Adjunctive fosfomycin for treatment of Staphylococcus aureus bacteraemia: protocol for a pooled post-hoc analysis of two randomised clinical trials (BACSAFO)

Adjunctive fosfomycin for treatment of Staphylococcus aureus bacteraemia: protocol for a pooled post-hoc analysis of two randomised clinical trials (BACSAFO) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adjunctive fosfomycin for treatment of Staphylococcus aureus bacteraemia: protocol for a pooled post-hoc analysis of two randomised clinical trials (BACSAFO) Francesc Escrihuela-Vidal1, Sean W X Ong, Isabel Oriol, Sara Grillo, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6612075/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background . Improving outcomes in patients with methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus bacteraemia (SAB) is a critical healthcare goal. Two recent randomised clinical trials (RCTs), the BACSARM trial and the SAFO trial, assessed the efficacy of fosfomycin as an adjunctive therapy for MRSA and MSSA SAB respectively. Although neither trial demonstrated statistically significant differences in their primary endpoints of treatment success and reduced mortality respectively, both studies observed lower rates of persistent bacteraemia in the fosfomycin groups. Methods. We will perform a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO trials, which will be referred to as the BACSAFO study. The primary exposure of interest is fosfomycin adjunctive therapy, and the primary outcome will be treatment success at 8 weeks, defined as the patient being alive, without signs of relapse, and showing improvement in clinical signs and symptoms. We will use both Bayesian and frequentist frameworks: the Bayesian analysis will use a hierarchical Bayesian log-binomial model, while the frequentist analysis will apply a hierarchical log-binomial model. In addition, we will investigate whether adjunctive fosfomycin is particularly beneficial in specific patient subgroups (created according to age, methicillin resistance, place of acquisition, and complicated bacteraemia status). Discussion . The BACSAFO study aims to clarify the role of fosfomycin as an adjunctive therapy for improving outcomes in SAB patients. Although previous trials have not demonstrated significant differences in the primary endpoints, the significant reductions in rates of persistent bacteraemia observed suggest that fosfomycin might offer a clinical benefit in certain cases. By analysing pooled data and attempting to identify subgroups that might benefit most, this study has the potential to refine treatment strategies and inform trial design and planning for future RCTs investigating combination antibiotic therapies for SAB. Ethics and dissemination . Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (EOM033/24). The results will be presented at international meetings and will be made available to patients and funders. Trial registration number . ClinicalTrials.gov Identifier: NCT06695832. Infectious Diseases Fosfomycin Staphylococcus aureus bacteraemia Daptomycin Cloxacillin BACKGROUND Staphylococcus aureus is a leading cause of both nosocomial and community-onset bacteraemia worldwide [ 1 – 3 ]. S. aureus bacteraemia (SAB) is associated with a mortality rate ranging from 20–40% [ 4 ] and contributes to significant morbidity and economic burden [ 5 , 6 ]. High-risk infection sources, such as endocarditis or pneumonia, as well as persistent bacteraemia, are associated with increased mortality and recurrent infections in both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) bacteraemia [ 4 , 7 – 10 ]. Despite ongoing efforts to optimise the management of SAB, patient prognosis has not improved, and this remains a matter of concern. There is a growing interest in enhancing standard antibiotic therapies by using adjunctive antibiotics with synergistic or anti-biofilm activity [ 11 , 12 ]. However, it remains uncertain whether combination antibiotic therapies offer a survival benefit over standard-of-care with monotherapy. Fosfomycin, a cell-wall synthesis inhibitor, has shown promise in experimental models of endocarditis caused by both MRSA [ 13 ] and MSSA [ 14 , 15 ], demonstrating synergistic and bactericidal effects when combined with standard antibiotics. Recent clinical evaluations of fosfomycin as adjunctive therapy in SAB have been conducted in two prospective, randomised, open-label clinical trials: the BACSARM [ 16 ] and SAFO [ 17 ] RCTs. The BACSARM trial assessed high-dose daptomycin plus fosfomycin against daptomycin monotherapy for MRSA bacteraemia. Although the combination therapy arm showed a 12% improvement in the primary outcome of treatment success at 6 weeks after end of treatment, this difference was not statistically significant. However, subgroup analyses showed that fosfomycin combination was potentially more effective than monotherapy in patients under 74 years of age and in those with more severe disease (Pitt bacteraemia score > 1 point). In the SAFO trial, cloxacillin combined with fosfomycin for treating MSSA bacteraemia was compared to cloxacillin alone, with no significant difference in treatment success at day 7. While neither trial demonstrated statistically significant differences in the primary endpoints, in both studies the administration of adjunctive fosfomycin was associated with significantly lower rates of persistent bacteraemia at day 3 compared to monotherapy. This finding did not translate into clinically significant outcomes, but this may have been due to the inclusion of a high proportion of low-risk SAB patients, 31–49% of whom had an intravascular catheter as the source of infection. In addition, the intrinsic heterogeneity of SAB makes it difficult to draw definitive conclusions from these trials. Therefore, the potential benefits of adjunctive fosfomycin in the treatment of SAB warrant further investigation. To address this issue, we will conduct a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO trials, known as the BACSAFO study. We will use both Bayesian and frequentist methodologies in our analyses. In addition, we will explore whether adjunctive fosfomycin is particularly beneficial for specific patient subgroups. Primary objective To determine whether fosfomycin combination therapy achieves a higher proportion of treatment success at 8 weeks than the administration of daptomycin or cloxacillin alone in the treatment of SAB. Secondary objectives To evaluate the impact of fosfomycin combination therapy on treatment success at day 14 and all-cause mortality at days 30 and 60. To determine whether adjunctive fosfomycin increases rates of bacteraemia clearance at days 3 and 7. To establish whether there is a specific subgroup of patients that could benefit from the use of adjunctive fosfomycin, i.e., depending on their age, methicillin resistance, place of acquisition, and complicated bacteraemia status. METHODS AND ANALYSIS Study design and setting The BACSAFO study will comprise a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO multicentre trials. Both these trials were conducted at Spanish hospitals and have been previously published elsewhere [ 16 , 17 ]. The main characteristics of the BACSARM and the SAFO trials are summarized in the Table 1 . Table 1 Main characteristics of the BACSARM and SAFO trials. BACSARM Reference [ 16 ] SAFO Reference [ 17 ] Design of the study Multicentre, open-label, randomised, phase III, interventional clinical trial with parallel allocation (1:1) with superiority design Multicentre, open-label, randomised, phase III-IV, interventional clinical trial with parallel allocation (1:1) with superiority design Intervention Daptomycin plus fosfomycin versus daptomycin alone Cloxacillin plus fosfomycin versus cloxacillin alone Duration of adjunctive fosfomycin therapy 10–14 days for uncomplicated bacteraemia, 28–42 days for complicated bacteraemia 7 days after randomisation; further treatment was determined by the attending physicians, usually ranging from 10 to 14 days for uncomplicated bacteraemia and from 28 to 42 days for complicated bacteraemia Participants Patients ≥ 18 years old with complicated or uncomplicated MRSA bacteraemia (N = 155 patients) Patients ≥ 18 years old with complicated or uncomplicated MSSA bacteraemia (N = 214 patients) Exclusion criteria in both trials Polymicrobial bacteraemia, severe clinical status with expected survival < 24 hours, severe liver disease with Child-Pugh score class C, diagnosis of prosthetic infective endocarditis, allergy or known resistance to study drugs, pregnancy at the time of inclusion, inclusion in another clinical trial Particular exclusion criteria for each trial Diagnosis of MRSA pneumonia, prior history of eosinophilic pneumonia, use of additional antibiotic therapy with microbiological activity against MRSA Prior history of myasthenia gravis, acute SARS-CoV2 infection Primary endpoint Treatment response at TOC (6 weeks after stopping therapy), defined