The results of a phase 3 clinical trial show an antibiotic used for treating pneumonia could be an option for treating bloodstream infections caused by antibiotic-resistant bacteria, researchers reported today in the New England Journal of Medicine.
The trial, which was led by investigators from Duke University and received funding from the US Department of Health and Human Services, found that the cephalosporin antibiotic ceftobiprole was noninferior to daptomycin for treatment of patients with complicated Staphylococcus aureus bacteremia, including methicillin-resistant S aureus (MRSA).
The investigators say ceftobiprole could be an important new option for an infection that is common and frequently lethal. An estimated 120,000 S aureus bacteremia cases occur in the United States each year, with a mortality rate of 25% at 3 months.
"This is an area of true need," Thomas Holland, MD, associate professor in the Department of Medicine at Duke University School of Medicine and chair of the study's data review committee, said in a press release. "There has not been a new antibiotic approved for the treatment of S. aureus bacteremia for over 15 years."
Results meet noninferiority criteria
For the double-blind ERADICATE trial, investigators enrolled 390 adults hospitalized with complicated S aureus bacteremia at 60 sites in 17 countries from August 2018 through March 2022. Participants were randomized 1:1 to receive either 500 milligrams (mg) of ceftobiprole intravenously or daptomycin at a dose of 6 mg per kilogram of body weight.
The primary efficacy outcome of the trial was overall treatment success—defined as survival, symptom improvement, S aureus bloodstream clearance, and absence of new complications—at 70 days. The noninferiority margin was 15%. Secondary outcomes included mortality and microbiologic eradication. Investigators also assessed adverse events.
Of the 390 patients enrolled, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had culture-confirmed S aureus bacteremia and received treatment. Of those treated, 94 (45 in the ceftobiprole group and 49 in the daptomycin group) had complicated MRSA bacteremia. Twenty-five patients had complicated S aureus bacteremia related to endocarditis on the right side of the heart.
Of the 189 patients who received ceftobiprole, 132 (69.8%) had overall treatment success, compared with 136 of 198 (68.7%) in the daptomycin group (adjusted difference, 2.0 percentage points; 95% –7.1 to 11.1), a result that met the noninferiority criteria. The findings were consistent in the key subgroups, including patients with MRSA and methicillin-susceptible S aureus (MSSA) bacteremia.
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.
Among the secondary outcomes, mortality was 9.0% and in the ceftobiprole group and 9.1% in the daptomycin group (adjusted difference, 0.5 percentage points; 95% CI, –6.2 to 5.2), and 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).
Adverse events were reported in 63.4% of ceftobiprole patients and 59.1% of daptomycin patients, with serious adverse events occurring in 18.8% and 22.7% of patients, respectively.
"The results of this double-blind trial show that ceftobiprole may be a useful treatment option for patients with complicated S. aureus bacteremia, including infective endocarditis on the right side of the heart, caused by either MSSA or MRSA," the investigators concluded.
FDA approval sought
Ceftobiprole is approved and marketed under the names Zevetra and Mabelio in Europe for the treatment of pneumonia. Swiss biopharmaceutical company Basilea Pharmaceutica, which sponsored the trial, submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) in 2008 seeking approval of the antibiotic for complicated skin infections, but the NDA was rejected.
Data from the ERADICATE trial is included in another NDA submitted by Basilea in August. The company is seeking FDA approval of the drug to treat S aureus bacteremia, including right-sided infective endocarditis. It's also seeking approval for treating acute bacterial skin and skin-structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP).
"Our completed Phase III programme demonstrates the efficacy of ceftobiprole in this complicated infection," Basilea chief medical officer Marc Engelhardt, MD, said in a company press release. "The additional successfully completed Phase III studies in ABSSSI and CABP support the broad clinical utility of ceftobiprole."
Basilea says it expects a decision from the FDA by the second quarter of 2024.