Clinical Infectious Diseases MAJOR ARTICLE Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial Miquel Pujol,1,a José-María Miró,2,a Evelyn Shaw,1 Jose-María Aguado,3 Rafael San-Juan,3 Mireia Puig-Asensio,4 Carles Pigrau,4 Esther Calbo,5 Miguel Montejo,6 Regino Rodriguez-Álvarez,6 María-Jose Garcia-Pais,7 Vicente Pintado,8 Rosa Escudero-Sánchez,8 Joaquín Lopez-Contreras,9 Laura Morata,2 Milagros Montero,10 Marta Andrés,11 Juan Pasquau,12 María-del-Mar Arenas,12 Belén Padilla,13 Javier Murillas,14 Alfredo Jover-Sáenz,15 Luis-Eduardo López-Cortes,16 Graciano García-Pardo,17 Oriol Gasch,18 Sebastian Videla,19 Pilar Hereu,19 Cristian Tebé,20 Natalia Pallarès,20 Mireia Sanllorente,19 María-Ángeles Domínguez,21 Jordi Càmara,21 Anna Ferrer,22 Ariadna Padullés,22 Guillermo Cuervo,1 and Jordi Carratalà1,a; for the Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 MRSA Bacteremia (BACSARM) Trial Investigators 1 Department of Infectious Diseases, Hospital Universitari de Bellvitge, Institut Investigacions Biomèdiques de Bellvitge, University of Barcelona, Barcelona, Spain, 2Department of Infectious Diseases, Hospital Clinic, Institut d’Investigacions Biomèdiques Agust Pi i Sunyer, University of Barcelona, Barcelona, Spain, 3Department of Infectious Diseases, Hospital Universitario 12 Octubre, Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain, 4Department of Infectious Diseases, Hospital Vall d’Hebron, Vall d’Hebron Institut de Recerca, Barcelona, Spain, 5 Infectious Diseases Unit, Hospital Universitari Mútua de Terrassa, Fundació Docència i Recerca Mútua de Terrassa, Universitat Internacional de Catalunya, Barcelona, Spain, 6Department of Infectious Diseases, Hospital Universitario Cruces, Biocruces Bizkaia, Bilbao, Spain, 7Infectious Diseases Unit, Hospital Lucus Augusti, Instituto de Investigación Sanitaria de Santiago de Compostela, Lugo, Spain, 8Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Instituto Ramon y Cajal de Investigación Sanitaria, Madrid, Spain, 9Department of Infectious Diseases, Hospital Universitari de Sant Pau, Institut d’Investigació Biomèdica de Sant Pau, Barcelona, Spain, 10Department of Infectious Diseases, Hospital del Mar, Institut de Recerca Hospital del Mar, Barcelona, Spain, 11Infectious Disease Unit, Consorci Sanitari de Terrassa, Terrassa, Spain, 12Department of Infectious Diseases, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Sanitaria Granada, Granada, Spain, 13Department of Clinical Microbiology and Infectious Diseases, Hospital Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, 14Department of Internal Medicine, Hospital Universitari Son Espases, Fundació Institut d’Investigació Sanitària Illes Balears, Mallorca, Spain, 15Territorial Unit of Nosocomial Infection, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, Lleida, Spain, 16Department of Infectious Diseases, Hospital Universitario Virgen Macarena, Instituto de Biomedicina de Sevilla, Sevilla, Spain, 17Department of Internal Medicine, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain, 18Department of Infectious Diseases, Consorci Sanitari Hospital Parc Taulí, Fundació Institut d’Investigació i Innovació Parc Taulí, Sabadell, Spain, 19Department of Clinical Pharmacology, Institut Investigacions Biomèdiques de Bellvitge, Clinical Research and Clinical Trials Unit, Plataforma Spanish Clinical Research Network, Barcelona, Spain, 20Biostatistics Unit, Institut Investigacions Biomèdiques de Bellvitge, L’Hospitalet Llobregat, L’Hospitalet del Llobregat, Spain, 21Department of Microbiology and Parasitology, Hospital Universitari de Bellvitge, Institut Investigacions Biomèdiques de Bellvitge, University of Barcelona, Barcelona, Spain, and 22 Department of Pharmacy, Hospital Universitari de Bellvitge, Institut Investigacions Biomèdiques de Bellvitge, University of Barcelona, Barcelona, Spain (See the Editorial Commentary by Karchmer on pages 1526–8.) Background. We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods. A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intra- venously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results. Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93–1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bac- teremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) re- ceiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions. Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this dif- ference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacte- remia, but it was more often associated with adverse events. Clinical Trials Registration. NCT01898338. Keywords. MRSA; bacteremia; daptomycin; fosfomycin; clinical trial. Received 24 February 2020; editorial decision 9 July 2020; accepted 27 July 2020; published © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases online July 29, 2020. Society of America. This is an Open Access article distributed under the terms of the Creative a M. P., J.-M. M., and J. C. contributed equally to this work. Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ Correspondence: M. Pujol, Department of Infectious Diseases, Hospital Universitari de by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Bellvitge, Feixa Llarga, s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain (mpujol@ medium, provided the original work is not altered or transformed in any way, and that the bellvitgehospital.cat). work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Clinical Infectious Diseases®  2021;72(9):1517–25 DOI: 10.1093/cid/ciaa1081 Treatment of MRSA Bacteremia • cid 2021:72 (1 May) • 1517 Bacteremia due to methicillin-resistant Staphylococcus au- combination of daptomycin plus fosfomycin vs daptomycin reus (MRSA) is a major healthcare problem worldwide [1, 2]. monotherapy for treatment of MRSA bacteremia have been Microbiological failures including persistent and recurrent in- performed to date. fection remain a major problem in the management of patients We designed the current randomized multicenter trial to test with MRSA bacteremia and endocarditis [3]. The persistently the hypothesis that daptomycin plus fosfomycin achieves higher high mortality rate in MRSA bacteremia, ranging from 13% treatment success than daptomycin alone in hospitalized adults to 30%, is a matter of concern [4–6]. A major factor contrib- with MRSA bacteremia and native valve endocarditis. uting to these adverse outcomes is the limited efficacy of the current standard antibiotic therapy with either vancomycin or METHODS daptomycin [7]. Study Design and Setting Vancomycin is the agent for which the greatest cumula- We performed a randomized (1:1), multicenter, phase 3, su- tive clinical experience is available for the treatment of MRSA periority, open-label and parallel-group clinical trial of adult bacteremia and endocarditis [8, 9]. Compared to β-lactams, inpatients with MRSA bacteremia at 18 Spanish hospitals. vancomycin has relatively slow bacterial killing, poor tissue Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 Participants were recruited between December 2013 and penetration, and potential for toxicity, all of which may be re- November 2017. The ethics committee at each participating sponsible for the clinical failures reported [10]. The use of van- center approved the study protocol. The trial was conducted comycin plus β-lactam therapy and adjunctive therapy with in agreement with the Declaration of Helsinki, the guidelines rifampicin to improve outcomes has proved unsatisfactory, for Good Clinical Practice, and Spanish regulatory require- providing little or no overall benefit over standard antibiotic ments. This academic trial is registered with ClinicalTrials.gov therapy and increasing toxicity [11–13]. In a significant ran- NCT01898338, and the protocol has been published elsewhere domized trial [14], daptomycin at a dose of 6 mg/kg once daily [25]. was not inferior to standard therapy for the treatment of S. au- reus bacteremia and endocarditis. Nevertheless, the emergence Participants of resistant strains and subsequent therapeutic failures using a Patients aged ≥18 years with MRSA bacteremia indicated by 1 once-daily dose of 6 mg/kg of daptomycin has led to the use or more positive blood cultures within the last 72 hours before of higher doses (8–10 mg/kg once daily) in some centers [7]. randomization and with symptoms and signs of infection were Despite the use of high doses, treatment failures due to persis- eligible for the study. Patients or authorized representatives pro- tent or relapsing infections have been reported [15]. Therefore, vided written informed consent. Exclusion criteria included life more effective strategies for the treatment of serious staphylo- expectancy ≤24 hours, polymicrobial bacteremia, pneumonia coccal infections are urgently needed. as a source of bacteremia, prosthetic valve endocarditis, severe The combination of daptomycin and fosfomycin is an ap- end-stage liver disease (Child-Pugh class C), New York Heart pealing strategy for the treatment of MRSA bacteremia. Association functional classification III/IV, prior history of eo- Fosfomycin has gained attention due to its broad spectrum and sinophilic pneumonia, any clinical condition that required ad- bactericidal activity against drug-resistant bacteria, including ditional antibiotic therapy active against MRSA, or allergy to MRSA [16]. Whereas daptomycin disrupts the cell membrane daptomycin or fosfomycin. synthesis of S. aureus [17], fosfomycin presents bactericidal activity by inhibiting an early stage of peptidoglycan synthesis Randomization and Masking [16]. Because daptomycin and fosfomycin have different mech- Patients were randomly assigned to receive either 10 mg/ anisms of action, they have a synergistic and rapid bactericidal kg of daptomycin intravenously daily plus 2 g of fosfomycin effect, and no cross-resistance has been observed between intravenously every 6 hours, or to receive 10 mg/kg of the drugs [18]. This synergistic activity may be explained by daptomycin intravenously daily, between 10 and 14 days fosfomycin PBP-1 inhibition [19, 20] and by its ability to modify for uncomplicated bacteremia and between 28 and 42 days cell-wall protein composition [21]. for complicated bacteremia. A centralized electronic com- In a rabbit model of experimental endocarditis, the combina- puter randomization schedule was developed by the Catalan tion of daptomycin and fosfomycin proved to be synergistic and Institute of Pharmacology. The randomization was performed rapidly bactericidal against MRSA [22]. Data from small se- in computed-generated variable blocks ranging from 4 to 8 ries of patients have shown that the combination of fosfomycin patients per center, to conceal the sequence until the inter- with either β-lactams or daptomycin was superior to standard vention was assigned. The code numbers for eligible patients antibiotic therapy for MRSA bacteremia [23, 24]. However, were assigned in ascending sequential order. The allocation list no randomized trials comparing the efficacy and safety of the was stored at the Catalan Institute of Pharmacology. At each 1518 • cid 2021:72 (1 May) • Pujol et al participating hospital, patients who provided written informed Primary and secondary endpoints were assessed by study consent and met the study criteria were randomized by investi- investigators in the modified intention-to-treat population. gators, who obtained the assigned treatment and code number A systematic, prioritized, risk-based approach to monitor AEs from a computer-assisted website. was developed to ensure that the trial was conducted, recorded, and reported according to good clinical practices [28]. AEs Procedures were recorded in all patients who received at least 1 dose of Daptomycin (Cubicin, Merck Sharp & Dohme B.V., Haarlem, the study medication. Clinical laboratory tests, vital signs, and the Netherlands) was administered intravenously by a 30-mi- other safety assessments were performed at scheduled visits. nute infusion once a day, and fosfomycin (Fosfocina, ERN S.A., An independent data and safety monitoring committee was Barcelona, Spain), was administered intravenously by at least established to review data when half of the sample had been one 60-minute infusion every 6 hours. Antibiotic dosage was recruited. Mortality and serious AEs leading to discontinua- adjusted according to creatinine clearance [25]. tion of therapy were considered key safety parameters. After a Patients were evaluated by researchers at inclusion, day 3, day safety monitoring meeting performed on 25 May 2016, no sig- 7, and end of therapy (EOT), and at the test of cure (TOC) visit nificant differences in serious events between groups were de- Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 6 weeks after EOT. Blood cultures were obtained at day 3, day tected, and a formal recommendation of continuing the study 7 (when positive at day 3), EOT, and TOC. Moreover, blood was established by the independent data and safety monitoring cultures and biochemistry analyses were