麻豆传媒

WASHINGTON -- Investigational ceftobiprole was just as effective as daptomycin for bacterial bloodstream infections caused by Staphylococcus aureus bacteremia, the phase III trial demonstrated.

In the randomized head-to-head comparison, post-treatment success at 70 days was 69.8% with ceftobiprole and 68.7% with daptomycin, meeting prespecified criteria for non-inferiority, Thomas Holland, MD, of Duke University in Durham, North Carolina, reported here at IDWeek.

"Results were robust and consistent across all the main subgroups we looked at -- for antibiotic resistance, infection site, and treatment before enrollment to the study," Holland said.

Along with the primary endpoint, non-inferiority was met for all secondary endpoints as well, including all-cause mortality and microbiological eradication.

"It's been more than 15 years since the last trial that led to a new drug for S. aureus bacteremia," Holland told 麻豆传媒 in an interview following his presentation.

Currently, only vancomycin and daptomycin are approved for these difficult-to-treat infections, which carry a mortality rate of between 20% and 25%, he noted.

"Hopefully with this trial we will have a third antibiotic," said Holland.

Ceftobiprole is an advanced-generation cephalosporin with activity against gram-positive pathogens -- including methicillin-resistant S. aureus (MRSA) -- and gram-negative pathogens.

While the antibiotic is approved for use in Canada and Europe, the FDA rejected an application for its use in the U.S. in 2009, citing clinical trial misconduct. Holland noted that ERADICATE was adjudicated by an independent data review committee to ensure everything was on the up and up. Developer Basilea Pharmaceutica announced to FDA for approval by year's end.

The double-blind international trial was conducted from 2018 to 2022 across 60 sites in 17 countries. The efficacy analysis included 387 patients with S. aureus-positive blood cultures (94 with MRSA) randomized 1:1 to either ceftobiprole, or daptomycin with or without aztreonam.

The primary endpoint of post-treatment success at day-70 evaluation was defined as survival with symptom improvement and infection clearance, as well as no new S. aureus bacteremia complications or treatment with other possibly effective antibiotics.

As noted, secondary endpoints were non-inferior for ceftobiprole versus daptomycin, respectively:

• All-cause mortality: 9% vs 9.1%
• Microbiological eradication: 82% vs 77.3%
• New metastatic lesions or complications: 5.8% vs 5.6%

Demographics were balanced between groups, Holland reported. Patients had an average age of 56-57 years, two-thirds were men, and over 95% were white.

Ceftobiprole treatment was given to patients in a 500-mg infusion every 6 hours (day 1 to 8), then every 8 hours (day 9 onward for up to 42 days), with dose adjustments for renal function. Daptomycin was dosed at a range of 6-10 mg/kg every 24 hours, according to institutional standards.

Holland noted that the 6 mg/kg daptomycin dose was mandated by the FDA. "We believe a higher dose is probably better, so we did allow all sites to use higher doses if that was what was consistent with their practice," he said.

Clearance of bloodstream bacteria, confirmed by at least two negative blood cultures taken more than 24 hours apart, was similar for both groups (94% vs 95.2%). Clearance occurred a median of 3 days with ceftobiprole and 4 days with daptomycin for methicillin-sensitive S. aureus (MSSA), and 5 days in both groups for MRSA.

Relapse was seen in two patients on ceftobiprole (both of whom had MSSA) and four patients on daptomycin (two with MSSA, two with MRSA). No patients taking ceftobiprole developed antibiotic resistance, while three patients on daptomycin developed resistance.

Adverse events (AEs) overall were similar in both groups, with serious AEs reported in 18.8% of the ceftobiprole group and 22.7% of the daptomycin group. Drug-related AEs were elevated in the ceftobiprole group, however (13.1% vs 5.6%).

Gastrointestinal disorders and nausea were more common with ceftobiprole and were associated with more treatment discontinuations (4.7% vs 1.5% with daptomycin).

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