Novel treatment for Staph aureus bloodstream infections fails superiority trial

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The combination of the experimental bactericidal drug exebacase with standard-of-care antibiotics failed to improve clinical response in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and infective endocarditis, researchers reported today in Clinical Infectious Diseases.

The investigators say the results of the DISRUPT trial, a superiority-design phase 3 study, were unexpected given the outcome of a phase 2 trial, which found that clinical recovery in MRSA patients who received exebacase plus antibiotics was 42.8% percent higher compared with those who received antibiotics alone. The Food and Drug Administration granted exebacase Breakthrough Therapy designation in 2020 based on the phase 2 results.

In the phase 3 trial, 259 patients aged 12 and older with S aureus bacteremia/endocarditis were randomly assigned 2:1 to receive a single dose of intravenous exebacase—a first-in-class anti-staphylococcal lysin—or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population.

Clinical response rates at day in the MRSA patients were 50% for the exebacase-plus-antibiotics group compared with 60.6% in the patients who received antibiotics alone, and failure rates were 46.9% versus 39.4%, respectively. Overall, the incidence of treatment-emergent adverse events was similar in both groups.

Trial stopped early

The trial was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board.

The investigators say heterogeneity within the study population and relatively small sample size in both the phase 2 and 3 trials "may have increased the probability of imbalances in multiple components of the day 14 outcome," and that a larger sample size, 1:1 randomization, and using both MRSA and methicillin-susceptible S aureus patients for the primary analysis could enhance the study design.

"The failure of this trial offers important considerations for future investigators seeking to design superiority trials for regulatory approval in similar indications," they wrote.

Contrafect, the company that developed exebacase, filed for bankruptcy in December 2023.

The failure of this trial offers important considerations for future investigators seeking to design superiority trials for regulatory approval in similar indications.

Avian flu infects more poultry in 3 states

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Lisa Schnirring

Over the past few days, three states reported more highly pathogenic avian influenza outbreaks in poultry, including a commercial turkey farm in Indiana, according to the latest updates from the US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS).

backyard poultry — Paul Korecky / Flickr cc

Indiana's outbreak—its first since May 2023—occurred at a facility in Daviess County that had 13,100 turkeys.

Elsewhere, Florida and Maine reported outbreaks involving backyard flocks. Florida's outbreak was in DeSoto County, and in Maine, the virus struck a location in Kennebec County.

Pace of outbreaks slows

After a steady rise in poultry outbreak that began in early October, the pace of newly reported events since early January has slowed dramatically. So far this month, outbreaks have affected 2.02 million birds, compared to 11.47 million in December.

In related developments, APHIS reported about 60 more H5N1 detections in wild birds, mostly waterfowl across a wide swath of the country, from the Southwest to the Northeast. Most were wild birds found dead, including a few raptors, a gull, and an American crow.

Gut microbes influence susceptibility to, severity of viral respiratory infections, mouse study suggests

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Mary Van Beusekom, MS

Georgia State University (GSU) researchers report that the susceptibility of mice to respiratory virus infections (RVIs), as well as the infections' severity, depends at least in part on the microbiota in their intestines.

The researchers measured viral concentrations in the lungs several days after infection to assess how differences in microbe mix can influence RVI outcomes in mice with different intestinal microbiomes and in those differing only in the presence or lack of segmented filamentous bacteria (SFB). The mice had been bred in captivity under well-controlled conditions that ensured the absence of specific microbes.

The findings were published yesterday in Cell Host & Microbe.

SFB are gram-positive, spore forming bacteria found in the gut of rodents, fish, and chickens. A relative of Clostridium, these bacteria have been found to trigger an immune response in mice.

Lung macrophages disabled flu virus

Whether naturally acquired or introduced, SFB protected mice against flu, respiratory syncytial virus (RSV), and SARS-CoV-2 infection (COVID-19). The protection required the presence of alveolar macrophages (AMs; immune cells) in the lungs at baseline. In mice without SFB, AMs were quickly depleted as RVI progressed, but AMs in SFB-positive mice were intrinsically altered to prevent flu-triggered depletion and inflammatory signaling.

These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.

AMs directly disabled influenza virus, and transfer of SFB-transformed AMs into SFB-negative mice reinforced SFB-mediated protection against flu.

"These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity," the study authors wrote.

Andrew Gewirtz, PhD, co-senior author and regents' professor in the Institute for Biomedical Sciences at GSU, said the team thinks it is highly unlikely that SFB is the only gut microbe that can alter AMs, and consequently, vulnerability to RVI.

"Rather, we hypothesize that gut microbiota composition broadly influences proneness to respiratory virus infection," he said in a GSU news release. "Microbiota mediated programming of basally resident alveolar macrophages may not only influence the severity of acute respiratory virus infection, but may also be a long-term post-respiratory virus infection health determinant."