By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In a randomized, controlled trial conducted by Holland and colleagues, no significant difference in overall treatment success of complicated Staphylococcus aureus bacteremia was observed in patients who received ceftobiprole as compared with patients who received daptomycin.
SOURCE: Holland TL, Cosgrove SE, Doernberg SB, et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. N Engl J Med 2023;389:1390-1401.
The ERADICATE trial, conducted by Holland and colleagues, assessed whether ceftobiprole was noninferior to daptomycin in overall treatment success in patients with complicated Staphylococcus aureus bacteremia (SAB).1 This was a double-blind, double-dummy, randomized controlled trial that was conducted at 60 sites in 17 countries between August 2018 and March 2022. The trial was designed and conducted by Basilea Pharmaceutica International, the company that produces ceftobiprole. It included adult patients who were hospitalized with complicated SAB, which was defined as persistently positive blood cultures for at least three days before randomization despite receipt of appropriate antimicrobial therapy; bacteremia associated with long-term hemodialysis; or bacteremia secondary to soft tissue infection, abdominal abscess, osteoarticular infection, septic thrombophlebitis, septic pulmonary embolus, epidural or cerebral abscess, or native-valve right-sided infective endocarditis. Participants were excluded if they had pneumonia or unremovable endovascular prosthetic material, or if they had received more than 48 hours of potentially effective antimicrobial therapy within seven days of randomization in the absence of persistent SAB.
Patients were randomized in a 1:1 ratio to receive either ceftobiprole 500 mg intravenously every six hours during the first eight days and then every eight hours thereafter, or daptomycin 6 mg/kg every 24 hours, with the option to use up to 10 mg/kg. Dummy infusions with placebo were provided to participants in both arms to match the drugs not administered to maintain blinding. Aztreonam was optional for the daptomycin arm for gram-negative infection coverage. Peripheral blood cultures were obtained in both study groups at baseline, daily for the first three days, and every 48 to 72 hours thereafter until they were negative at two time points at least 24 hours apart. The primary outcome of the trial was overall treatment success at 70 days after randomization, which was defined as survival, improvement in symptoms, S. aureusbloodstream clearance, absence of new SAB-related complications, and no use of other potentially effective antimicrobial therapy.
A total of 390 patients were enrolled, with 387 patients included in the modified intention-to-treat (ITT) analysis. Baseline characteristics were similar between the groups. The median age of participants was 58 years (range 19 to 91). The vast majority (96%) were white and most of the participants (93%) were enrolled at sites in Europe. The median duration of antibiotics was 21 days in both groups, with an interquartile range (IQR) of 21-25 in the ceftobiprole group and 21-23 in the daptomycin group. One hundred seventy-six of 198 (89%) in the daptomycin group received daptomycin at a dose of 7 mg/kg per day or less. Very few participants were immunosuppressed or had a history of preexisting or acquired valvular heart disease. The majority of cases (61.4% in the ceftobiprole group and 61.1% in the daptomycin group) had SAB associated with soft-tissue infections. Ninety-four patients (24.3%) in the modified ITT group had methicillin-resistant S. aureus (MRSA) bacteremia (45 in the ceftobiprole group and 49 in the daptomycin group).
Rates of the primary outcome were similar in both groups; 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Seven deaths in the ceftobiprole group and six in the daptomycin group were attributed by the data review committee to SAB. There was no statistically significant difference in either microbiologic eradication nor SAB-related complications between the groups, and the median time to S. aureus bloodstream clearance was the same (4 days; 95% CI, 3 to 5) for both. In addition, there were no significant differences with respect to treatment success among subgroups, including patients with either MRSA or methicillin-susceptible S. aureus (MSSA) infection.
Reinfection with a different S. aureus strain was detected in two participants who received ceftobiprole, based on genotyping data, but there were no cases of relapse. Three cases of relapse were confirmed by genotyping of paired bacterial isolates in the daptomycin group. There were three cases of resistance that developed during treatment with daptomycin, with increases of at least a factor of 4 in the mean inhibitory concentration (MIC); one of these had confirmed relapse. No resistance during treatment was detected in the ceftobiprole group.
