Impact of Antibiotic Duration on Gut Microbiome Composition and Antimicrobial Resistance: A Substudy of the BALANCE Randomized Controlled Trial

Abstract

Background: Maintaining a diverse gut microbiome and minimizing antimicrobial resistance gene (ARG) carriage through reduced antibiotic utilization may decrease antimicrobial resistance. We compared gut microbiome disruption and ARG carriage following 7 or 14 days of antibiotics for treatment of bacteremia in a substudy of the BALANCE randomized controlled trial.

Methods: The BALANCE randomized controlled trial enrolled 3631 participants with bacteremia, who were randomized 1:1 to receive 7 or 14 days of antibiotics. Rectal swabs were collected from 131 participants and analyzed with metagenomic sequencing to characterize the gut microbiome and ARGs. The primary outcome was change in gut microbiome diversity at day 7 vs 14.

Results: Forty-one participants (n = 28 in the 14-day group, n = 13 in the 7-day group) had samples available for the primary analysis, with an imbalance in piperacillin-tazobactam exposure between groups. Change in gut microbiome diversity at day 7 vs 14 was comparable between the 14-day group (median, 0.07; IQR, -0.46 to +0.51) and 7-day group (median, 0.19; IQR, -0.77 to +0.22; P = .49). Change in ARG abundance at day 7 vs 14 did not differ by treatment duration, nor did the abundance of individual ARGs. We did not observe any change in gut microbiome diversity or ARG carriage at enrollment vs day 7.

Conclusions: In this subset of patients from the BALANCE randomized controlled trial, we did not detect greater gut microbiome disruption or ARG carriage among participants who received 14 vs 7 days of antibiotics, but we were limited by small sample size and imbalances between groups.

Keywords: antibiotics; antimicrobial resistance; antimicrobial stewardship; bacteremia; microbiome.

Figure 1.

CONSORT diagram of BALANCE randomized controlled trial enrollment and inclusion in the microbiome substudy. BALANCE ClinicalTrials.gov NCT03005145 [12].

Figure 2.

Impact of antibiotic treatment duration on gut microbiome composition. A, Gut microbiome composition at the phylum level in both treatment groups at days 7 and 14. Comparison of change in gut microbiome from day 7 to 14 between treatment groups: B, Shannon diversity; C, species richness; D, evenness; and E, Berger-Parker index. F, Comparison of Bray-Curtis dissimilarity of day 7 and 14 samples between treatment groups. B–F, Data are presented as median (IQR). P values obtained with the Mann-Whitney U test.

Figure 3.

Change in gut microbiota composition from day 7 to 14 based on antibiotic duration. Comparison of gut microbiota between days 7 and 14 in both treatment groups: A, Shannon diversity; B, species richness; C, evenness; and D, Berger-Parker index. P values obtained with the Wilcoxon matched pairs signed-rank test.

Figure 4.

Impact of antibiotic treatment duration on gut resistome composition and ARG burden. A, Overall composition of the gut resistome at the ARG level at days 7 and 14 in both treatment groups. Change from day 7 to 14 between treatment groups: B, total ARG abundance; C, clinically significant ARG abundance. B–C, Data are presented as median (IQR) P values obtained with the Mann-Whitney U test. ARG, antimicrobial resistance gene; RPKM, reads per kilobase per million.