as resolution of clinical signs and symptoms plus negative blood cultures: 54.1% for daptomycin plus fosfomycin versus 42.0% for daptomycin alone (RR 1.29; 95% CI 0.93–1.8) Treatment success at day 7 after randomisation, defined as a composite of patient alive and afebrile, with clinical improvement measured by SOFA score and with negative blood cultures: 79.8% for cloxacillin plus fosfomycin versus 74.5% for cloxacillin alone (risk difference 5.3%; 95% CI -5.95-16.48, P = 0.360) Persistent bacteraemia Day 3: 2.7% daptomycin plus fosfomycin vs 18.5% daptomycin alone (RR 0.15; 95% CI 0.04–0.63) Day 7: 0% daptomycin plus fosfomycin vs 6.2% daptomycin alone (RR -6.2; 95% CI -11.4 to -0.9) Day 3: 4.3% cloxacillin plus fosfomycin vs 17.2% cloxacillin alone (risk difference − 12.9; 95% CI -22.43 to -3.4) Day 7: 2.3% cloxacillin plus fosfomycin vs 4.2% cloxacillin alone (risk difference − 1.9; 95% CI -8.13-4.26) MRSA: methicillin-resistant S. aureus ; MSSA: methicillin-susceptibly S. aureus ; SOFA: Sequential Organ Failure Assessment; TOC: test-of-cure. Study population In the BACSARM trial, 155 adult patients with MRSA bacteraemia were randomised 1:1 to receive daptomycin in combination with fosfomycin or daptomycin alone [ 16 ]. In the SAFO trial, 214 adult patients with MSSA bacteraemia were randomised 1:1 to receive cloxacillin in combination with fosfomycin or cloxacillin alone [ 17 ]. As this is a pooled analysis of all SAB, all patients included in the intention-to-treat analysis of the BACSARM and SAFO trials will be included in the present study, regardless of their susceptibility to methicillin. The intention-to-treat population included all the randomised patients who received at least one day of antibiotics. Inclusion criteria common to both trials were: 1) age ≥ 18 years, 2) at least one blood culture positive for MRSA or MSSA ≤ 72 hours before inclusion and with evidence of active infection. The present study will include both uncomplicated and complicated SAB. Both the BACSARM and SAFO trials excluded patients with polymicrobial bacteraemia, allergy to the study drugs, severe liver disease (Child-Pugh score class C), prosthetic valve endocarditis, pregnancy, expected survival < 24 hours, and inclusion in another trial. The BACSARM trial excluded patients with MRSA pneumonia (given that use of daptomycin is not recommended in the setting of pneumonia). The SAFO trial, which was partially conducted during the COVID-19 pandemic, excluded patients with acute SARS-CoV-2 infection. Patient and Public Involvement Patients and public were not involved in the design and will not be involved in the conduct, reporting or dissemination of the BACSAFO study. Study groups and interventions The experimental group will include all patients receiving adjunctive fosfomycin (the combination therapy group). The control group will include all patients not receiving fosfomycin (the standard-of-care [SOC] group). In the BACSARM trial, fosfomycin 2g every 6 hours was administered for 10–14 days for uncomplicated SAB and 28–42 days for complicated SAB. In the SAFO trial, fosfomycin 3g every 6 hours was administered during the first 7 days after randomisation; after the first week, the choice and duration of antibiotics were determined by the attending physician. In both trials, recommendations were provided on the adjustment of the dose of fosfomycin to renal function. In the SAFO trial, recommendations for the prevention, identification and management of hypokalaemia, hypocalcaemia and sodium overload were included in the protocol and provided to attending physicians. In the present study, complicated SAB will be defined as the presence of metastatic infection (progression of infection beyond the primary focus, skin alterations suggestive of acute systemic infection, endocarditis), persistent SAB (defined as persistence of positive blood cultures for S. aureus after 72–96 hours from the start of antibiotics), and presence of a non-catheter endovascular device. Outcomes In the BACSARM trial, test-of-cure was performed at 6 weeks after stopping therapy. In the SAFO trial, test-of-cure was performed at 12 weeks after randomisation. For the present study, the primary outcome will be treatment success at 8 weeks from the time of randomisation, a composite outcome available from the information collected in both trials and based on the fulfilment of all the following criteria: Alive at week 8 from the time of randomisation. Absence of relapse within 8 weeks after randomisation, defined as isolation of S. aureus in blood cultures after the index blood cultures were cleared. Improvement of clinical signs and symptoms as assessed by investigators of the BACSARM and SAFO trials at week 8 from the time of randomisation. Secondary outcomes will be: Persistent bacteraemia, as defined by positive blood cultures for S. aureus at days 3 and 7 from the time of randomisation. Mortality at days 14, 30 and 60 from the time of randomisation. Adverse events leading to treatment discontinuation during adjunctive fosfomycin therapy. Statistical analysis Sample size No sample size calculation will be performed, since this is a post-hoc analysis of two previously completed trials. The study will include 369 patients: 155 from the BACSARM trial and 214 from the SAFO trial. Missing data The proportions of missing data for all variables will be presented. In the BACSARM and SAFO trials, missing data in individual variables was below 5%. There are no missing data for the primary outcome in either trial. The proportion of missing covariate data was < 5%, and hence complete case analyses discarding the observations with missing data will be conducted for the adjusted analyses and subgroup analyses [ 18 ]. Analyses The primary exposure of interest is fosfomycin adjunctive therapy. To account for potential clustering by site, in the primary model we will include study site (18 sites in BACSARM, 19 sites in the SAFO, including the same 18 as in BACSARM) as a random effect with random intercept. Bayesian analyses The Bayesian primary analysis will use a hierarchical Bayesian log-binomial model, using a log-link and binomial likelihood with random effect by hospital site. As the clinical evidence studying the effect of fosfomycin combination therapy is limited, we will use a minimally informative prior distribution ( N (0,5)), centred at no effect (i.e., risk ratio [RR] of 1.0). We will assume independence between priors of random effect and the fixed effect parameter, with default priors for the random intercept. We will use Markov Chain Monte Carlo methods to estimate the RR with 95% credible intervals of each outcome from 50th, 2.5th, and 97.5th percentiles of the posterior distribution. In a secondary analysis, we will additionally include other covariates that are prognostically important for the outcomes of treatment success, persistent bacteraemia, and mortality. These include: (i) age (as a continuous variable), (ii) Pitt bacteremia score [ 19 ], (iii) methicillin susceptibility (MSSA vs MRSA), (iv) Charlson’s comorbidity index (as a summary measure of comorbidity) [ 20 ], (v) acquisition of infection (community-acquired vs nosocomial), and (vi) infection source. The secondary analysis will include an adjusted analysis using the same log-binomial model, but additionally including the covariates listed above. Minimally informative prior distributions will be used for each of these covariates. Lastly, subgroup analyses will be conducted using the same primary log-binomial model (again with random effect by hospital site) but including terms for subgroup indicators and an interaction term with the primary treatment variable (fosfomycin combination treatment). The subgroups examined will include age (≥ 65 years old vs < 65 years old), methicillin resistance (MSSA vs MRSA), acquisition of infection (community-acquired vs nosocomial), and complicated bacteraemia status (complicated vs uncomplicated). Subgroup analyses will estimate the posterior probability of a subgroup effect, i.e., that fosfomycin combination therapy is more effective in subgroup 1 vs subgroup 2 for each subgroup variable. Analysis of the secondary outcomes will use a hierarchical Bayesian log-binomial model with random effect by hospital site. Models for the secondary outcomes will be unadjusted and will not include any of the covariate terms. All models will be examined for model fit using posterior predictive plots and model convergence using leave-one-out cross-validation. We will examine the impact of the prior distribution on the primary analysis by varying the prior distribution to reflect variable pre-existing beliefs among clinicians. In addition to the minimally informative prior distribution, we will also use a sceptical prior distribution (N (0, 0.25)) centred at no effect (RR of 1.0), an optimistic prior distribution (N (0.18, 0.15)) centred around a positive effect on treatment success (RR of 1.2), and a pessimistic prior distribution (N (-0.22, 0.15)) centred around a negative effect on treatment success (RR of 0.8). Lastly, we will examine the impact of excluding the random effect by hospital site in the primary model by re-running the primary model without random effect, to assess whether this impacts the study conclusions. All Bayesian analyses will be conducted using R software, v.4.4.1 or higher. Frequentist analyses The frequentist primary analysis of treatment success will use a hierarchical log-binomial model, using a log-link and binomial likelihood with random effect by hospital site, to estimate the RR of success on combined treatment at week 8. The secondary analysis will add adjustment covariates to the model (described above in the Bayesian analysis section). The secondary analysis will also include the raw and adjusted analysis of persistent bacteraemia, and mortality using the same type of models as described previously. The same subgroups as in the Bayesian analysis will be tested using the primary log-binomial model including terms for subgroup indicators and an interaction with the study treatment. All frequentist analyses will be conducted using R software, v.4.4.1 or higher. DISCUSSION In this post-hoc study of the BACSARM and SAFO RCTs we will assess the impact of fosfomycin in combination with the standard treatment in the management of MRSA and MSSA bacteraemia. This analysis will combine two previously completed inconclusive trials to estimate the likelihood that fosfomycin combination therapy is effective and beneficial in terms of treatment success, persistent bacteraemia, and mortality. Additionally, it will estimate the probability of harm by estimating the likelihood that fosfomycin combination therapy leads to increased adverse events. There are no ongoing clinical trials studying fosfomycin combination therapy, despite the indication of a benefit found in previously completed trials and the absence of definitive conclusions. The results of our analysis will thus be impactful. First, they will aid clinicians in individualising the decision to administer adjunctive fosfomycin, based on the characteristics of patients affected by SAB and the safety profile of fosfomycin (21). Second, it will provide guidance to investigators for determining whether further clinical trials are required to examine this question. In addition, these results can aid clinical trial design and planning by providing treatment effect estimates to guide sample size determination (if a frequentist framework is used) or simulations (if a Bayesian framework is used). We believe our study has several strengths. First, the data derive from two large RCT including more than 350 patients. Second, a Bayesian re-analysis is beneficial in this circumstance since it is not dependent on the sample size of the cohort and can estimate a posterior probability of treatment benefit, as opposed to providing a binary “answer” of rejecting or not rejecting a frequentist null hypothesis. Nor is it subject to issues of multiple testing in a post-hoc analysis, since a Bayesian framework allows multiple examinations of the data without compromising type I error rate. One limitation of this analysis is that it combines data from two previously completed clinical trials, and so any candidate variables included in the analysis are limited to variables collected by these studies. We are unable to use the same primary outcomes as in the original trials, as they were assessed at different time points (day 7 in SAFO and 6 weeks after end of treatment in BACSARM). The primary outcome selected for this analysis is thus based on a common time point of assessment at which data were collected in both trials. The same limitations apply for the selection of the secondary outcomes. In summary, the BACSAFO study seeks to clarify the role of fosfomycin as an adjunctive therapy to improve outcomes in patients with SAB. By analyzing pooled data and attempting to identify subgroups that might benefit most, this study has the potential to refine treatment strategies and guide the design of future RCTs on combination antibiotic therapies for SAB. Strenghts and limitations of this study The primary endpoint is a composite outcome assessing mortality and clinical and microbiological failure at week 8 from the time of randomisation. The study includes cases of SAB from two randomised clinical trials. Bayesian and frequentist analyses will be performed to describe the effect of fosfomycin addition in the outcomes of patients with SAB. Patients with prosthetic endocarditis and advanced liver cirrhosis were excluded due to potential sodium overload with the administration of fosfomycin. Declarations Ethics approval and consent to participate The present study was approved by the local ethics committee (Comitè d’Ètica en Investigació de Medicaments de l’Hospital Universitari de Bellvitge) with reference EOM033/24. The BACSARM and SAFO trials were approved by the local ethics committee (Comitè d’Ètica en Investigació de Medicaments de l’Hospital Universitari de Bellvitge) with references AC032/13 and AC069/18 respectively. Consent for publication Not applicable. Availability of data and materials Individual data cannot be shared because of privacy restrictions. Raw anonymised data relating to primary and secondary outcomes and safety can be shared upon request to researchers who provide a methodologically reasonable proposal. The request for data can be sent to the corresponding author (J.C.). A period of 18 months after publication of the main study results should elapse before requests are made, so as to allow authors to publish substudies. Interested researchers must obtain the approval of the Bellvitge University Hospital Ethics Committee. Competing interests In the last three years JMM has received consulting honoraria and/or research grants from Angelini, Contrafect, Genentech, Gilead Sciences, Jansen, Lysovant, , MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work. JMM received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–25. M.P. received a research grant from Laboratorios ERN. J.C. has received honoraria from MSD for educational activities. The rest of the authors do not declare any conflicts of interest. Funding The BACSAFO study was supported by the CIBERINFEC. Instituto de Salud Carlos III, Madrid, Spain. The BACSARM trial was supported by grant funding from the National Institute of Health Research, Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad. Gobierno de España (FIS PI12/01907). The SAFO trial was supported by a competitive grant awarded by the Fondo de Investigaciones Sanitarias at the Spanish government’s National Institute of Health Research, Instituto de Salud Carlos III (ISCIII), (FIS PI17/01116). Authors’ contributions F.E., S.O., M.P., N.P, C.T., S.T. and J.C. conceived and developed the design of the study. S.O. and K.L. performed the Bayesian analyses. N.P. and C.T. pooled the individual patient data of the two clinical trials and performed the Frequentist analyses. S.G., M.P., JMM and J.C. design, coordinated and carried out the BACSARM and SAFO trials. F.E., I.O. and S.G. participated in the BACSARM and SAFO trials. All authors have read, revised, and approved the manuscript. Acknowledgements We thank the CERCA Programme/Generalitat de Catalunya for their institutional support. References Martínez Pérez-Crespo PM, López-Cortés LE, Retamar-Gentil P et al (2021) Epidemiologic changes in bloodstream infections in Andalucía (Spain) during the last decade. Clin Microbiol Infect 27:283. .e9-283.e16 Diekema DJ, Hsueh P-R, Mendes RE et al (2019) The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 63:e00355–e00319. 10.1128/AAC.00355-19 IHME Pathogen Core Group (2024) Global burden associated with 85 pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Infect Dis 24:868–895. 10.1016/S1473-3099(24)00158-0 Kaasch AJ, Barlow G, Edgeworth JD et al (2014) Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect 68:242–251. 10.1016/j.jinf.2013.10.015 Stewardson AJ, Allignol A, Beyersmann J et al (2016) The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and Staphylococcus aureus in European hospitals, 2010 and 2011: a multicentre retrospective cohort study. Euro Surveill 21:30319. 10.2807/1560-7917.ES.2016.21.33.30319 Inagaki K, Lucar J, Blackshear C et al (2019) Methicillin-susceptible and Methicillin-resistant Staphylococcus aureus Bacteremia: Nationwide Estimates of 30-Day Readmission, In-hospital Mortality, Length of Stay, and Cost in the United States. Clin Infect Dis 69:2112–2118. 10.1093/cid/ciz123 Minejima E, Mai N, Bui N et al (2020) Defining the Breakpoint Duration of Staphylococcus aureus Bacteremia Predictive of Poor Outcomes. Clin Infect Dis 70:566–573. 10.1093/cid/ciz257 Kuehl R, Morata L, Boeing C et al (2020) Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis 20:1409–1417. 10.1016/S1473-3099(20)30447-3 Gasch O, Camoez M, Dominguez MA et al (2013) Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect 19:1049–1057. 