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

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 3 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/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 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 6 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% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). CONCLUSIONS: 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. CLINICAL TRIALS REGISTRATION: NCT01898338.

Switching Ratio from Parenteral to Oral Methadone 1:1.2 Is Safer Compared with Ratio 1:2 in Patients with Controlled Cancer Pain: A Multicenter Randomized-Controlled Trial (RATIOMTD-010810).

Background: The most commonly used switching ratio from parenteral to oral methadone is 1:2. Methadone is highly bioavailable and a lower ratio might result in similar analgesia with less toxicity. Objective: To compare success and side effects with two ratios from parenteral to oral methadone: 1:2 versus 1:1.2 in hospitalized patients with cancer pain. Design: A multicenter double-blind randomized clinical trial. Settings/Particiants: Inpatients with well-controlled cancer pain with parenteral methadone requiring rotation to the oral route. Measurements: Outcomes included pain intensity (Brief Inventory Pain), opioid toxicity (Common Toxicology Criteria for Adverse Events), and methadone dose. Success was defined as no toxicity with good pain control at 72 hours. Results: Thirty-nine of forty-four randomized patients were evaluable: 21 in ratio 1:2 and 18 in ratio 1:1.2. Seventy-one percent male. Median age 65 years. No significant differences in basal clinical characteristics between both groups. Median methadone dose pre/post switching was 24.5 mg ±13.5 and 49 mg ±27.3 for ratio 1:2, versus 23.3 mg ±9.4 (p: not significant) and 28 mg ±11.3 (p < 0.01) for ratio 1:1.2. Pain was well controlled without differences between both ratios. Drowsiness at day +1 (p < 0.017) and myoclonus at day +3 (p < 0.019) were more prevalent in group 1:2. Success was observed in 12 patients in ratio 1:2 versus 18 in ratio 1:1.2 (p < 0.001). Methadone side effects were observed in 12 patients in ratio 1:2 (mainly neurotoxicity symptoms) versus 2 in ratio 1:1.2 (p < 0.005). Conclusion: Ratio 1:1.2 when changing from parenteral to oral methadone resulted in lower toxicity and no difference in analgesia. More conservative dose adjustment during methadone route change should be considered. European Clinical Trials Register (EudraCT No. 2010-024092-39).