Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial

Abstract

IntroductionDespite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone.Methods and analysisA multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis.Ethics and disseminationThe protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study.Trial registration numberNCT01898338.

Fosfomycin

“…In addition, several of them were conducted years or even decades ago, and their findings may not apply to the resistance profiles of contemporary isolates or the complexity and severity of diseases and infections that patients face nowadays. Data from RCTs are still not available, but RCTs evaluating the comparative efficacy of fosfomycin and meropenem for bacteremic UTIs and fosfomycin in addition to daptomycin for MRSA bacteremia are under way (238,239). Similarly, fosfomycin is being evaluated in combination with other antibiotics for MDR or XDR infections (NCT01297894, NCT02142751, and NCT00871104).…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Fosfomycin doses of 3 g orally have been well established to treat UTIs, and bloodstream infections have been treated with fosfomycin at 50 mg/kg of body weight three to four times daily in combination with a ␤-lactam agent (4,8,9). Other studies have utilized fosfomycin doses of 2 g every 6 or 8 h (10,11). Developed in 1969, fosfomycin has drawn increasing attention for use in multidrug-resistant bacterial infections as combination therapy due to the increase in antimicrobial resistance and lack of novel antimicrobial development (6,12,13).…”

“…Developed in 1969, fosfomycin has drawn increasing attention for use in multidrug-resistant bacterial infections as combination therapy due to the increase in antimicrobial resistance and lack of novel antimicrobial development (6,12,13). While most of the data on fosfomycin-based antimicrobial combinations come from small in vitro studies, clinical trials are ongoing in Europe to evaluate the combination of daptomycin and intravenous fosfomycin for treatment of MRSA bacteremia (11).…”

Clinical pharmacological approach for balancing the use of daptomycin and linezolid in comparison with that of vancomycin in the treatment of MRSA-related infections

“…It was shown that the addition of either oxacillin [52,53] or cloxacillin [54] might be beneficial in preventing daptomycin treatment failure. A multicenter open-label, randomized Phase III study is currently ongoing to test whether combination therapy of daptomycin plus fosfomycin may achieve higher clinical success rates in the treatment of MRSA bacteremia than daptomycin alone [55].…”