The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5‐benzylidene‐4‐oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen‐matrix model of biofilm infection.

Background Besides anti-staphylococcal beta-lactams and source control, there are limited validated antimicrobial salvage options in patients with prolonged methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including infective endocarditis (IE). Methods MSSA IE cases treated with ertapenem (ETP) plus cefazolin (CZ) were compared to matched IE cases treated with standard beta-lactam monotherapy. The bactericidal activity of ETP plus CZ was also compared to nafcillin (NAF), CZ and ETP alone using an in vitro MSSA biofilm model. Results The median duration of bacteremia experienced by patients (n=12) while on CZ or NAF was 4 days (range 1-16 days) compared to 1 day (range 1-3 days) for patients (n=5) treated with ETP+CZ (p=0.01, Mann Whitney U test). CZ and NAF alone or in combination did not achieve biofilm eradication at clinically relevant concentrations. However, the addition of ETP to CZ led to bactericidal eradication within biofilms at standard dosing. Conclusions ETP reduces CZ concentrations required to eradicate MSSA biofilms to those achievable in vivo by standard dosing, translating into shorter bacteremia duration in patients with MSSA endocarditis. Larger studies are needed to investigate ETP plus CZ therapy in the treatment of biofilm-related MSSA infections such as endocarditis.

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