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
Authors: Grillo Sara , Cuervo Guillermo , Carratala Jordi , San-Juan Rafael , Aguado Jose M , Morata Laura , Gomez-Zorrilla Silvia , López-Contreras Joaquín , Gasch Oriol , Gomila-Grange Aina , Iftimie Simona , Garcia-Pardo Graciano , Calbo Esther , Boix-Palop Lucía , Oriol Isabel , Jover-Sáenz Alfredo , López-Cortés Luis Eduardo , Euba Gorane , Aguirregabiria Malen , Garcia-Pais Maria Jose , Gioia Francesca , Paño Jose Ramón , Pedro-Botet Maria Luisa , Benítez Rosa Maria , Pérez-Rodríguez Maria Teresa , Meije Yolanda , Loeches-Yagüe Maria Belén , Horna Gertrudis , Berbel Damaris , Domínguez Maria Ángeles , Padullés Ariadna , Cobo Sara , Hereu Pilar , Videla Sebastian , Tebe Cristian , Pallarés Natàlia , Miro Josep M , Pujol Miquel 
Published: November 2022

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.