10.1111/1469-0691.12108 GBD 2021 Antimicrobial Resistance Collaborators (2024) Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet 404:1199–1226. 10.1016/S0140-6736(24)01867-1 Paul M, Zemer-Wassercug N, Talker O et al (2011) Are all beta-lactams similarly effective in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia? Clin Microbiol Infect 17:1581–1586. 10.1111/j.1469-0691.2010.03425.x Liu C, Bayer A, Cosgrove SE et al (2011) Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:e18–55. 10.1093/cid/ciq146 García-de-la-Mària C, Gasch O, García-Gonzalez J et al (2018) The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis. Antimicrob Agents Chemother 62:e02633–e02617. 10.1128/AAC.02633-17 Kastoris AC, Rafailidis PI, Vouloumanou EK et al (2010) Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. Eur J Clin Pharmacol 66:359–368. 10.1007/s00228-010-0794-5 García-de-la-Mària C, Gasch O, Castañeda X et al (2020) Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis. J Antimicrob Chemother 75:3586–3592. 10.1093/jac/dkaa354 Pujol M, Miró J-M, Shaw E et al (2021) Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial. Clin Infect Dis 72:1517–1525. 10.1093/cid/ciaa1081 Grillo S, Pujol M, Miró JM et al (2023) Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible Staphylococcus aureus bacteremia: a randomized trial. Nat Med 29:2518–2525. 10.1038/s41591-023-02569-0 Jakobsen JC, Gluud C, Wetterslev J et al (2017) When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol 17:162. 10.1186/s12874-017-0442-1 Chow JW, Yu VL (1999) Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: a commentary. Int J Antimicrob Agents 11:7–12. 10.1016/s0924-8579(98)00060-0 Charlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383. 10.1016/0021-9681(87)90171-8 Swets MC, Bakk Z, Westgeest AC et al (2024) Clinical sub-phenotypes of Staphylococcus aureus bacteraemia. Clin Infect Dis. 10.1093/cid/ciae338 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6612075","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":453255576,"identity":"30efd415-4239-4eeb-bb6a-e61a424884b7","order_by":0,"name":"Francesc Escrihuela-Vidal1","email":"","orcid":"","institution":"Department of Infectious Diseases, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain","correspondingAuthor":false,"prefix":"","firstName":"Francesc","middleName":"","lastName":"Escrihuela-Vidal1","suffix":""},{"id":453263292,"identity":"d70016d7-5dc1-4cf0-ad24-5dceefa6c18b","order_by":1,"name":"Sean W X Ong","email":"","orcid":"","institution":"3.\tVictorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.","correspondingAuthor":false,"prefix":"","firstName":"Sean","middleName":"W X","lastName":"Ong","suffix":""},{"id":453263293,"identity":"a03f8cd1-b30e-4568-90f1-09103b3725a1","order_by":2,"name":"Isabel Oriol","email":"","orcid":"","institution":"Department of Infectious Diseases, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain","correspondingAuthor":false,"prefix":"","firstName":"Isabel","middleName":"","lastName":"Oriol","suffix":""},{"id":453263294,"identity":"e95c89ee-8f0a-4454-9021-094ed25b62ee","order_by":3,"name":"Sara Grillo","email":"","orcid":"","institution":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Grillo","suffix":""},{"id":453263295,"identity":"a9d1c96e-ac2e-4782-b606-2aa2a41fcc54","order_by":4,"name":"Miquel Pujol","email":"","orcid":"","institution":"Department of Infectious Diseases, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain","correspondingAuthor":false,"prefix":"","firstName":"Miquel","middleName":"","lastName":"Pujol","suffix":""},{"id":453263296,"identity":"ecfb6c68-bd41-462f-9503-cebeb9f84573","order_by":5,"name":"Natàlia Pallarès","email":"","orcid":"","institution":"Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Spain.","correspondingAuthor":false,"prefix":"","firstName":"Natàlia","middleName":"","lastName":"Pallarès","suffix":""},{"id":453263297,"identity":"1100c7ae-5d95-4dbe-94cc-0255853322d4","order_by":6,"name":"Cristian Tebé","email":"","orcid":"","institution":"Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Spain.","correspondingAuthor":false,"prefix":"","firstName":"Cristian","middleName":"","lastName":"Tebé","suffix":""},{"id":453263298,"identity":"6722c3cb-a6ef-42e3-966a-a288fc4f7eea","order_by":7,"name":"Kuan Liu","email":"","orcid":"","institution":"Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.","correspondingAuthor":false,"prefix":"","firstName":"Kuan","middleName":"","lastName":"Liu","suffix":""},{"id":453263299,"identity":"e240a6cf-857a-49b0-96f6-734684a1ccb9","order_by":8,"name":"Jose M Miró","email":"","orcid":"","institution":"Department of Infectious Diseases, Hospital Clínic, Barcelona, Spain","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"M","lastName":"Miró","suffix":""},{"id":453263300,"identity":"f00034c1-861d-46cb-9a11-bb3496d8a0c3","order_by":9,"name":"Steven Y C Tong","email":"","orcid":"","institution":"Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"Y C","lastName":"Tong","suffix":""},{"id":453263301,"identity":"e3a725dc-ba65-41c0-adc8-83fcf19717bd","order_by":10,"name":"Jordi Carratalà","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3209-2563","institution":"Department of infectious Diseases, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain","correspondingAuthor":true,"prefix":"","firstName":"Jordi","middleName":"","lastName":"Carratalà","suffix":""}],"badges":[],"createdAt":"2025-05-07 12:31:32","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6612075/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6612075/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82233475,"identity":"c5a99f45-1a05-4c7b-8de4-b19737e31442","added_by":"auto","created_at":"2025-05-08 06:37:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":755330,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6612075/v1/57ef3668-ed9a-417e-a8c9-951cd210ee88.pdf"},{"id":82232384,"identity":"94734713-a3b5-4372-a781-f86ab69a378c","added_by":"auto","created_at":"2025-05-08 06:21:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33063,"visible":true,"origin":"","legend":"\u003cp\u003eSPIRIT\u003c/p\u003e","description":"","filename":"SupplementarymaterialSPIRIT.docx","url":"https://assets-eu.researchsquare.com/files/rs-6612075/v1/2849538d6b26ce8f45dcf239.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAdjunctive fosfomycin for treatment of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eStaphylococcus aureus\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e bacteraemia: protocol for a pooled post-hoc analysis of two randomised clinical trials (BACSAFO)\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003e \u003cem\u003eStaphylococcus aureus\u003c/em\u003e is a leading cause of both nosocomial and community-onset bacteraemia worldwide [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. \u003cem\u003eS. aureus\u003c/em\u003e bacteraemia (SAB) is associated with a mortality rate ranging from 20\u0026ndash;40% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and contributes to significant morbidity and economic burden [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. High-risk infection sources, such as endocarditis or pneumonia, as well as persistent bacteraemia, are associated with increased mortality and recurrent infections in both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) bacteraemia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite ongoing efforts to optimise the management of SAB, patient prognosis has not improved, and this remains a matter of concern. There is a growing interest in enhancing standard antibiotic therapies by using adjunctive antibiotics with synergistic or anti-biofilm activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, it remains uncertain whether combination antibiotic therapies offer a survival benefit over standard-of-care with monotherapy.\u003c/p\u003e \u003cp\u003eFosfomycin, a cell-wall synthesis inhibitor, has shown promise in experimental models of endocarditis caused by both MRSA [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and MSSA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], demonstrating synergistic and bactericidal effects when combined with standard antibiotics. Recent clinical evaluations of fosfomycin as adjunctive therapy in SAB have been conducted in two prospective, randomised, open-label clinical trials: the BACSARM [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and SAFO [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] RCTs.\u003c/p\u003e \u003cp\u003eThe BACSARM trial assessed high-dose daptomycin plus fosfomycin against daptomycin monotherapy for MRSA bacteraemia. Although the combination therapy arm showed a 12% improvement in the primary outcome of treatment success at 6 weeks after end of treatment, this difference was not statistically significant. However, subgroup analyses showed that fosfomycin combination was potentially more effective than monotherapy in patients under 74 years of age and in those with more severe disease (Pitt bacteraemia score\u0026thinsp;\u0026gt;\u0026thinsp;1 point).