Combination Cefazolin With Ertapenem for Methicillin-susceptible Staphylococcus Aureus Bacteremia

Cefazolin is licensed in Canada for the management of infections due to susceptible Staphylococcus aureus, including bacteremia. It has been commonly used for decades in this disease and, when compared in observational studies to anti-staphylococcal penicillins, has demonstrated reduced mortality. Nevertheless, in the treatment of methicillin-susceptible S. aureus (MSSA) bacteremia, there remains significant opportunities to improve clinical outcomes. Indeed, S. aureus bacteremia kills more Canadians annually than myeloma, melanoma, renal, ovarian or stomach cancers. Overall mortality approached 18% in a recent Canadian clinical trial performed by our group (Cheng et al, 2020). The duration of bacteremia, particularly after antibiotherapy is recognized as a major risk factor for mortality. Interventions which reduce the duration of bacteremia, without increasing the frequency of renal failure like gentamicin (Cosgrove et al, 2009) or the combination of vancomycin and flucloxacillin in MRSA (Tong et al, 2020), are among the most promising candidates for larger phase 3 studies designed to impact patient mortality. Ertapenem is a commonly used antibiotic which has been on the Canadian market for more than 15 years. It is most commonly used in patients with infections caused by extended-spectrum beta-lactamase producing Enterobacteraciae; however, it has a broad spectrum of activity including Gram-positive bacteria such as S. aureus. Indeed, the drug is licensed in Canada for the treatment of complicated skin and soft tissue infections commonly caused by S. aureus. In S. aureus the carbapenem antibiotics like ertapenem have exceptional affinity to the essential penicillin-binding protein (PBP), PBP1, exceeding even that of the antistaphylococcal β-lactams (Chambers et al, 1990). This complements the relative PBP2 proclivity of cefazolin (Bamberger et al, 2002). The combination of cefazolin with ertapenem has also been shown to be synergistic in vitro (Sakoulas et al, 2016), in vivo in the mouse and rat models (Sakoulas et al, 2016; Ulloa et al, 2020), and in a small human case series (Ulloa et al, 2020). Based on this data, there is compelling theory (attack on 2 PBPs), in vitro, in vivo, and human case evidence to support an exploratory phase 2 RCT of cefazolin-ertapenem for the treatment of MSSA bacteremia.