Phase IV-III Clinical Trial, randomized, controlled, open and multicentric, with parallel groups, to evaluate the efficacy of Cloxacillin and fosfomycin combination versus Cloxacillin monotherapy in the treatment of methicillin-susceptible Staphylococcus aureus bacteraemia.

INTERVENTION: Product Name: CLOXACILINA Pharmaceutical Form: Concentrate and solvent for solution for infusion INN or Proposed INN: CLOXACILLIN CAS Number: 61‐72‐3 Current Sponsor code: CLOXACILINA Other descriptive name: CLOXACILINA Product Name: FOSFOMYCIN Product Code: J01XX01 Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: FOSFOMYCIN CAS Number: 23155‐02‐4 Current Sponsor code: FOSFOMICINA Other descriptive name: FOSFOMICINA Product Name: CLOXACILLIN Pharmaceutical Form: Concentrate and solvent for solution for infusion INN or Proposed INN: CLOXACILLIN CAS Number: 61‐72‐3 Current Sponsor code: CLOXACILINA Other descriptive name: CLOXACILINA CONDITION: Methicilin‐susceptible S.aureus bacteraemia. ; MedDRA version: 20.0 Level: LLT Classification code 10058863 Term: Staphylococcus aureus bacteraemia System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Bacterial Infections and Mycoses [C01] INCLUSION CRITERIA: 1) 18 years of age or over. 2) Patients hospitalised with 1 or more MSSA‐positive blood cultures obtained within the 72 hours prior to inclusion in the study, in a context suggesting an infection. 3) The subject or their legal representative grants informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 150 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 150 PRIMARY OUTCOME: ; Main Objective: We established two primary object. with hierarchical testing: 1) First primary endpoint: Early success of therapy defined by all of the following criteria met after randomization: ‐ Patient alive at day 7; Clinical success defined as clinical improvement measured by stable or improved quick SOFA score (compared with baseline) AND fever resolved at day 7; Blood cultures negative for S. aureus at day 7. No isolation of S. aureus in another sterile site from day 8 until TOC visit at 12 weeks after random allocation.; 2) Second primary endpoint: Success of therapy is defined at TOC by presence of all of the following (“long time successâ€?): Patient alive at 12 weeks after random allocation; No isolation of S. aureus from sterile site (e.g. blood, joint fluid, tissue) > 14 days from randomization until TOC visit at 12 weeks after random allocation. For both endpoints the use of an additional MSSA‐active iv antibiotic until day 7 will be considered as treatment failure (“no successâ€?).; ; Secondary Objective: 1)Clinical Obj:All‐cause mortality at different visits.Persistent bacteraemia at 3 and 7 days after random allocation.Microbiological relapse as defined by (at least one)positive blood culture for MSSA at least 72h after a preceding negative culture.Complicated bacteraemia.Duration of intravenous antibiotic treatment.Length of stay in hospital.Microbiological secondary endpoints.Pharmacologic secondary endpoints.Sub group analysis for; patients at high risk.2)Microbiological Obj:To establish duration of bacteraemia,persistent and recurrent bacteraemia.Emergence of fosfomycin resistance.To establish functionality of agr operon and its relationships with changes in vancomycin (VAN) and daptomycin(DAP) MIC and biofilm production.To establish"in vitro"synergy of clox‐fos combinations.Sequencing of complete bacterial genome and changes in patients with therapeutic failure3)Pharmacodynamic Obj:To determine the min. and max. concentrations reached in the steady state of free clox. and fos.; Primary end point(s): Proportion of patients “respondersâ€? at day 7 after randomization. Early success of treatment is defined as patients who have completed the study treatment cycle AND without bacteraemia at day 7 AND alive at 7 days AND with clinical improvement at day 7 (qSOFA improvement and resolution of fever) AND without S.aureus isolation from sterile samples from day 8 to 12 weeks after random allocation. Long time success is defined as the proportion of patients "responders" at 12 weeks of having completed the cycle of complete antibiotic treatment (TOC). Timepoint(s) of evaluation of this end point: The principal endpoint is to demonstrate the effectiveness of the combination of cloxacillin and fosfomycin versus cloxacillin alone in patients with MSSA bacteraemia at 7 days and 12 weeks after random allocation. SECONDARY OUTCOME: ; Secondary end point(s): 1) Clinical:; 1.1) All‐cause mortality at days 7, 14, EOT after random allocation.; 1.2) Number of patients withdrew from the study.; 1.3) Persistent bacteraemia (at least one positive blood culture) at day 3 and at day 7; 1.4) Recurrent bacteraemia during the study period.; 1.5) Patients with persistent and recurrent bacteraemia.; 1.6) Number of patients with complicated bacteraemia; 1.7) Duration of intravenous antibiotic treatment.; 1.8) Length of stay in intensive care unit and in hospital, clinical success at day 3, 7, and the end of the antibiotic study treatment (EOT) and test of cure visit (TOC).; 1.9) Sub group analysis for patients at high risk.; ; 2)Microbiological:; 2.1) Resistance to fosfomycin during treatment;; 2.2) Minimum inhibitory concentration (MIC) for vancomycin, daptomycin, dalvabancin and its relationship with MSSA complications;; 2.3) Accessory gene regulator (agr) polymorphism;; 2.4) “In vitroâ€? synergy between cloxacillin‐fosfomycin;; 2.5) Whole genome sequencing and association of genome changes and patients with therapeutic unsuccessful.; ; 3) Pharmacokinetics:; 3.1) Minimum concentration (Cmin.),; 3.2) Mid‐dosing interval concentration and maximum concentration (Cmax.) reached at the different sampling times.; 3.3) Relationship between PK variables and efficacy.; ; 4) Security:; 4.1) Incidence of adverse events, serious adverse events, adverse drug reactions, dropouts and its relationship with the study treatment.; Timepoint(s) of evaluation of this end point: Secondary variables will be evaluated in different moments depending on each variable definition