performed whenever committee. it was considered necessary by the attending physicians and/ Microbiological methods are detailed in the Supplementary or researchers, according to the patient’s clinical evolution. Appendix. Echocardiograms were performed at the discretion of the at- tending physicians. Removal of pacemaker was not specifi- Statistical Analysis cally recorded, but it was the standard of care when considered Assuming a level of treatment success of 60% among patients re- the source of bacteremia in all of the participating centers. ceiving daptomycin alone at TOC, a sample size of 103 patients Definitions of persistent, recurrent, complicated MRSA bac- per group was calculated to reject the null hypothesis of equal teremia, and endocarditis are provided in the Supplementary effect, with a power of 80% and a significance level of 5%, for a Appendix [26, 27]. 20% difference in treatment success among patients receiving fosfomycin plus daptomycin. A 20% dropout rate was antici- Outcomes and Measurements pated. In November 2017, the number of recruited patients was The primary endpoint was treatment success at TOC (6 weeks 167 and the dropout rate was <5%. Considering the low dropout after EOT). Treatment success was considered when patient was rate and the time elapsed since the trial was initiated, the study alive and had resolution of clinical manifestations of infection committee decided to recalculate the sample size. Thus, a size of and negative blood cultures at TOC after completion of therapy. 81 patients per arm was considered enough to find significant Treatment failure was considered in any of the following situ- differences of 20% between arms with a power of 80% and an α ations: lack of clinical improvement at day 3 or later after the risk of .05. With this additional information, the trial was closed start of therapy, persistent MRSA bacteremia at day 7 or later, when 167 patients had been enrolled and followed up. Patients premature discontinuation of therapy due to adverse events who failed to continue in the study trial because they were ran- (AEs) or based on clinical judgment, recurrent MRSA bacte- domized in error or received <1 day of antibiotic treatment were remia before or at TOC, additional antimicrobial therapy active considered dropouts. As previously stated, study outcomes were against MRSA administered before TOC, lack of blood cultures assessed in the modified intention-to-treat population, which obtained at TOC, and/or death due to any cause before TOC. included all appropriately randomized patients according to the Only patients without treatment failure could have treatment study inclusion criteria who received ≥24 hours of antibiotic success. For analysis purposes, patients lost to follow-up (with therapy. Main efficacy analyses and the proportion of treatment missing TOC data) were classified as treatment failure. success at TOC were compared between groups using a 2-sided The secondary endpoints were MRSA bacteremia at day 3, χ 2 test. Relative risk for study outcomes were calculated and re- day 7, and/or at TOC; microbiological failure; complicated bac- ported with 95% confidence intervals (CIs). The homogeneity teremia; AEs leading to treatment discontinuation, and mor- of the treatment effect was tested in several subgroups defined tality due to any cause at day 7 and at TOC. Microbiological in the statistical analysis plan: age, Pitt score, and presence of failure was considered in the case of persistent bacteremia, re- endocarditis. The incidences of events in secondary, safety, and current bacteremia, and the emergence of resistance to study subgroup analyses were compared using χ 2 test or Fisher exact drugs during treatment. test. The global benefits and risks of the combination therapy Treatment of MRSA Bacteremia • cid 2021:72 (1 May) • 1519 were evaluated in a post hoc analysis using the approach of the plus fosfomycin was significantly associated with lower rates of Desirability of Outcome Ranking (DOOR) [29]. The compo- positive blood cultures than daptomycin alone (2 of 74 patients nents of this analysis were (1) death before TOC; (2) clinical [2.7%] vs 15 of 81 [18.5%], respectively). At day 7, 0 of 74 pa- or microbiological failure; and (3) premature discontinuation of tients (0%) who received daptomycin plus fosfomycin vs 5 of 81 