\u003c/p\u003e \u003cp\u003eIn the SAFO trial, cloxacillin combined with fosfomycin for treating MSSA bacteraemia was compared to cloxacillin alone, with no significant difference in treatment success at day 7. While neither trial demonstrated statistically significant differences in the primary endpoints, in both studies the administration of adjunctive fosfomycin was associated with significantly lower rates of persistent bacteraemia at day 3 compared to monotherapy. This finding did not translate into clinically significant outcomes, but this may have been due to the inclusion of a high proportion of low-risk SAB patients, 31\u0026ndash;49% of whom had an intravascular catheter as the source of infection. In addition, the intrinsic heterogeneity of SAB makes it difficult to draw definitive conclusions from these trials.\u003c/p\u003e \u003cp\u003eTherefore, the potential benefits of adjunctive fosfomycin in the treatment of SAB warrant further investigation. To address this issue, we will conduct a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO trials, known as the BACSAFO study. We will use both Bayesian and frequentist methodologies in our analyses. In addition, we will explore whether adjunctive fosfomycin is particularly beneficial for specific patient subgroups.\u003c/p\u003e\n\u003ch3\u003ePrimary objective\u003c/h3\u003e\n\u003cp\u003eTo determine whether fosfomycin combination therapy achieves a higher proportion of treatment success at 8 weeks than the administration of daptomycin or cloxacillin alone in the treatment of SAB.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary objectives\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTo evaluate the impact of fosfomycin combination therapy on treatment success at day 14 and all-cause mortality at days 30 and 60.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo determine whether adjunctive fosfomycin increases rates of bacteraemia clearance at days 3 and 7.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo establish whether there is a specific subgroup of patients that could benefit from the use of adjunctive fosfomycin, i.e., depending on their age, methicillin resistance, place of acquisition, and complicated bacteraemia status.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e "},{"header":"METHODS AND ANALYSIS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eThe BACSAFO study will comprise a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO multicentre trials. Both these trials were conducted at Spanish hospitals and have been previously published elsewhere [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The main characteristics of the BACSARM and the SAFO trials are summarized in the Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMain characteristics of the BACSARM and SAFO trials.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBACSARM\u003c/p\u003e \u003cp\u003eReference [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSAFO\u003c/p\u003e \u003cp\u003eReference [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDesign of the study\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMulticentre, open-label, randomised, phase III, interventional clinical trial with parallel allocation (1:1) with superiority design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulticentre, open-label, randomised, phase III-IV, interventional clinical trial with parallel allocation (1:1) with superiority design\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntervention\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDaptomycin plus fosfomycin versus daptomycin alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCloxacillin plus fosfomycin versus cloxacillin alone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDuration of adjunctive fosfomycin therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u0026ndash;14 days for uncomplicated bacteraemia, 28\u0026ndash;42 days for complicated bacteraemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 days after randomisation; further treatment was determined by the attending physicians, usually ranging from 10 to 14 days for uncomplicated bacteraemia and from 28 to 42 days for complicated bacteraemia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients\u0026thinsp;\u0026ge;\u0026thinsp;18 years old with complicated or uncomplicated MRSA bacteraemia (N\u0026thinsp;=\u0026thinsp;155 patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients\u0026thinsp;\u0026ge;\u0026thinsp;18 years old with complicated or uncomplicated MSSA bacteraemia (N\u0026thinsp;=\u0026thinsp;214 patients)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExclusion criteria in both trials\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePolymicrobial bacteraemia, severe clinical status with expected survival\u0026thinsp;\u0026lt;\u0026thinsp;24 hours, severe liver disease with Child-Pugh score class C, diagnosis of prosthetic infective endocarditis, allergy or known resistance to study drugs, pregnancy at the time of inclusion, inclusion in another clinical trial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParticular exclusion criteria for each trial\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiagnosis of MRSA pneumonia, prior history of eosinophilic pneumonia, use of additional antibiotic therapy with microbiological activity against MRSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrior history of myasthenia gravis, acute SARS-CoV2 infection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary endpoint\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTreatment response at TOC (6 weeks after stopping therapy), defined as resolution of clinical signs and symptoms plus negative blood cultures: 54.1% for daptomycin plus fosfomycin versus 42.0% for daptomycin alone (RR 1.29; 95% CI 0.93\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment success at day 7 after randomisation, defined as a composite of patient alive and afebrile, with clinical improvement measured by SOFA score and with negative blood cultures: 79.8% for cloxacillin plus fosfomycin versus 74.5% for cloxacillin alone (risk difference 5.3%; 95% CI -5.95-16.48, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.360)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePersistent bacteraemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay 3: 2.7% daptomycin plus fosfomycin vs 18.5% daptomycin alone (RR 0.15; 95% CI 0.04\u0026ndash;0.63)\u003c/p\u003e \u003cp\u003eDay 7: 0% daptomycin plus fosfomycin vs 6.2% daptomycin alone (RR -6.2; 95% CI -11.4 to -0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDay 3: 4.3% cloxacillin plus fosfomycin vs 17.2% cloxacillin alone (risk difference \u0026minus;\u0026thinsp;12.9; 95% CI -22.43 to -3.4)\u003c/p\u003e \u003cp\u003eDay 7: 2.3% cloxacillin plus fosfomycin vs 4.2% cloxacillin alone (risk difference \u0026minus;\u0026thinsp;1.9; 95% CI -8.13-4.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eMRSA: methicillin-resistant \u003cem\u003eS. aureus\u003c/em\u003e; MSSA: methicillin-susceptibly \u003cem\u003eS. aureus\u003c/em\u003e; SOFA: Sequential Organ Failure Assessment; TOC: test-of-cure.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003eIn the BACSARM trial, 155 adult patients with MRSA bacteraemia were randomised 1:1 to receive daptomycin in combination with fosfomycin or daptomycin alone [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the SAFO trial, 214 adult patients with MSSA bacteraemia were randomised 1:1 to receive cloxacillin in combination with fosfomycin or cloxacillin alone [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As this is a pooled analysis of all SAB, all patients included in the intention-to-treat analysis of the BACSARM and SAFO trials will be included in the present study, regardless of their susceptibility to methicillin. The intention-to-treat population included all the randomised patients who received at least one day of antibiotics. Inclusion criteria common to both trials were: 1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years, 2) at least one blood culture positive for MRSA or MSSA\u0026thinsp;\u0026le;\u0026thinsp;72 hours before inclusion and with evidence of active infection. The present study will include both uncomplicated and complicated SAB. Both the BACSARM and SAFO trials excluded patients with polymicrobial bacteraemia, allergy to the study drugs, severe liver disease (Child-Pugh score class C), prosthetic valve endocarditis, pregnancy, expected survival\u0026thinsp;\u0026lt;\u0026thinsp;24 hours, and inclusion in another trial. The BACSARM trial excluded patients with MRSA pneumonia (given that use of daptomycin is not recommended in the setting of pneumonia). The SAFO trial, which was partially conducted during the COVID-19 pandemic, excluded patients with acute SARS-CoV-2 infection.