Background:Staphylococcus aureus is one of the most clinically significant bacterial pathogens and can cause a wide range of infections, from mild skin and soft tissue infections to invasive bloodstream infections with severe complications. The standard of care for methicillin-susceptible S. aureus (MSSA) bloodstream infections has been an antistaphylococcal penicillin or a first-generation cephalosporin, such as cefazolin (CZ). Recent literature has shown no efficacy difference between CZ and antistaphylococcal penicillins, but has shown that CZ may be associated with less side effects. This has led to CZ becoming the preferred agent for MSSA bacteremia at our institution. MSSA is also covered by most broad-spectrum β-lactams, including piperacillin-tazobactam (TZP), cefepime (FEP), ertapenem (ETP), and meropenem (MEM). These broad-spectrum agents are primarily used for their activity against Pseudomonas aeruginosa or pathogens at high risk for inducible AmpC production, such as Enterobacter cloacae or Klebsiella aerogenes. Of note, ETP lacks anti-pseudomonal coverage but is used for treatment of other resistant pathogens, such as extended-spectrum β-lactamase (ESBL) producing organisms. In cases of polymicrobial infections, these broad-spectrum β-lactams may be used as targeted therapy for MSSA in addition to the gram-negative pathogens. These agents are also sometimes used in neutropenic patients to treat MSSA while maintaining anti-pseudomonal prophylaxis when indicated. While in vitro activity is expected, there are limited data examining the clinical outcomes of these broad-spectrum β-lactams as targeted therapy for invasive MSSA infections.
Methods: This was a system-wide, retrospective, cohort study conducted at ECU Health assessing hospitalized adults with MSSA bacteremia. Included patients were treated with ≥ 7 days of monotherapy CZ or one of the following broad-spectrum β-lactams: TZP, FEP, ETP, or MEM between August 2019 and December 2025. Patients were excluded if they had MRSA isolated or if they received other antibiotics active against MSSA while receiving the study drug. Patients were identified using SlicerDicer within EPIC and then screened for inclusion. The primary outcome was treatment failure, defined as a composite of 90-day all-cause mortality, 90-day hospital re-admission, and 90-day recurrent MSSA bacteremia. Secondary outcomes included the individual components of the primary outcome at 30 days and 90 days, 90-day C. difficile infections, and new multidrug-resistant organisms isolated within 90 days.
Results: 1,435 patients with S. aureus blood cultures from August 2019 to December 2025 were screened. Of these, 33 patients on broad-spectrum β-lactams were eligible for inclusion (TZP=12, FEP=9, ETP=6, and MEM=6). 33 patients on CZ were then identified for balanced sample sizes, with a total of 66 patients included in the analysis. Average age, BMI, and duration of therapy, were similar between the two groups. The most common reason for exclusion was receiving the study drug for < 7 days (62%). Patients in the broad-spectrum group had nearly twice as long hospital length of stay compared to the CZ group (31 vs 17 days). Patients treated with broad-spectrum β-lactams were more likely to meet the 90-day primary outcome compared to those treated with CZ (OR 0.29; 95% CI 0.10-0.79; p=0.01). This was primarily driven by reduced 90-day mortality and 90-day re-admission.
Conclusion: This study showed a significant benefit in patients that received CZ over broad-spectrum β-lactams in the treatment of MSSA bacteremia. This study adds to the small amount of data comparing outcomes in patients with MSSA bacteremia treated with broad-spectrum β-lactams. Larger, prospective studies are warranted to further explore the most optimal broad-spectrum β-lactam for MSSA when additional coverage is needed.
