Researchers published their findings in the New England Journal of Medicine today. The phase 3 clinical trial’s outcomes suggest that an antibiotic currently used to treat pneumonia may also be a viable treatment for bloodstream infections brought on by bacteria resistant to antibiotics.
For the treatment of patients with complicated Staphylococcus aureus bacteremia, including methicillin-resistant S aureus (MRSA), the cephalosporin antibiotic ceftobiprole was found to be noninferior to daptomycin in a trial headed by investigators from Duke University and funded by the US Department of Health and Human Services.
Ceftobiprole, according to the researchers, may represent a significant new treatment option for a common and frequently fatal infection. An estimated 120,000 cases of S aureus bacteremia with a 25% mortality rate at three months are reported in the US each year.
Thomas Holland, MD, an associate professor in the Duke University School of Medicine’s Department of Medicine and the chair of the study’s data review committee, stated in a press release that “this is an area of true need.” “For more than 15 years, no new antibiotic has been approved for the treatment of S. aureus bacteremia.”
Results meet noninferiority criteria
In August 2018 through March 2022, researchers enrolled 390 adults hospitalized with complicated S aureus bacteremia at 60 sites across 17 countries for the double-blind ERADICATE trial. A 1:1 randomization was used to assign participants to receive 500 mg of ceftobiprole intravenously or 6 mg of daptomycin per kilogram of body weight.
Overall treatment success, which is characterized as survival, symptom improvement, bloodstream clearance of S aureus, and lack of new complications at 70 days, was the main efficacy outcome of the trial. There was a 15% noninferiority margin. Microbiologic eradication and mortality were secondary outcomes. The investigators evaluated adverse events as well.
387 of the 390 patients who were enrolled (189 in the group treated with ceftobiprole and 198 in the group treated with daptomycin) had S aureus bacteremia that was confirmed by culture and were treated. 94 patients received treatment for complicated MRSA bacteremia (45 in the ceftobiprole group and 49 in the daptomycin group). A complex case of S aureus bacteremia associated with right ventricular endocarditis affected twenty-five patients.
The noninferiority criteria were met by 132 (69.8%) of the 189 patients who received ceftobiprole, as opposed to 136 of 198 (68.7%) in the daptomycin group (adjusted difference, 2.0 percentage points; 95% –7.1 to 11.1). The results held true for the major subgroups of patients, such as those with bacteremia caused by MRSA and methicillin-susceptible S aureus (MSSA).
This is an area of true need….There has not been a new antibiotic approved for the treatment of S. aureus bacteremia for over 15 years.
As for the secondary outcomes, 82% of ceftobiprole patients had microbiologic eradication, compared with 77.3% of daptomycin patients (adjusted difference, 5.1 percentage points; 95% –2.9 to 13.0). Mortality was 9.0% in the ceftobiprole group and 9.1% in the daptomycin group (adjusted difference, 0.5 percentage points; 95% CI, –6.2 to 5.2).
Serious adverse events occurred in 18.8% and 22.7% of patients, respectively, out of 63.4% and 59.1% of patients who reported having adverse events while taking ceftobiprole and daptomycin, respectively.
“This double-blind trial’s results indicate that ceftobiprole may be a helpful treatment option for patients with complicated S. aureus bacteremia, such as right-sided infective endocarditis brought on by either MSSA or MRSA,” the researchers wrote in their conclusion.
FDA approval sought
In Europe, ceftobiprole is licensed and sold to treat pneumonia under the brand names Zevetra and Mabelio. The US Food and Drug Administration (FDA) rejected the New Drug Application (NDA) that the trial’s sponsor, the Swiss biopharmaceutical company Basilea Pharmaceutica, filed in 2008 to request approval of the antibiotic for severe skin infections.
Another NDA that Basilea filed in August contains data from the ERADICATE trial. In order to treat S aureus bacteremia, which includes right-sided infective endocarditis, the company is requesting FDA approval for the medication. Additionally, it is requesting approval to treat community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin-structure infections (ABSSSIs).
“Our finished Phase III program shows the effectiveness of ceftobiprole in this complex infection,” Marc Engelhardt, MD, chief medical officer at Basilea, stated in a press release from the business. The wider clinical utility of ceftobiprole is supported by the two Phase III studies in ABSSSI and CABP that were successfully completed.
Basilea states that it anticipates hearing back from the FDA by 2024’s second quarter.