\u003c/p\u003e\n\u003ch3\u003ePatient and Public Involvement\u003c/h3\u003e\n\u003cp\u003ePatients and public were not involved in the design and will not be involved in the conduct, reporting or dissemination of the BACSAFO study.\u003c/p\u003e\n\u003ch3\u003eStudy groups and interventions\u003c/h3\u003e\n\u003cp\u003eThe experimental group will include all patients receiving adjunctive fosfomycin (the combination therapy group). The control group will include all patients not receiving fosfomycin (the standard-of-care [SOC] group). In the BACSARM trial, fosfomycin 2g every 6 hours was administered for 10\u0026ndash;14 days for uncomplicated SAB and 28\u0026ndash;42 days for complicated SAB. In the SAFO trial, fosfomycin 3g every 6 hours was administered during the first 7 days after randomisation; after the first week, the choice and duration of antibiotics were determined by the attending physician. In both trials, recommendations were provided on the adjustment of the dose of fosfomycin to renal function. In the SAFO trial, recommendations for the prevention, identification and management of hypokalaemia, hypocalcaemia and sodium overload were included in the protocol and provided to attending physicians.\u003c/p\u003e \u003cp\u003eIn the present study, complicated SAB will be defined as the presence of metastatic infection (progression of infection beyond the primary focus, skin alterations suggestive of acute systemic infection, endocarditis), persistent SAB (defined as persistence of positive blood cultures for \u003cem\u003eS. aureus\u003c/em\u003e after 72\u0026ndash;96 hours from the start of antibiotics), and presence of a non-catheter endovascular device.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eIn the BACSARM trial, test-of-cure was performed at 6 weeks after stopping therapy. In the SAFO trial, test-of-cure was performed at 12 weeks after randomisation. For the present study, the primary outcome will be treatment success at 8 weeks from the time of randomisation, a composite outcome available from the information collected in both trials and based on the fulfilment of all the following criteria:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAlive at week 8 from the time of randomisation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAbsence of relapse within 8 weeks after randomisation, defined as isolation of \u003cem\u003eS. aureus\u003c/em\u003e in blood cultures after the index blood cultures were cleared.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eImprovement of clinical signs and symptoms as assessed by investigators of the BACSARM and SAFO trials at week 8 from the time of randomisation.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eSecondary outcomes will be:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePersistent bacteraemia, as defined by positive blood cultures for \u003cem\u003eS. aureus\u003c/em\u003e at days 3 and 7 from the time of randomisation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMortality at days 14, 30 and 60 from the time of randomisation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAdverse events leading to treatment discontinuation during adjunctive fosfomycin therapy.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eNo sample size calculation will be performed, since this is a post-hoc analysis of two previously completed trials. The study will include 369 patients: 155 from the BACSARM trial and 214 from the SAFO trial.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMissing data\u003c/h2\u003e \u003cp\u003eThe proportions of missing data for all variables will be presented. In the BACSARM and SAFO trials, missing data in individual variables was below 5%. There are no missing data for the primary outcome in either trial. The proportion of missing covariate data was \u0026lt;\u0026thinsp;5%, and hence complete case analyses discarding the observations with missing data will be conducted for the adjusted analyses and subgroup analyses [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAnalyses\u003c/h2\u003e \u003cp\u003eThe primary exposure of interest is fosfomycin adjunctive therapy. To account for potential clustering by site, in the primary model we will include study site (18 sites in BACSARM, 19 sites in the SAFO, including the same 18 as in BACSARM) as a random effect with random intercept.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eBayesian analyses\u003c/h2\u003e \u003cp\u003eThe Bayesian primary analysis will use a hierarchical Bayesian log-binomial model, using a log-link and binomial likelihood with random effect by hospital site. As the clinical evidence studying the effect of fosfomycin combination therapy is limited, we will use a minimally informative prior distribution (\u003cem\u003eN\u003c/em\u003e (0,5)), centred at no effect (i.e., risk ratio [RR] of 1.0). We will assume independence between priors of random effect and the fixed effect parameter, with default priors for the random intercept. We will use Markov Chain Monte Carlo methods to estimate the RR with 95% credible intervals of each outcome from 50th, 2.5th, and 97.5th percentiles of the posterior distribution.\u003c/p\u003e \u003cp\u003eIn a secondary analysis, we will additionally include other covariates that are prognostically important for the outcomes of treatment success, persistent bacteraemia, and mortality. These include: (i) age (as a continuous variable), (ii) Pitt bacteremia score [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], (iii) methicillin susceptibility (MSSA vs MRSA), (iv) Charlson\u0026rsquo;s comorbidity index (as a summary measure of comorbidity) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], (v) acquisition of infection (community-acquired vs nosocomial), and (vi) infection source. The secondary analysis will include an adjusted analysis using the same log-binomial model, but additionally including the covariates listed above. Minimally informative prior distributions will be used for each of these covariates.\u003c/p\u003e \u003cp\u003eLastly, subgroup analyses will be conducted using the same primary log-binomial model (again with random effect by hospital site) but including terms for subgroup indicators and an interaction term with the primary treatment variable (fosfomycin combination treatment). The subgroups examined will include age (\u0026ge;\u0026thinsp;65 years old vs\u0026thinsp;\u0026lt;\u0026thinsp;65 years old), methicillin resistance (MSSA vs MRSA), acquisition of infection (community-acquired vs nosocomial), and complicated bacteraemia status (complicated vs uncomplicated). Subgroup analyses will estimate the posterior probability of a subgroup effect, i.e., that fosfomycin combination therapy is more effective in subgroup 1 vs subgroup 2 for each subgroup variable.\u003c/p\u003e \u003cp\u003eAnalysis of the secondary outcomes will use a hierarchical Bayesian log-binomial model with random effect by hospital site. Models for the secondary outcomes will be unadjusted and will not include any of the covariate terms. All models will be examined for model fit using posterior predictive plots and model convergence using leave-one-out cross-validation.\u003c/p\u003e \u003cp\u003eWe will examine the impact of the prior distribution on the primary analysis by varying the prior distribution to reflect variable pre-existing beliefs among clinicians. In addition to the minimally informative prior distribution, we will also use a sceptical prior distribution (N (0, 0.25)) centred at no effect (RR of 1.0), an optimistic prior distribution (N (0.18, 0.15)) centred around a positive effect on treatment success (RR of 1.2), and a pessimistic prior distribution (N (-0.22, 0.15)) centred around a negative effect on treatment success (RR of 0.8). Lastly, we will examine the impact of excluding the random effect by hospital site in the primary model by re-running the primary model without random effect, to assess whether this impacts the study conclusions. All Bayesian analyses will be conducted using R software, v.4.4.1 or higher.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFrequentist analyses\u003c/h2\u003e \u003cp\u003eThe frequentist primary analysis of treatment success will use a hierarchical log-binomial model, using a log-link and binomial likelihood with random effect by hospital site, to estimate the RR of success on combined treatment at week 8. The secondary analysis will add adjustment covariates to the model (described above in the Bayesian analysis section). The secondary analysis will also include the raw and adjusted analysis of persistent bacteraemia, and mortality using the same type of models as described previously. The same subgroups as in the Bayesian analysis will be tested using the primary log-binomial model including terms for subgroup indicators and an interaction with the study treatment. All frequentist analyses will be conducted using R software, v.4.4.1 or higher.