therapy due to AEs or based on clinical judgment. All analyses patients (6.2%) who received daptomycin alone had persistent were performed with a 2-sided significance level of .05 and con- bacteremia. Recurrent bacteremia from EOT to the TOC visit ducted with the use of R software, version 3.5. occurred in 0 of 74 (0%) patients receiving daptomycin plus fosfomycin vs 4 of 81 (3.7%) who received daptomycin alone. The final microbiological evaluation at TOC found that no pa- RESULTS tient treated with daptomycin plus fosfomycin had microbiolog- From 16 December 2013 to 27 November 2017, we assessed ical failure compared with 9 patients treated with daptomycin 674 patients with MRSA bacteremia for eligibility, of whom 507 alone, among whom bacteremia was considered persistent in 5, were not suitable for inclusion (Figure 1). A total of 167 patients and recurrent in 4 patients (P = .003). were randomly assigned to receive daptomycin plus fosfomycin Development of resistance to daptomycin during treatment Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 (82 patients) or daptomycin alone (85 patients). After excluding was documented in 1 patient with persistent bacteremia in the 12 patients who were randomized in error (5 patients) or did daptomycin alone group; the minimum inhibitory concentra- not receive the allocated study drug (7 patients) and conse- tion increased from 0.5 mg/L to 2 mg/L. Among the 9 patients quently were excluded from the primary analysis population, with microbiological failure, 6 had consecutive isolates available the remaining 155 were included in the modified intention-to- for pulsed-field gel electrophoresis typing. All pairs of isolates treat population; 74 received daptomycin plus fosfomycin and obtained from the same patient showed the same band pattern, 81 were given daptomycin alone. and so microbiological failure was considered as a relapse. Baseline characteristics of the patients were similar in the 2 Complicated bacteremia at TOC was observed in 12 of treatment groups except for a higher number of patients with 74 patients (16.2%) who had received daptomycin plus chronic kidney disease in the daptomycin alone group (Table 1). fosfomycin and in 26 of 81 (32.1%) who had received Echocardiography was performed in 112 (72%) patients, and daptomycin alone (relative risk, 0.51 [95% CI, .28–.94]; χ 2 test a final diagnosis of left-side endocarditis was established in 18 P = .022). No significant differences in overall mortality were (11.6%) patients in this subgroup. Overall, the median duration observed at TOC between patients receiving daptomycin plus of antibiotic therapy since randomization was 14 days (inter- fosfomycin and those receiving daptomycin alone (24.3% vs quartile range [IQR], 10–18 days) (Table 1). 27.2%; P = .687). Treatment success at TOC was achieved in 40 of 74 (54.1%) Patients receiving daptomycin plus fosfomycin had a higher patients who received daptomycin plus fosfomycin and in 34 rate of AEs leading to discontinuation of therapy than patients of 81 (42.0%) patients who were given daptomycin alone (rel- receiving daptomycin alone (17.6% vs 4.9%; P = .012) (Table 4). ative risk, 1.29 [95% CI, .93–1.8]; χ 2 test P = .133) (Table 2 and No differences were observed between the groups at TOC in Figure 2). Treatment failure at TOC occurred in 34 (45.9%) pa- terms of overall mortality, lack of blood cultures, or loss to fol- tients receiving daptomycin plus fosfomycin and in 47 (58%) low-up. A total of 103 AEs was recorded in 160 randomized receiving daptomycin alone (P = .133). Reasons for treatment patients who received any dose of study drug (Supplementary failure at TOC are detailed in Table 3. No cases of clinical or Table 5). The number of patients with AEs and serious AEs did microbiological failure were observed in patients receiving not vary between the groups, but there were differences in the daptomycin plus fosfomycin, whereas 12 patients receiving frequency of AEs related to the study drugs. The most frequent daptomycin alone had treatment failure (clinical in 3 and micro- serious AEs in patients receiving daptomycin plus fosfomycin biological in 9 [0% vs 14.8%]; P < .001). More patients receiving were cardiac failure in 5 cases and hypokalemia in 2. A 10-fold daptomycin alone required the administration of nonstudy increase in