Discussion
comorbidity, endocarditis, bacteremia, infection, MSSA bacteremia, bloodstream infections
BLOODSTREAM INFECTION, RECURRENCE, ENDOCARDITIS, ADVERSE EVENTS, DISEASE, RECRUITMENT, INFECTION, SECONDARY
This open-label, phase III–IV superiority randomized clinical trial conducted in 19 Spanish hospitals aimed to evaluate whether the combination of cloxacillin and fosfomycin achieved better treatment success than cloxacillin alone in patients with MSSA bacteremia. The primary endpoint was chosen based on the recommendations of international experts that proposed primary endpoints for use in clinical trials comparing treatment options for bloodstream infections in adultsThe main finding of our trial is that cloxacillin plus fosfomycin did not achieve better treatment success at day 7 than cloxacillin alone among patients with MSSA bacteremia. Secondary endpoints, including adverse events leading to discontinuation of therapy, were similar in the two treatment groups, with the exception of persistent bacteremia at day 3, which was less common in the combination treatment arm.The results of our study are in line with the findings of the few randomized clinical trials carried out to date assessing different antibiotic combinations, which have also failed to improve treatment success rates and outcomes in patients with MSSA bacteremia and endocarditis, as shown in a recent meta-analysisAs stated above, we found that persistent bacteremia at day 3 after randomization was less frequent in patients receiving cloxacillin plus fosfomycin than in patients receiving cloxacillin alone. However, this finding did not translate into improved survival at day 7. This result contrasts with those of some observational studies that have found that each day of persistent bacteremia is associated with increased mortalityWe did not find significant differences in all-cause mortality at day 7 or at end of therapy and TOC visits. Nevertheless, mortality at TOC was higher in patients treated with cloxacillin alone, although the difference was not statistically significant. Of note, median age, the proportion of male patients, mean Charlson comorbidity index score and the prevalence of implants were slightly higher in patients receiving cloxacillin alone, who were also more likely to have a high-risk source of bacteremia, including endocarditis at TOC. Moreover, mortality was low in both treatment groups, and the trial was not powered to detect survival differences.We found similar rates of adverse events leading to treatment discontinuation during the first 7 days of therapy in the two study groups. In a previous trial comparing daptomycin plus fosfomycin versus daptomycin alone in patients with methicillin-resistant Our study has limitations. The first is the open-label design, which may have introduced a bias in the assessment of treatment success. Nevertheless, this limitation was mitigated by including objective data in the composite primary endpoint, which was also adjudicated by an independent committee blinded to treatment allocation. It should be noted that our trial mainly focused on treatment effect during the first 7 days (when fosfomycin was administered in the combination treatment arm) and assessed relevant secondary endpoints at TOC (12 weeks after randomization). Therefore, we cannot rule out disease recurrence or relapse occurring beyond 12 weeks after randomization. Unfortunately, there are no standardized primary endpoints to be used in trials comparing different strategies for antibiotic treatment of MSSA bacteremia, and efforts should be made to reach consensus regarding the endpoints that should be used in future trials. Another limitation of our study is that it was conducted in a single country, and its findings might not be generalizable to other populations. Furthermore, when enrollment of half of the sample size had been achieved, the independent committee raised no concerns regarding safety, but mentioned the differences between the success rate specified in the sample size calculation and the rate observed in the planned interim analysis, and recommended ceasing patient recruitment owing to futility. Moreover, the number of patients who had high-risk MSSA bacteremia was relatively low, and the trial was not powered to detect survival differences. Finally, our trial did not include patients with prosthetic endocarditis, therefore we cannot draw conclusions about the hypothetical benefits of adjunctive fosfomycin in this setting.In conclusion, cloxacillin plus fosfomycin did not achieve better treatment success at day 7 of therapy than cloxacillin alone in hospitalized adult patients with MSSA bacteremia. Further large randomized controlled trials should be conducted to evaluate new strategies of treatment aimed at improving outcomes in patients with MSSA bacteremia. Ideally, these trials should be designed taking into account the intrinsic heterogeneity of the infection, by using a more stratified and personalized approach and by including a long-term follow-up.