麻豆传媒

In the single-center clinical trial, most renal transplant recipients were negative for multidrug-resistant pathogens shortly after receiving fecal microbiota transplants (FMT), with longer times to recurrent infections.

Eight of 10 participants who received at least one FMT, and eight of nine participants who received all FMT treatments were multidrug-resistant organism (MDRO) negative by day 36 after their last study visit, reported Michael Woodworth, MD, MSc, of the Emory University School of Medicine in Atlanta, Georgia, and colleagues in .

"As an infectious disease doctor, one of the main things we do is prescribe antibiotics, and you don't always have full confidence that you're doing the right thing," Woodworth told 麻豆传媒. "But I think that ... for all the challenges of antibiotic resistance, it's very attractive to look towards the future when hopefully we can find ways without antibiotics to slow the emergence of antibiotic resistance."

The median time to negative stool culture was significantly shorter in the group who received FMT to start compared with the group that started with an observation period (35 days vs 88 days, P=0.046). When compared to a contemporaneous control group of renal transplant recipients who met PREMIX inclusion criteria but did not receive FMT, trial participants had a longer time to recurrent MDRO infection at 180 days (P=0.037).

Unexpectedly, researchers found that after FMT in some participants, certain MDRO strains were replaced by bacteria of the same species though less antibiotic-resistant, termed "conspecific strain competition."

"It looked like before FMT, this resistant strain was there," Woodworth said. "But then, after the time of FMT, we saw a signal that more susceptible bacterium was then more strongly detected, so this suggested to us that they might be competing." They conducted in vitro studies to test this theory, combining the resistant strain with its less-resistant relative, and found that "they actually make a little zone of clearance where they're like kind of killing each other."

Through metagenomic sequencing, researchers also identified two microbiome "trajectories" among participants -- one group had a baseline microbiome composition that was more dissimilar to the donor, with higher relative abundance of certain bacteria. This group appeared to respond more quickly to FMT, with more key donor taxa in recipients after FMT.

"We were able to identify a smaller group of bacteria that look very likely to have come from the donor, and have kind of taken root or engrafted in the recipients over time, and that are likely to be a good set of bacteria to focus on for future studies," Woodworth said.

Renal transplant patients are at greater risk of MDRO infections -- like from vancomycin-resistant enterococci (VRE) or gram-negative -- because they are committed to antibiotics after transplant and have high levels of exposure to potential infections from extended time spent in hospitals. Many of the "last line" antibiotics used for MDROs are nephrotoxic.

Previous promising recurrent Clostridioides difficile infections with FMT, but these results may not be generalizable to patients with "milder states of microbiome dysfunction," the authors noted. studies have FMT is safe for transplant recipients, and that changes to the gut microbiota might reduce urinary tract infections (UTIs) in this population, but researchers thought this may be the first clinical trial of FMT for solid organ transplant recipients.

There were 11 renal transplant patients enrolled between May 2018 and February 2020 who completed at least one visit cycle. Patients were randomly assigned to polyethylene glycol bowel preparation or preparation followed by FMT delivery as retention enema. The observation group waited 36 days after preparation for their first FMT. Any participants with MDRO growth in stool after the first 36-day FMT cycle got another cycle. Visits within each cycle for observation or sample collection were at days 1, 2, 15, and 36. Follow-up was at 180 days for recurring MDRO infection.

All FMT doses were from a single donor, who received blood, urine, and stool testing, with screening for behavioral risk factors and potentially transmissible pathogens, including MDROs and Escherichia coli pathotypes. Samples from participants were subject to DNA extraction, bacterial draft genome analyses, metagenomic analyses, and metabolomic analyses. Based on initial findings, researchers also conducted in vitro bacterial strain competition experiments with samples from four participants.

Participants were 55% female, with a median age of 65. All 11 participants had a history of extended-spectrum β-lactamase (ESBL) UTIs. One had a history of ESBL pneumonia, and many were colonized with additional MDROs, including VRE, carbapenem-resistant Enterobacterales, and multidrug-resistant Pseudomonas aeruginosa, which were among the target MDROs, as informed by CDC antibiotic resistance threat reports and local epidemiology.

All 11 participants were MDRO-positive. All completed at least one visit cycle, and nine completed all treatments. The therapy was well tolerated with few severe adverse events.

Study limitations included recruitment interrupted by COVID-19, which meant enrollment fell short of powering their secondary efficacy endpoint. Also, it was possible that participants were colonized with MDROs at levels too low to detect.

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