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this post-hoc study of the BACSARM and SAFO RCTs we will assess the impact of fosfomycin in combination with the standard treatment in the management of MRSA and MSSA bacteraemia. This analysis will combine two previously completed inconclusive trials to estimate the likelihood that fosfomycin combination therapy is effective and beneficial in terms of treatment success, persistent bacteraemia, and mortality. Additionally, it will estimate the probability of harm by estimating the likelihood that fosfomycin combination therapy leads to increased adverse events.\u003c/p\u003e \u003cp\u003eThere are no ongoing clinical trials studying fosfomycin combination therapy, despite the indication of a benefit found in previously completed trials and the absence of definitive conclusions. The results of our analysis will thus be impactful. First, they will aid clinicians in individualising the decision to administer adjunctive fosfomycin, based on the characteristics of patients affected by SAB and the safety profile of fosfomycin (21). Second, it will provide guidance to investigators for determining whether further clinical trials are required to examine this question. In addition, these results can aid clinical trial design and planning by providing treatment effect estimates to guide sample size determination (if a frequentist framework is used) or simulations (if a Bayesian framework is used).\u003c/p\u003e \u003cp\u003eWe believe our study has several strengths. First, the data derive from two large RCT including more than 350 patients. Second, a Bayesian re-analysis is beneficial in this circumstance since it is not dependent on the sample size of the cohort and can estimate a posterior probability of treatment benefit, as opposed to providing a binary \u0026ldquo;answer\u0026rdquo; of rejecting or not rejecting a frequentist null hypothesis. Nor is it subject to issues of multiple testing in a post-hoc analysis, since a Bayesian framework allows multiple examinations of the data without compromising type I error rate.\u003c/p\u003e \u003cp\u003eOne limitation of this analysis is that it combines data from two previously completed clinical trials, and so any candidate variables included in the analysis are limited to variables collected by these studies. We are unable to use the same primary outcomes as in the original trials, as they were assessed at different time points (day 7 in SAFO and 6 weeks after end of treatment in BACSARM). The primary outcome selected for this analysis is thus based on a common time point of assessment at which data were collected in both trials. The same limitations apply for the selection of the secondary outcomes.\u003c/p\u003e \u003cp\u003eIn summary, the BACSAFO study seeks to clarify the role of fosfomycin as an adjunctive therapy to improve outcomes in patients with SAB. By analyzing pooled data and attempting to identify subgroups that might benefit most, this study has the potential to refine treatment strategies and guide the design of future RCTs on combination antibiotic therapies for SAB.\u003c/p\u003e"},{"header":"Strenghts and limitations of this study","content":"\u003cul\u003e\n \u003cli\u003eThe primary endpoint is a composite outcome assessing mortality and clinical and microbiological failure at week 8 from the time of randomisation.\u003c/li\u003e\n \u003cli\u003eThe study includes cases of SAB from two randomised clinical trials.\u003c/li\u003e\n \u003cli\u003eBayesian and frequentist analyses will be performed to describe the effect of fosfomycin addition in the outcomes of patients with SAB.\u003c/li\u003e\n \u003cli\u003ePatients with prosthetic endocarditis and advanced liver cirrhosis were excluded due to potential sodium overload with the administration of fosfomycin.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was approved by the local ethics committee (Comitè d’Ètica en Investigació de Medicaments de l’Hospital Universitari de Bellvitge) with reference EOM033/24. The BACSARM and SAFO trials were approved by the local ethics committee (Comitè d’Ètica en Investigació de Medicaments de l’Hospital Universitari de Bellvitge) with references AC032/13 and AC069/18 respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual data cannot be shared because of privacy restrictions. Raw anonymised data relating to primary and secondary outcomes and safety can be shared upon request to researchers who provide a methodologically reasonable proposal. The request for data can be sent to the corresponding author (J.C.). A period of 18 months after publication of the main study results should elapse before requests are made, so as to allow authors to publish substudies. Interested researchers must obtain the approval of the Bellvitge University Hospital Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the last three years JMM has received consulting honoraria and/or research grants from Angelini, Contrafect, Genentech, Gilead Sciences, Jansen, Lysovant, , MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work.\u0026nbsp;JMM received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–25. M.P. received a research grant from Laboratorios ERN. J.C. has received honoraria from MSD for educational activities. The rest of the authors do not declare any conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe BACSAFO study was supported by the CIBERINFEC. Instituto de Salud Carlos III, Madrid, Spain. The BACSARM trial was supported by grant funding from the National Institute of Health Research, Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad. Gobierno de España (FIS PI12/01907). The SAFO trial was supported by a competitive grant awarded by the Fondo de Investigaciones Sanitarias at the Spanish government’s National Institute of Health Research, Instituto de Salud Carlos III (ISCIII), (FIS PI17/01116).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF.E., S.O., M.P., N.P, C.T., S.T. and J.C. conceived and developed the design of the study. S.O. and K.L. performed the Bayesian analyses. N.P. and C.T. pooled the individual patient data of the two clinical trials and performed the Frequentist analyses. S.G., M.P., JMM and J.C. design, coordinated and carried out the BACSARM and SAFO trials. F.E., I.O. and S.G. participated in the BACSARM and SAFO trials. All authors have read, revised, and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the CERCA Programme/Generalitat de Catalunya for their institutional support.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez P\u0026eacute;rez-Crespo PM, L\u0026oacute;pez-Cort\u0026eacute;s LE, Retamar-Gentil P et al (2021) Epidemiologic changes in bloodstream infections in Andaluc\u0026iacute;a (Spain) during the last decade. Clin Microbiol Infect 27:283. .e9-283.e16\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiekema DJ, Hsueh P-R, Mendes RE et al (2019) The Microbiology of Bloodstream Infection: 20-Year Trends from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 63:e00355\u0026ndash;e00319. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1128/AAC.00355-19\u003c/span\u003e\u003cspan address=\"10.1128/AAC.00355-19\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIHME Pathogen Core Group (2024) Global burden associated with 85 pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Infect Dis 24:868\u0026ndash;895. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1473-3099(24)00158-0\u003c/span\u003e\u003cspan address=\"10.1016/S1473-3099(24)00158-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaasch AJ, Barlow G, Edgeworth JD et al (2014) \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect 68:242\u0026ndash;251. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jinf.2013.10.015\u003c/span\u003e\u003cspan address=\"10.1016/j.jinf.2013.10.015\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStewardson AJ, Allignol A, Beyersmann J et al (2016) The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and \u003cem\u003eStaphylococcus aureus\u003c/em\u003e in European hospitals, 2010 and 2011: a multicentre retrospective cohort study. Euro Surveill 21:30319. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2807/1560-7917.ES.2016.21.33.30319\u003c/span\u003e\u003cspan address=\"10.2807/1560-7917.ES.2016.21.33.30319\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInagaki K, Lucar J, Blackshear C et al (2019) Methicillin-susceptible and Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e Bacteremia: Nationwide Estimates of 30-Day Readmission, In-hospital Mortality, Length of Stay, and Cost in the United States. Clin Infect Dis 69:2112\u0026ndash;2118. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciz123\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciz123\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinejima E, Mai N, Bui N et al (2020) Defining the Breakpoint Duration of \u003cem\u003eStaphylococcus aureus\u003c/em\u003e Bacteremia Predictive of Poor Outcomes. Clin Infect Dis 70:566\u0026ndash;573. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciz257\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciz257\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuehl R, Morata L, Boeing C et al (2020) Defining persistent \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis 20:1409\u0026ndash;1417. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1473-3099(20)30447-3\u003c/span\u003e\u003cspan address=\"10.1016/S1473-3099(20)30447-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGasch O, Camoez M, Dominguez MA et al (2013) Predictive factors for mortality in patients with methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect 19:1049\u0026ndash;1057. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/1469-0691.12108\u003c/span\u003e\u003cspan address=\"10.1111/1469-0691.12108\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGBD 2021 Antimicrobial Resistance Collaborators (2024) Global burden of bacterial antimicrobial resistance 1990\u0026ndash;2021: a systematic analysis with forecasts to 2050. Lancet 404:1199\u0026ndash;1226. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S0140-6736(24)01867-1\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(24)01867-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaul M, Zemer-Wassercug N, Talker O et al (2011) Are all beta-lactams similarly effective in the treatment of methicillin-sensitive \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bacteraemia? Clin Microbiol Infect 17:1581\u0026ndash;1586. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1469-0691.2010.03425.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1469-0691.2010.03425.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu C, Bayer A, Cosgrove SE et al (2011) Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e infections in adults and children. Clin Infect Dis 52:e18\u0026ndash;55. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciq146\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciq146\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-de-la-M\u0026agrave;ria C, Gasch O, Garc\u0026iacute;a-Gonzalez J et al (2018) The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e in a Rabbit Model of Experimental Endocarditis. Antimicrob Agents Chemother 62:e02633\u0026ndash;e02617. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1128/AAC.02633-17\u003c/span\u003e\u003cspan address=\"10.1128/AAC.02633-17\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKastoris AC, Rafailidis PI, Vouloumanou EK et al (2010) Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. Eur J Clin Pharmacol 66:359\u0026ndash;368. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00228-010-0794-5\u003c/span\u003e\u003cspan address=\"10.1007/s00228-010-0794-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-de-la-M\u0026agrave;ria C, Gasch O, Casta\u0026ntilde;eda X et al (2020) Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis. J Antimicrob Chemother 75:3586\u0026ndash;3592. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jac/dkaa354\u003c/span\u003e\u003cspan address=\"10.1093/jac/dkaa354\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePujol M, Mir\u0026oacute; J-M, Shaw E et al (2021) Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant \u003cem\u003eStaphylococcus aureus\u003c/em\u003e Bacteremia and Endocarditis: A Randomized Clinical Trial. Clin Infect Dis 72:1517\u0026ndash;1525. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciaa1081\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciaa1081\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrillo S, Pujol M, Mir\u0026oacute; JM et al (2023) Cloxacillin plus fosfomycin versus cloxacillin alone for methicillin-susceptible \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bacteremia: a randomized trial. Nat Med 29:2518\u0026ndash;2525. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41591-023-02569-0\u003c/span\u003e\u003cspan address=\"10.1038/s41591-023-02569-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJakobsen JC, Gluud C, Wetterslev J et al (2017) When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol 17:162. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12874-017-0442-1\u003c/span\u003e\u003cspan address=\"10.1186/s12874-017-0442-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChow JW, Yu VL (1999) Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: a commentary. Int J Antimicrob Agents 11:7\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0924-8579(98)00060-0\u003c/span\u003e\u003cspan address=\"10.1016/s0924-8579(98)00060-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373\u0026ndash;383. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0021-9681(87)90171-8\u003c/span\u003e\u003cspan address=\"10.1016/0021-9681(87)90171-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwets MC, Bakk Z, Westgeest AC et al (2024) Clinical sub-phenotypes of Staphylococcus aureus bacteraemia. Clin Infect Dis. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/cid/ciae338\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciae338\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"118a2959-53a0-41d2-9575-29d749d194e0","identifier":"10.13039/501100004587","name":"Instituto de Salud Carlos III","awardNumber":"CIBERINFEC","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Bellvitge University Hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fosfomycin, Staphylococcus aureus bacteraemia, Daptomycin, Cloxacillin","lastPublishedDoi":"10.21203/rs.3.rs-6612075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6612075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e. Improving outcomes in patients with methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) \u003cem\u003eStaphylococcus aureus\u003c/em\u003e bacteraemia (SAB) is a critical healthcare goal. Two recent randomised clinical trials (RCTs), the BACSARM trial and the SAFO trial, assessed the efficacy of fosfomycin as an adjunctive therapy for MRSA and MSSA SAB respectively. Although neither trial demonstrated statistically significant differences in their primary endpoints of treatment success and reduced mortality respectively, both studies observed lower rates of persistent bacteraemia in the fosfomycin groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e We will perform a post-hoc analysis of pooled individual patient data from the BACSARM and SAFO trials, which will be referred to as the BACSAFO study. The primary exposure of interest is fosfomycin adjunctive therapy, and the primary outcome will be treatment success at 8 weeks, defined as the patient being alive, without signs of relapse, and showing improvement in clinical signs and symptoms. We will use both Bayesian and frequentist frameworks: the Bayesian analysis will use a hierarchical Bayesian log-binomial model, while the frequentist analysis will apply a hierarchical log-binomial model. In addition, we will investigate whether adjunctive fosfomycin is particularly beneficial in specific patient subgroups (created according to age, methicillin resistance, place of acquisition, and complicated bacteraemia status).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e. \u0026nbsp;The BACSAFO study aims to clarify the role of fosfomycin as an adjunctive therapy for improving outcomes in SAB patients. Although previous trials have not demonstrated significant differences in the primary endpoints, the significant reductions in rates of persistent bacteraemia observed suggest that fosfomycin might offer a clinical benefit in certain cases. By analysing pooled data and attempting to identify subgroups that might benefit most, this study has the potential to refine treatment strategies and inform trial design and planning for future RCTs investigating combination antibiotic therapies for SAB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination\u003c/strong\u003e. Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (EOM033/24). The results will be presented at international meetings and will be made available to patients and funders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number\u003c/strong\u003e. ClinicalTrials.gov Identifier: NCT06695832.\u003c/p\u003e","manuscriptTitle":"Adjunctive fosfomycin for treatment of Staphylococcus aureus bacteraemia: protocol for a pooled post-hoc analysis of two randomised clinical trials (BACSAFO)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 06:20:55","doi":"10.21203/rs.3.rs-6612075/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"335b5d7f-4600-4c14-b053-38416a5b5983","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48202522,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2025-05-08T06:20:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-08 06:20:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6612075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6612075","identity":"rs-6612075","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}