LB2302. Ceftobiprole Compared to Daptomycin With or Without Optional Aztreonam for the Treatment of Complicated Staphylococcus aureus (SAB): Results of a Phase 3, Randomized, Double-Blind Trial (ERADICATE)

Abstract

Background SAB is common, serious, and potentially lethal. Antibiotic options are limited, especially for MRSA. Ceftobiprole is an advanced-generation cephalosporin with bactericidal activity against Gram-positive (including MRSA) and Gram-negative pathogens, with efficacy and safety demonstrated in previous Phase 3 studies in acute bacterial skin infections and pneumonia. The present study evaluated ceftobiprole in patients with complicated SAB. Methods ERADICATE was a randomized (1:1), double-blind, multicenter, Phase 3, non-inferiority trial comparing ceftobiprole (BPR) vs daptomycin (DAP) ± optional aztreonam, for up to 42 days of treatment, in patients with complicated SAB (NCT03138733). The primary efficacy endpoint was overall clinical success 70 days post-randomization, adjudicated by a blinded independent Data Review Committee. Success required survival, no new SAB complications, symptom improvement, SAB clearance, and no receipt of other potentially effective antibiotics. The non-inferiority margin for the difference in success rates was -15% (BPR-DAP, 95% CI, 2-sided, lower bound). Safety was assessed through adverse events (AE) and laboratory data. Results Of 390 patients randomized, 387 (189 BPR, 198 DAP) were in the modified intent-to-treat (mITT) population who received study medication and had a positive baseline blood culture for S. aureus (94 MRSA). Median treatment duration was 21 days for both groups. Key baseline characteristics were balanced (Fig. 1). In the BPR group 69.8% experienced success, compared to 68.7% for DAP (adjusted difference 2.0%, 95% CI -7.1% to 11.1%, Fig. 2). There were no significant differences in mortality, microbiological eradication, or in key subgroup analyses (Fig. 3). The proportion of patients experiencing ≥1 AE was 63% for BPR and 59% for DAP. Treatment-related severe or serious AEs were infrequent. Gastrointestinal AEs, mostly mild nausea, were more frequent with BPR, consistent with data from previous Phase 3 studies. Conclusion Ceftobiprole is non-inferior to daptomycin for overall success in patients with complicated SAB. All-cause mortality, microbiological eradication rates and new SAB complications were similar between treatment groups. Both treatments were well tolerated. Disclosures Thomas L. Holland, MD, Aridis: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|Karius: Advisor/Consultant|Lysovant: Advisor/Consultant Sara E. Cosgrove, MD, Basilea: Advisor/Consultant|Debiopharma: Advisor/Consultant Sarah B. Doernberg, MD, MAS, Basilea: Advisor/Consultant|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Johnson and Johnson: Advisor/Consultant|NIH: Grant/Research Support|Regeneron: Grant/Research Support Maziar Assadi Gehr, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Marc Engelhardt, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Kamal Hamed, MD, Basilea Pharmaceutica: previous full time employee of Basilea Pharmaceutica International Ltd|Lysovant: full time employee of Lysovant Daniel Ionescu, MD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Mark Jones, PhD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Mikael Sauley, MSc, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Jennifer Smart, PhD, Basilea Pharmaceutica: full time employee of Basilea Pharmaceutica International Ltd Harald Seifert, MD, Basilea Pharmaceutica: Advisor/Consultant|Debiopharm: Advisor/Consultant|Eumedica: Advisor/Consultant|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|Shionogi: Advisor/Consultant Timothy C. Jenkins, MD, Basilea: Clinical outcomes adjudication committee Vance G. Fowler, Jr, MD, MHS, Armata Valanbio Akagera Aridis Roche: Advisor/Consultant|BASILEA: Grant/Research Support|Basilea Novartis Debiopharm Genentech: Advisor/Consultant|MedImmune Bayer Janssen Contrafect Regeneron Destiny Amphliphi Integrated Bioth: Advisor/Consultant|NIH MedImmune Allergan Theravance Novartis Merck Contrafect Karius Genentech Regeneron Janssen: Grant/Research Support.

New Antimicrobials and New Therapy Strategies for Endocarditis: Weapons That Should Be Defended

“…According to the promising results of the recent ERADICATE RCT, which included 20 patients with S. aureus IE, a green/yellow colour was attributed to BPR for S. aureus, similar to the evidence available for BPR and DAP (Figure 1A) [39]. However, we believe that the use of BPR for the treatment of staphylococcal IE (alone or in combination with DAP) will increase over time.…”

“…Daptomycin (DAP) was administered at a dosage ranging from 6 mg/Kg to 10 mg/Kg q24h, while BPR was given at a dosage of 500 mg q6h from Day 1 to Day 8 and 500 mg q8h from Day 9 onwards, with dose adjustments according to renal function. The study showed the non-inferiority of BPR compared to DAP in terms of mortality rates, microbiological eradication, and the occurrence of new complications associated with bacteraemia (overall clinical success: 69.8% in BPR-regimen vs 68.7% in DAP-regimen) [39,41].…”

“…The evidence available in the literature concerning the use of BPR in IE consists of a double-blinded, randomised, controlled non-inferiority study and observational and retrospective studies, case series, and case reports [7,[35][36][37][38][39][40] (Table 1). improvement with resolution of all signs and symptoms of infection during BPR treatment or at the end of therapy.…”

“…As shown in Figure 1A, the evidence supporting the use of CPT and BPR (alone or in combination with DAP), FOS, and long-acting DAL and ORI for staphylococcal IE has accumulated over time [7,[9][10][11]14,39,65,68,182]. Despite exhibiting pre-clinical evidence, the new beta-lactams and their associations with DAP have garnered less clinical evidence for MSSA IE, which has been limited to case series/case reports (shown as yellow or yellow/green colour, Figure 1A); this could be possibly explained by the strong efficacy of the currently recommended agents (i.e., cefazolin) [39,65].…”

Optimal drug therapy for Staphylococcus aureus bacteraemia in adults

“…8-hourly useful for pathogens with higher MICs or difficult to penetrate sites of infection [52]. In a phase 3, randomized, double blind trial, ceftobiprole was noninferior to daptomycin (with or without aztreonam) for complicated SAB [53]. Daptomycin was dosed as 6 mg/kg (up to 10 mg/kg) i.v.…”