Treatment-related adverse events were more common with ceftobiprole (13.1%) than with daptomycin (5.6%), with higher rates of gastrointestinal disorders (9.4% vs. 1.5%) and hypokalemia (8.9% vs. 2.5%). Serious adverse events attributed by investigators to the study drugs were rare, occurring in two of 191 (1.0%) in the ceftobiprole group and four of 198 (2.0%) in the daptomycin group. The rates of overall treatment success in patients who received daptomycin doses greater than 7 mg/kg per day were 36% as compared with 73% for those who received daptomycin doses of 7 mg/kg per day or less.
COMMENTARY
S. aureus is a major pathogen and leading cause of bacteremia.2 Approximately 1 in 4 patients with SAB die within three months of infection.3 Intravenous therapy for SAB has been primarily limited to oxacillin, nafcillin, or cefazolin for MSSA, and vancomycin or daptomycin for MRSA. Daptomycin is a lipopeptide with activity against gram-positive organisms. It is approved in the United States for the treatment of complicated SAB and right-sided infective endocarditis, based on randomized controlled trial data that demonstrated that it was noninferior to low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin.4 Daptomycin is highly bactericidal with concentration-dependent activity.5 Doses of daptomycin used for SAB typically range from 6 mg/kg per day to 10 mg/kg per day. Although a small retrospective study found relatively high rates of daptomycin nonsusceptibility among patients treated with a dose of 6 mg/kg per day, it remains uncertain whether higher doses are associated with a lower risk of daptomycin nonsusceptibility developing on therapy and better clinical outcomes.6
In the ERADICATE trial, patients who received daptomycin doses above 7 mg/kg per day had lower rates of overall treatment success compared to doses of 7 mg/kg per day or lower, but since only a small fraction of participants received higher doses, the study clearly was not powered to evaluate differences in efficacy according to different doses. Its once-daily dosing, excellent tolerability, and spectrum of activity that is limited to gram-positive organisms are important advantages of daptomycin with respect to targeted use in SAB.
Ceftobiprole is a fifth-generation, MRSA-active cephalosporin, which also has enhanced activity against Streptococcus pneumoniae and Enterococcus faecalis, as well as broad gram-negative activity, including activity against Pseudomonas aeruginosa that is comparable to that of ceftazidime.7 While this impressively wide spectrum of activity may make ceftobiprole appealing for empiric treatment in select patients with risk factors for MRSA and P. aeruginosa infections, its use for targeted therapy should be limited. In addition to its broad spectrum of activity, the frequent dosing of ceftobiprole (every six to eight hours), extended infusion times (one to two hours), and limited availability are important reasons why the results of this study are unlikely to lead to wide uptake of this novel agent with a limited niche.
In summary, this well-conducted randomized, double-blind trial demonstrated that ceftobiprole was noninferior to daptomycin for the treatment of complicated SAB, although the role of ceftobiprole as targeted therapy for SAB remains uncertain.
REFERENCES
- Holland TL, Cosgrove SE, Doernberg SB, et al. Ceftobiprole for treatment of complicated Staphylococcus aureus bacteremia. N Engl J Med 2023;389:1390-1401
- Tong SYC, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015;28:603-661.
- Bai AD, Lo CKL, Komorowski AS, et al. Staphylococcus aureus bacteraemia mortality: A systematic review and meta-analysis. Clin Microbiol Infect 2022;28:1076-1084.
- Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653-665.
- Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007;45:601-608.
- Sharma M, Riederer K, Chase P, Khatib R. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2008;27:433-437.
- Barbour A, Schmidt S, Rand KH, Derendorf H. Ceftobiprole: A novel cephalosporin with activity against gram-positive and gram-negative pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 2009;34:1-7.