creatinine phosphokinase values was observed in antibiotics active against MRSA before TOC than those treated 1 patient receiving daptomycin plus fosfomycin and in 2 pa- with daptomycin plus fosfomycin (23.4% vs 12.1%; P = .068). tients receiving daptomycin alone. AEs leading to treatment Subgroup analyses suggested that patients aged <73 years discontinuation occurred in 13 of 77 patients (16.9%) receiving and those with a Pitt score >1 could particularly benefit from daptomycin plus fosfomycin and in 4 of 83 patients (4.8%) re- receiving the combination of daptomycin plus fosfomycin to ceiving daptomycin alone (P = .013; Table 4). The median time achieve treatment success at TOC. No differences were ob- from randomization to discontinuation of the antibiotic treat- served in patients with or without endocarditis (Figure 2). ment due to serious AEs was 10 days (IQR, 4–14 days) in pa- The results for secondary endpoints are shown in Table 2 and tients receiving daptomycin plus fosfomycin and 10.5 days Supplementary Figure 3. At day 3 of follow-up, daptomycin (IQR, 10–11.5 days) in those given daptomycin alone. 1520 • cid 2021:72 (1 May) • Pujol et al Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 Figure 1. Trial profile. *Reasons for exclusion after randomization were as follows: patient randomized twice (n = 2); positive blood culture >72 hours before randomization (n = 3); patient received <1 day of antibiotic treatment (n = 3); protocol violation (n = 4). When benefits and risks of the intervention were analyzed by this difference did not reach statistical significance. Of note, the DOOR approach, the probability that a patient randomly the antibiotic combination therapy precluded microbiological assigned to daptomycin plus fosfomycin combination would failure and complicated bacteremia at TOC but was more often have a better DOOR ranking than if assigned to daptomycin associated with AEs leading to treatment discontinuation. Our alone was 61.6% (95% CI, 60.4%–62.8%). results suggest that daptomycin plus fosfomycin could be more effective than daptomycin alone in younger patients and in DISCUSSION those with more severe disease, but this needs to be confirmed In this randomized clinical trial, daptomycin plus fosfomycin after further study. Our findings were reinforced by the DOOR provided a 12% higher rate of treatment success than daptomycin post hoc analysis showing that patients randomly assigned to alone at 6 weeks after end of therapy for MRSA bacteremia, but daptomycin plus fosfomycin combination would have a better Treatment of MRSA Bacteremia • cid 2021:72 (1 May) • 1521 Table 1. Characteristics of Patients at Baseline in the Modified Intention-to-Treat Population Daptomycin Plus Fosfomycin Daptomycin Alone Characteristic (n = 74) (n = 81) Age, y, median (IQR) 74.0 (60.8–80.8) 72 (62.0–80.0) Male sex 48 (64.9) 56 (69.1) Charlson comorbidity index, median (IQR)a 3 (2–5) 4 (2–5.8) Diabetes mellitusb 29 (30.3) 34 (41.9) Diabetes mellitus with end organ damageb 13 (17.6) 18 (22.2) Chronic kidney diseaseb 19 (25.7) 35 (43) Congestive heart failureb 13 (17.6) 19 (23.4) Malignancyb 18 (24.3) 16 (19.7) Pitt score, mean (SD)c 1.15 (1.7) 1.22 (2.0) Implants 20 (27.0) 27 (33.3) Orthopedic 11 (14.9) 13 (16.0) Pacemaker 8 (10.8) 4 (4.9) Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 Previous antibiotic therapyd 59 (79.7) 65 (80.2) Acquisition Community-acquired 7 (9.4) 4 (4.9) Nosocomial infection 36 (48.6) 35 (43.2) Healthcare-associated 31 (41.8) 42 (51.8) Main source of infection Intravascular catheter 31 (41.9) 39 (48.1) Skin and soft tissue infection 10 (13.5) 19 (23.5) Surgical site infection 7 (9.5) 4 (4.9) Urinary tract infection 6 (8.1) 3 (3.7) Unknown source 14 (18.9) 8 (9.9) Other 6 (7.4) 8 (9.9) Echocardiography 53 (71.6) 59 (72.8) Endocarditise 9 (12.2) 9 (11.1) Days of therapy, median (IQR) 14 (11–21) 14 (10–18.5) Data are presented as no. (%) unless otherwise indicated. Abbreviations: IQR, interquartile range; SD, standard deviation. a Provides a 10-year mortality risk, based on weighted comorbid conditions. b Based on the definitions within the Charlson comorbidity index assessment. c Provides a measure of in-hospital mortality risk in patients with bloodstream infection based on clinical variables. d Based on administration of any antibiotic in the 10 days prior