No Effect of Lactobacillus rhamnosus GG on Eradication of Colonization by Vancomycin-Resistant Enterococcus faecium or Microbiome Diversity in Hospitalized Adult Patients

Abstract

The purpose of this trial was to evaluate the efficacy of a 4-week supplementation of Lactobacillus rhamnosus GG (LGG) in eliminating the gastrointestinal carrier state of vancomycin-resistant Enterococcus faecium (VREfm) in hospitalized adults. The primary outcome of the study was the number of patients with cleared VREfm colonization after the 4-week intervention. Secondary outcomes were clearance of VREfm colonization at weeks 8, 16, and 24, number of VREfm infections (isolated from nonintestinal foci), and changes in fecal microbiome diversity after the intervention. The trial was a multicenter, randomized, double-blind, placebo-controlled trial in hospitalized adult VREfm carriers. Patients were enrolled and randomized to receive 60 billion CFU of LGG daily or placebo for 4 weeks. For a subgroup of patients, rectal swabs for VREfm were collected also at 8, 16, and 24 weeks and analyzed using shotgun metagenomics. Patients ingesting a minimum of 50% of the probiotic during the 4-week intervention were included in subsequent outcome analyses (48 of 81 patients). Twelve of 21 patients in the LGG group (57%) compared to 15 of 27 patients in the placebo group (56%) cleared their VREfm carriage. Eighteen patients completed the entire 24-week intervention with the same minimum compliancy. Of these, almost 90% in both groups cleared their VREfm carriage. We found a statistically significant difference between VREfm clearers and nonclearers regarding metronidazole and vancomycin usage as well as length of hospitalization after inclusion. The microbiome analyses revealed no significant difference in alpha diversity between the LGG and the placebo group. Beta diversity differed between the groups and the different time points. This study did not show an effect of LGG in eradication of VREfm after a 4-week intervention. IMPORTANCE Whereas other studies exploring the effect of L. rhamnosus in clearing VREfm from the intestine included children and adults, with a wider age range, our study consisted of a geriatric patient cohort. The natural clearance of VREfm in this study was almost 60% after 4 weeks, thus much higher than described previously. Also, this study characterizes the microbiome of VREfm patients in detail. This article showed no effect of the probiotic L. rhamnosus in clearing VREfm from the intestine of patients.

Keywords: Lactobacillus rhamnosus; gut microbiome; probiotics; vancomycin-resistant Enterococcus faecium.

FIG 1

Flowchart based on CONSORT Reference (48) for patients screened and enrolled in the study. ITT, intention to treat; PP analysis, per protocol analysis.

FIG 2

Microbiome diversity. Alpha diversity in terms of (A) richness and (B) Shannon diversity for the LGG and placebo groups at baseline, 4 weeks, and 24 weeks. Beta diversity in terms of PCoA of Aitchison distances colored by treatment arm (C), patient (D), clearers and nonclearers of VREfm (E), and length of hospitalization after inclusion as well as use of vancomycin or metronidazole (F). (C to E) Squares represent baseline, stars week 4, and open circles week 24. (F) Stars represent VREfm clearers, squares represent VREfm nonclearers. B, baseline; W4, week 4; W24, week 24; van, vancomycin; met, metronidazole.

FIG 3

Study set-up for participants analyzed in outcome analyzes and number of patients in follow-up visits at each time point.