ERADICATE: Ceftobiprole Noninferior to Daptomycin for Complicated Staphylococcus aureus Bacteremia

(Adobe Stock)

Ceftobiprole is noninferior to daptomycin, with or without aztreonam, in adult patients with bacterial bloodstream infections caused by Staphylococcus aureus (SAB),according to the late-breaking results of the phase 3 ERADICATE trial (NCT03138733), presented at IDWeek 2022, held October 19-23, 2022, in Washington, DC.

Thomas Holland, MD, associate professor of medicine at Duke University School of Medicine and chair of the ERADICATE Data Review Committee, reported that the study met its primary and secondary endpoints comparing ceftobiprole versus daptomycin with or without aztreonam, with all-cause mortality, microbiological eradication rates, and new SAB complications ranking similar between the treatment groups.

“This is a landmark study in an area with a high need to provide new treatments to patients. Complicated Staphylococcus aureus bloodstream infections are common and associated with high morbidity and significant mortality and available antibiotic treatment options are limited, especially when methicillin-resistant Staphylococcus aureus (MRSA) is involved,” Holland said in a statement that first announced the topline results.

The IDWeek presentation detailed the efficacy and safety of ceftobiprole, an advanced-generation cephalosporin with bactericidal activity against Gram-positive (including MRSA) and Gram-negative pathogens, and which has demonstrated benefit in previous phase 3 trials involving acute bacterial skin infections and pneumonia.

The randomized (1:1), double-blind, multicenter, phase 3 noninferiority ERADICATE trial compared ceftobiprole (BPR) with daptomycin (DAP) + optional aztreonam in patients with complicated SAB for up to 42 days of treatment. Overall clinical success 70 days post-randomization was the primary efficacy end point, with success requiring survival, no new SAB complications, symptom improvement, SAB clearance, and no receipt of other potentially effective antibiotics.

Investigators assessed safety via adverse events (AE) and laboratory data, and set a noninferiority margin for the difference in success rates at -15% (BPR-DAP, 95% CI, 2-sided, lower bound).

A total of 390 patients were randomized, with 387 ultimately included in the modified intent-to-treat (mITT) population (189 BPR, 198 DAP). Baseline characteristics across both groups were similar, such as mean age (55.5, 10–89, and 56.5, 19–91 in the BPR and DAP arms, respectively), and a majority of participants were white and male (180 [95.2%] and 128 [67.7%] in the BPR arm, and 192 [97.0%] and 140 [70.7%] in the DAP arm). All participants had a positive baseline culture for S aureus, with 94 cases of MRSA, and the median treatment duration was 21 days in both groups.

The dose for BPR medocaril was 500 mg every 6 hours, administered as an intravenous 2-hour infusion from study Day 1 to Day 8, and then 500 mg every 8 hours from study Day 9 onward, with dose adjustments as needed depending on renal function. DAP was dosed at 6 mg/kg (up to 10 mg/kg) every 24 hours administered as a 0.5-hour infusion, with dose adjustments as needed depending on renal function. Aztreonam was administered using a standard dose regimen.

A total of 69.8% of participants experienced success in the BPR group compared with 68.7% in the DAP group (adjusted difference 2.0%, 95% CI -7.1% to 11.1%), and investigators noted no significant differences in mortality, microbiological eradication, or key subgroup analyses.

Treatment-related severe or serious AEs were infrequent, and the proportion of patients who experienced > 1 AE was 63% and 59% in the BPR and DAP groups, respectively. Consistent with previous phase 3 trial data, the most frequent AEs reported with BPR were gastrointestinal in nature, including mild nausea.

Armed with the ERADICATE data, developer Basilea is planning to submit a New Drug Application for BPR to the US Food and Drug Administration by the end of the year.