Reviewed by S. Shaefer Spires, MD, Duke Center for Antimicrobial Stewardship and Infection Prevention, Durham, NC
Long story short, it’s worse than we thought. The authors of this study in Cell Reports used both quantitative microbiologic culture and metagenomic sequencing to describe both the acute effects of a few commonly used antibiotics on the healthy volunteer gut microbiome as well as a persistent increase in antibiotic resistance genes observed for up to 6 months! We have all seen studies examining the impact of antibiotics in hospitalized patients’ gut microbiome, but all clearly have multiple confounding factors that likely impact the relative diversity of the microbiome other than antibiotics. This research group out of Washington University in St. Louis used healthy volunteers and shotgun metagenomics that allowed them to not only study the taxonomic diversity but also the resistome composition change over time associated with just 5-day courses of commonly used antibiotics.
They recruited 20 volunteers, randomized to 1 of 4 groups, to receive (1) azithromycin, (2) levofloxacin, (3) cefpodoxime, or (4) cefpodoxime + azithromycin. They sampled the gut microbiomes at 15 different timepoints, 4 before antibiotics and 11 after. To no one’s surprise they found that all the antibiotics decreased the microbiome overall bacterial load (mean reduction of 4.78 log-transformed CFU and 2.90 in aerobic and anaerobic bacterial titers respectively) as well as the species richness (Day 6 decreased by a mean of 11.5 when compared to 2 weeks before antibiotics). While most volunteers’ microbiome returned to similar species richness at 2 months, the overall composition and resistome were significantly different. However, those in the azithromycin group exhibited a significant delay in recovery of species richness. The non-azithromycin groups showed a recovery to baseline in CFU/ml counts and species richness by day 19 for both aerobic and anaerobic cultures, but the azithromycin groups (azithromycin and the cefpodoxime + azithromycin) continued to have significantly lower species richness until day 65.
Regarding the differences over time in the resistome, the antimicrobial resistance gene burden increased significantly for those volunteers receiving cefpodoxime, azithromycin, and the combination of the two. More specifically three resistance elements, cfxA, tetO, and tet40, increased significantly. These resistance elements can have substantial clinical implications but interestingly do not convey resistance to any of the antibiotics given in the study. Somewhat unexpectedly the levofloxacin group did not exhibit a significant change in the resistance burden over time.
In conclusion, this study was able to quantify what we all know is true, that even short courses of antibiotics have acute disturbances in the gut microbiome and may take months to recover. But they were also able to describe the long-lasting consequences on the resistance gene burden and composition differences of the gut microbiome even when the overall microbial burden recovers. Specifically, azithromycin (and its long half-life) resulted in delayed recovery and greater compositional differences throughout the end of the study. The authors should be applauded for their rigorous work and my antimicrobial stewardship talks will certainly contain several of the graphics from this study in the near future.
Reference:
Winston E. Anthony et al., “Acute and Persistent Effects of Commonly Used Antibiotics on the Gut Microbiome and Resistome in Healthy Adults,” Cell Reports 39, no. 2 (April 12, 2022). https://doi.org/10.1016/j.celrep.2022.110649