to randomization. e Based on assessment at test-of-cure visit according to modified Duke criteria [27]. Table 2. Primary and Secondary Outcomes Daptomycin Plus Fosfomycin, No. Daptomycin Alone, No. of Relative Risk Outcome of Patients/Total (%) Patients/Total (%) (95% CI) Primary endpoint Treatment success at TOC 40/74 (54.1) 34/81 (42.0) 1.29 (.93–1.8) Secondary endpoints Positive blood cultures at day 3 2/74 (2.7) 15/81 (18.5) 0.15 (.04–.63) Positive blood cultures at day 7 0/74 (0.0) 5/81 (6.2) −6.2 (−11.4 to −.9)a Positive blood cultures at TOC 0/74 (0.0) 4/81 (4.9) −4.9 (−9.7 to −.2)a Microbiological failure at TOC 0/74 (0.0) 9/81 (11.1) −11.1 (−18.0 to –4.3)a No. of episodes of complicated bacteremia 12/74 (16.2) 26/81 (32.1) 0.51 (.28–.94) at TOC Any AE leading to treatment discontinuation 13/74 (17.6) 4/81 (4.9) 3.56 (1.21–10.44) Overall mortality at day 7 3/74 (4.1) 6/81 (7.4) 0.55 (.14–2.12) Overall mortality at TOC 18/74 (24.3) 22/81 (27.2) 0.9 (.53–1.54) Abbreviations: AE, adverse event; CI, confidence interval; TOC, test of cure. a Proportion difference, as it was not possible to estimate the relative risk. 1522 • cid 2021:72 (1 May) • Pujol et al Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 Figure 2. Primary endpoint. DOOR ranking, and thus a better outcome, than if assigned to bacteremia at TOC. Rapid clearance of MRSA bacteremia is an daptomycin alone. important target, since the persistence of positive blood cultures We found that no patient receiving daptomycin plus beyond day 3 has been closely related to worse clinical out- fosfomycin had persistent bacteremia at day 7 and/or relapsing comes [30, 31]. Importantly, we found that patients receiving Table 3. Reasons for Treatment Failure at Test of Cure Daptomycin Plus Fosfomycin, Daptomycin Alone, No. Proportion Differ- P Reason for Treatment Failure No. (%) of Patients (n = 74) (%) of Patients (n = 81) ence (95% CI) Valuea Treatment failureb 34 (45.9) 47 (58.0) −12.1 (−27.7 to 3.6) .133 Mortality at TOC 18 (24.3) 22 (27.1) −2.8 (−16.6 to 10.9) .687 Clinical failurec 0 (0.0) 3 (3.7) −3.7 (−7.8 to .4) .247d Microbiological failure 0 (0.0) 9 (11.1) −11.1 (−18.0 to –4.3) .003d Any AE leading to treatment 13 (17.6) 4 (4.9) 12.6 (2.8–22.5) .012 discontinuation Additional antimicrobial therapy 9 (12.1) 19 (23.4) −11.3 (−23.2 to .6) .068 administered before TOCe Lack of blood cultures at TOC 8 (10.8) 4 (4.9) 5.9 (−2.6 to 14.4) .172 Loss to follow-up 1 (1.3) 3 (3.7) −2.4 (−7.2 to 2.5) .622d Data are presented as no. (%) unless otherwise indicated. Abbreviations: AE, adverse event; CI, confidence interval; TOC, test of cure. a Unless otherwise specified, P value derived from χ 2 test. b Patients might have >1 reason for treatment failure (ie, mortality at TOC, clinical or microbiological failure, any AE leading to treatment discontinuation, additional antimicrobial therapy ad- ministered before TOC, lack of blood cultures before TOC). c Lack of clinical improvement ≥3 days after the start of therapy. d Fisher exact test. e Receipt of potentially effective nonstudy antibiotics active against methicillin-resistant Staphylococcus aureus before TOC visit. Treatment of MRSA Bacteremia • cid 2021:72 (1 May) • 1523 Table 4. Adverse Events Leading to Treatment Discontinuation Daptomycin Plus Fosfomycin Daptomycin Alone Relation to Antibiotic Adverse Event (n = 77) (n = 83) Treatment Patients with AE leading to treatment discontinuation, No. (%) 13 (16.9) 4 (4.8) … AE leading to treatment discontinuation, No. (%) 16 (20.8) 4 (4.8) … Cardiac failure, No. 4 … R Hypokalemia (<3 mmol/L), No. 2 … R Hypocalcemia (corrected serum total calcium level <2.12 mmol/L), No. 1 … R Acute renal failure, No. 1 1 NR Creatinine phosphokinase increase (>10-fold), No. 1 1 R Respiratory failure, No. … 1 NR Respiratory tract infection, No. 2 1 NR Acute liver injury, No. 1 … NR Severe acute digestive bleeding, No. 1 … NR Nausea/vomiting, No. 2 … R Downloaded from https://academic.oup.com/cid/article/72/9/1517/5877897 by guest on 06 October 2023 Abbreviations: AE, adverse event; NR, nonrelated; R, related. combination therapy developed complicated bacteremia less Supplementary Data often and that no antibiotic resistance occurred in any pa- Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted tients in this group. Our results concur with those reported