176 Chapter 8 2b randomized clinical trial (DOTS trial) [157]. A potential role for dalbavancin in persistent bacteremia naturally warrants more follow-up research. Driven by the lack of major breakthroughs in antibiotic treatment to improve clinical outcomes in SAB, new nonantibiotic antimicrobial modalities are an increasing subject of research. Exebacase, an anti-staphylococcal lysin, as an addition to standard-of-care antibiotics, led to a higher clinical response rate in patients with MRSAB in a proofof-concept study [158]. A subsequent randomized trial addressing the superiority of exebacase in addition to standard-of-care antibiotics in both MSSA and MRSAB (DISRUPT trial) was terminated early for futility, following interim efficacy analysis [159]. A second anti-staphylococcal lysin, LSVT-1701, showed reduced bacterial bioburden in MRSA animal studies and demonstrated a good safety profile in a Phase I study in healthy human subjects [160]. In June 2022, further development of this asset was terminated by Roivant Sciences. Furthermore, bacteriophage therapy as an adjunctive intravenous therapy for SAB patients is currently being investigated. It was shown to be well tolerated in a group of 13 patients with severe S. aureus infections, including endocarditis and septic shock [161]. The diSArm trial is a phase 1b/2a randomized trial on the efficacy and safety of adjunctive bacteriophage therapy in SAB patients, which is estimated to be completed at the end of 2023 [162]. In conclusion, the unfavorable safety profiles of many combinations of antibiotics have prevented them from replacing vancomycin as the most frequently used antibiotic treatment in MRSAB. High-dose daptomycin (with a second antibiotic agent to prevent treatment-emergent resistance) and the addition of ceftaroline are currently the best practice in persistent MRSAB. Future treatment options may include dalbavancin, ceftobiprole, and novel non-antibiotic agents such as bacteriophages. Conclusions Persistent MRSAB is a devastating and complex disease. Understanding the interaction between host and pathogen is crucial to the challenge of improving patient outcomes. Given the lack of major breakthroughs in patient outcomes in the last decades, there seems to be a need for novel diagnostics and treatment options. Trials on genetics, biomarkers, and novel non-antibiotic agents in persistent MRSAB should be encouraged, as well as the implementation in daily practice of those that were successful. Meanwhile, it is promising that antibiotic agents such as dalbavancin [157] and ceftobiprole [154] are being studied in randomized clinical trials for SAB. These new high-quality studies represent an important step towards better understanding and ultimately improving clinical outcomes in patients with SAB.
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