Multicentre, randomised, open-label, phase IV–III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptibleStaphylococcus aureusbacteraemia: study protocol for the SAFO trial

Abstract

Introduction Methicillin-susceptibleStaphylococcus aureus(MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin againstS. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. Methods We will perform a superiority, randomised, open-label, phase IV–III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician. Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation). We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). Ethics and dissemination Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. Trial registration number The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier:NCT03959345; Pre-results.

Therapeutic Options for Adult Patients With Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Narrative Review

“…In addition, the SAFO trial, a multicenter randomized trial comparing the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in patients with MSSA bacteremia, was terminated due to poor recruitment following data safety and monitoring board recommendations. 87 Adjunctive levofloxacin. Previous in vitro and in vivo reports described successful treatment of MSSA with fluoroquinolones.…”

Ethical Aspects of Personalized Research and Management of Systemic Inflammatory Response Syndrome (SIRS) in Children

“…The process of providing research participants with all available details, properly and effectively, is defined as a moral duty which (a) sets an ethical training for doctors involved in clinical studies as a requirement and (b) refines the definition of medical professionalism as comprising ethical competence [16,25] and trained communication skills. A communicative competence should teach doctors to tailor their language and medical information to patient's individual level of health literacy, as well as to that of their families [16], and to respect patient's preferences in the framework of confidentiality [17,23,[26][27][28][29]. Ethically informed medical professionalism is also described in the literature as fundamental to shared decision-making [16,23], which ensures that patients are supported to reach a decision that suits them and the preferences of those involved.…”

“…Trained communication skills have also been defined as the obligation of physicians to act for the benefit of the patient [25,27]. Indeed, the need for qualified agents to provide benefits-i.e., positive beneficence-and to balance benefits, risks and costs, i.e., utility, is the aim of continuing medical education [16,25,27,36,37]; whereas the goal of clinical research is to be twofold, namely reaching a scientific understanding leading to sound clinical interventions and designing a common ground in research for future collection and interpretation of data [15,19,28,35,41,42,[44][45][46][47]. Another major ethical issue germane to ethical research with children, and which has been associated in the literature with the principle of beneficence, is medical paternalism.…”

“…With regard to the principle of "non-maleficence", one of the major ethical issues that has come to the foreground in the literature is the debate over alternatives models of informed consent for research with biological samples, e.g., broad, waived or deferred consent [7,18,24,25,27]. Furthermore, it has been pointed out that ethical standards for clinical research need to be clearly defined in multicentre intensive care trials so that all clinical researchers involved have the same competencies to fulfil the same obligations [25,27]. Germane to the obligations of non-maleficence which ought to be met in omics research, there is not only that of "not causing harm" to patients by negligence in the conduct of research, but also that of "not imposing risks" on patients.…”

“…Germane to the obligations of non-maleficence which ought to be met in omics research, there is not only that of "not causing harm" to patients by negligence in the conduct of research, but also that of "not imposing risks" on patients. Consensus is also that many of the skills clinical researchers should be equipped with as a requirement for avoiding harm extend beyond clinical competence [16,24,26,27]. These include a discretionary effort to put empathy into action and thus connect to research purposes by mitigating patients' fears [25], and ad-hoc communication skills for physicians who benefit enormously from training in how to navigate emotionally charged conversations [16,27].…”