Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial

Abstract

Background We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods A randomized (1:1) phase III superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg of daptomycin intravenously per kilogram daily plus 2 g of fosfomycin intravenously every six hours, or 10 mg of daptomycin intravenously per kilogram daily. Primary endpoint was treatment success six weeks after the end of therapy. Results Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at six weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs. 42.0%; relative risk: 1.29, 95%CI 0.93 to 1.8, p=0.135). At six weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs. 9 patients, p=0.003) and lower complicated bacteremia (16.2% vs. 32.1%; p=0.022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in four of 81 patients (4.9%) receiving daptomycin alone (p=0.018). Conclusion Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.

New-Generation Antibiotics for Treatment of Gram-Positive Infections: A Review with Focus on Endocarditis and Osteomyelitis

“…In an experimental endocarditis model in rabbits, daptomycin and fosfomycin showed synergy and rapid bactericidal activity [52]. In an RCT on MRSA BSI and IE with 155 patients, treatment success rate was 12% higher for daptomycin in combination with fosfomycin compared to daptomycin monotherapy, albeit not statistically significant [53].…”

The Effect of Combination Therapy on Mortality and Adverse Events in Patients with Staphylococcus aureus Bacteraemia: A Systematic Review and Meta-analysis of Randomized Controlled Trials

“…Of the remaining 48 studies, we excluded 34 studies from the full-text evaluation for five main reasons. In total, after the full-text screening, we included 14 RCTs [13][14][15][16][24][25][26][27][28][29][30][31][32][33] in the qualitative synthesis. Of these 14 studies, 9 were multicentre studies [13-16, 24-27, 30] and 5 were single-centre studies [28,29,[31][32][33].…”

“…In vitro laboratory data, animal models, and observational studies have suggested that combination antimicrobial therapy may be beneficial for S. aureus [8][9][10][11][12]. Over the past several years, there has been an increase in the number of randomized controlled trials (RCTs) involving patients with SAB, including the use of adjunctive rifampicin, fosfomycin, or ceftaroline for SAB [13][14][15][16]; however, the evidence supporting combination therapy in SAB is unclear. Several efforts have been made through meta-analyses to investigate whether combination antibiotic therapy is associated with better clinical outcomes than monotherapy.…”

Select controversies in the management of methicillin-resistant Staphylococcus aureus bacteremia: answers and remaining questions from recent evidence

“…In vitro studies demonstrate synergistic activity between daptomycin and fosfomycin, a broad-spectrum bactericidal antibiotic with activity against MRSA 47 – 49 . A recent open-label, multicenter, randomized clinical trial in patients with MRSA bacteremia and endocarditis compared daptomycin monotherapy (10 mg/kg per day) with the combination of daptomycin and intravenous fosfomycin (2 g every 6 hours) 50 . The protocol directed that the duration of treatment be 10 to 14 days for uncomplicated bacteremia and 28 to 42 days for complicated bacteremia.…”