired downstream protective effects. However, these previous studies have been conducted in healthy volunteers who are unlikely to acquire infections and not in critically ill patients. This trial will test inulin for the prevention of antibiotic resistant infections in the ICU by randomizing 90 ICU patients 1:1:1 to receive placebo or one of two inulin doses for 7 days. The aims of the trial are to assess the safety and feasibility of inulin administration in ICU patients, as well as to assess the ability of inulin to limit the spread of antibiotic resistance in these patients. The trial directly addresses the Topic Area of Antimicrobial Resistance.

By facilitating the development of an intervention that is likely to be well tolerated and easy to implement, this trial has the potential to help prevent MDR infections in all critically ill patients. Specific features of inulin make it uniquely useful in military situations: ease of oral administration, lack of storage constraints (it is stable as a lightweight dry powder for 4+ years), low likelihood of side effects, and low cost. Current practice guidelines do not recommend routine supplementation with inulin or other prebiotic fibers during critical illness; if successful, the proposed approach would lead to a novel therapy with the potential to benefit millions of at-risk civilians, military personnel, and Veterans.