Omadacycline Demonstrates Safety, Possible Utility for Healthcare-Associated Infection Compared to Vancomycin

Antibiotic utility for different indications remains an important area of research. One specific, antibiotic, omadacycline, may be a suitable treatment for Clostridioides difficile infection (CDI) due to its ability to achieve high fecal concentrations and produce distinct gut microbiota diversity changes while preserving key Firmicutes groups, as shown in a phase 1 clinical trial.

Compared to vancomycin, a commonly used and guideline-preferred antibiotic associated with a high CDI recurrence rate, omadacycline produced rapidly detectable fecal concentrations and significant, distinct changes in the microbiome’s beta diversity, highlighting the importance of changes in the gut microbiome for monitoring antibiotic development.¹

“Both the omadacycline and vancomycin groups showed significant changes in their microbiomes when we looked at how diverse they were internally (alpha diversity). However, when we compared the changes between the two groups (beta diversity), they were noticeably different from each other,” said Kevin Garey, MS, PharmD, Robert L Boblitt Endowed Professor of Drug Discovery at the University of Houston College of Pharmacy, in a press release.²

The US Centers for Disease Control and Prevention estimates Clostridioides difficile causes nearly 500,000 infections in the United States every year, with about 1 in 6 patients experiencing reinfection in the subsequent 2-8 weeks. CDI can affect anyone, but it is commonly associated with the use of broad-spectrum antibiotics due to their disruption of the gut microbiota. Although omadacycline has previously shown potent in vitro activity against Clostridioides difficile, its fecal pharmacokinetics and gut microbiome changes require further exploration and comparison to existing CDI antibiotics.³

To assess the fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin, Garey and a team of investigators conducted a nonblinded, randomized clinical trial in healthy volunteers aged 18–40 years, limited to patients without a history of cardiovascular disease, gastrointestinal disease, hepatic disease, renal disease, diabetes, depression, vertigo, tinnitus, or diminished hearing, and who were not current tobacco users. Patients were excluded from the study if they received an antibiotic within 90 days prior to enrollment, were currently taking anticoagulants or probiotics, were pregnant, or were allergic to the study medications.¹

In total, 16 healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years and who were predominantly male (62.5%) were enrolled in the study and randomly assigned to receive a 10-day course of once-daily omadacycline or vancomycin given 4 times daily. Stool samples were collected at baseline prior to dosing, daily during therapy, and at 2 follow-up visits. Investigators assessed omadacycline and vancomycin stool concentrations and compared microbiome changes, further examining the rate of adverse events in both treatment groups.¹

All stool samples across both groups were categorized as ≤ type 4 on the Bristol stool chart. Of the 7 stool samples provided by the omadacycline group on day 1, 85.7% demonstrated omadacycline concentrations >10 µg/g stool, and all showed concentrations >900 µg/g stool by day 2. In the vancomycin group, 57.1% of day 1 stool samples had no measurable vancomycin concentrations and 28.6% still had unmeasurable concentrations on day 2.¹

What You Need to Know

Notable differences in microbiome beta diversity were observed between the omadacycline and vancomycin groups, emphasizing the importance of monitoring microbiome changes in antibiotic development.

The study compared the fecal pharmacokinetics and gut microbiome effects of oral omadacycline to oral vancomycin in a nonblinded, randomized clinical trial with healthy volunteers.

Both omadacycline and vancomycin groups experienced significant reductions in Firmicutes and Actinobacteria phyla, with a proportional increase in Proteobacteria phylum abundance.

However, by day 3 of antibiotic therapy, investigators noted both groups had similar drug concentrations. Maximum mean concentrations were achieved on day 2 for omadacycline (4785 µg/g stool) and on day 9 for vancomycin (3990 µg/g stool).¹

A significant difference in alpha diversity as measured by Shannon diversity index was observed following therapy in both the omadacycline and vancomycin groups. Compared to baseline, Shannon diversity decreased significantly during therapy in both the omadacycline (P = .0078) and vancomycin (P = .016) groups and continued to be significantly reduced at the end of therapy compared to baseline (P = .0078 for omadacycline and P = .025 for vancomycin).¹

A total of 272 fecal samples from the 16 participants were included for qPCR and DNA metagenomic analyses. Both groups experienced significant reductions in Firmicutes phylum and Actinobacteria phylum with a significant proportional increase in Proteobacteria phylum abundance (all P < .0001). Investigators also pointed out a distinct decrease of Bifidobacteriaceae (−1.3, ± 0.2%; P < .0001) in the vancomycin group compared to the omadacycline group.¹

Safety analyses revealed omadacycline was well tolerated with a similar adverse event profile compared to vancomycin. A total of 18 adverse events were reported from 12 study participants, with 7 in the omadacycline group and 5 in the vancomycin group, all ranking as mildly (n = 16) or moderately (n = 2) severe and not lasting more than 24 hours. Of note, 15 adverse events were categorized as suspected or possibly related to the study drug and occurred equally in both groups, except vomiting, which only occurred in the omadacycline group.¹

“Omadacycline caused a distinctly different effect on the microbiome than vancomycin. This could explain why Omadacycline is a safe drug to give to patients at high risk for C diff infection,” Garey said.² “This could become a new method in drug development to see if antibiotics are not only killing the bacteria causing infections but not causing harm to the beneficial microbes that live in our body.”