in materials are not copyedited and are the sole responsibility of the authors, so small series of patients treated with β-lactams or daptomycin questions or comments should be addressed to the corresponding author. plus fosfomycin [23, 24]. Additionally, the combination of daptomycin plus fosfomycin might prevent the emergence of Notes drug resistance. The single patient who developed resistance to Acknowledgments. The authors thank the study collaborators from all of daptomycin was receiving daptomycin alone. the centers that participated in the MRSA Bacteremia (BACSARM) trial: We found that AEs leading to treatment discontinuation Alex Soriano, PhD, and Manel Almela, PhD (Hospital Clinic, Barcelona, Spain); Frederic Gómez, MD (Hospital Joan XXIII, Tarragona, Spain); were more frequent in patients receiving daptomycin plus Fernando Chávez, PhD (Hospital 12 Octubre, Madrid, Spain); Beatriz fosfomycin. The antibiotic combination was more often asso- Mirelis, PhD (Hospital Santa Creu i Sant Pau, Barcelona, Spain); Emma ciated with cardiac failure and electrolyte disorders, particu- Padilla, MD (Catlab–Hospital de Terrassa, Terrassa, Spain); Maria Dolores Pérez-Ramírez, MD (Hospital Virgen de las Nieves, Granada, Spain); Mateu larly hypokalemia and hypocalcemia. It has been suggested Espasa, MD (Hospital del Parc Taulí, Sabadell, Spain); Ana Maria Sánchez- that hypokalemia could be avoided in some cases by the ex- Díaz (Hospital Ramón y Cajal, Madrid, Spain); Emilia Cercenado, PhD tended infusion of fosfomycin over a 4-hour period [32]. The (Hospital Gregorio Marañón, Madrid, Spain); Enrique Ruiz de Gopegui, fact that fosfomycin-related serious AEs appeared after a me- PhD (Son Espases, Mallorca, Spain); Ana Siverio (Hospital del Mar, Barcelona, Spain); Marina de Cueto, PhD (Hospital Virgen de la Macarena, dian of 10 days of therapy and the high microbiological efficacy Sevilla, Spain); Fernando García-Garrote (Hospital Lucus Augusti, Lugo, achieved at 3 and 7 days of the combination therapy suggest that Spain); Mercè Garcia (Hospital Arnau de Vilanova, Lleida, Spain); Mariona fosfomycin should essentially be administered during the first Xercavins (Hospital Mútua de Terrassa, Terrassa, Spain); and Maria Nieves Larrosa, PhD (Hospital Vall Hebron, Barcelona, Spain). week of treatment. Disclaimer. The study’s funders were not involved in the study design, Our randomized trial has several limitations. The study was data interpretation or analysis, or the revision of the final report. The corre- not blinded for the investigators, and this might have impact de- sponding author had full access to all study data and had final responsibility for the decision to submit the paper for publication. cisions to discontinue the therapy due to clinical worsening or Financial support. This work was supported by the Spanish Ministry suspected AE. The effect of this potential bias was minimized by of Science, Innovation and Universities (PI12/01907); Spanish Network including microbiological analyses in the treatment success defi- for Research in Infectious Diseases (RD16/0016/0005); Instituto de nition. Furthermore, the study was performed in a single country Salud Carlos III (ISCIII); and Spanish Ministry of Economy, Industry and Competitiveness. This work was also supported by the European and this might have limited the generalizability of our results. Development Regional Fund “A way to achieve Europe,” Operational In conclusion, daptomycin plus fosfomycin provided a 12% Programme Intelligent Growth 2014–2020; Spanish Clinical Research higher rate of treatment success than daptomycin alone, but Network (SCReN), co-financed by the Plan Nacional de I+D and ISCIII, Subdirección General de Evaluación y Fomento de la Investigación this difference did not reach statistical significance. Our results (PT13/0002/0007); and the Grupo de Estudio de la Infección Relacionada suggest that this antibiotic combination could be more effec- con la Asistencia Sanitaria. J. M.-M. received a personal 80:20 research tive in younger patients and those with more severe disease. grant from the Institut d’Investigacions Biomèdiques Agust Pi i Sunyer, Daptomycin plus fosfomycin precluded microbiological failure Barcelona, Spain, during 2017–2021. Potential conflicts of interest. 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