Ceftriaxone as Definitive OPAT for MSSA Bloodstream Infections

Bacteremia due to Methicillin-Sensitive Staphylococcus aureus (MSSA) bacteremia is a large clinical problem and has a mortality of 10-30%.1 Dreaded complications include endocarditis, septic arthritis, and epidural abscess. Current guidelines for the treatment of endocarditis and catheter -related bloodstream infections with MSSA recommend the use of a beta-lactamase resistant semi-synthetic penicillin such as Oxacillin and Nafcillin, or the first-generation cephalosporin Cefazolin. These agents are easily administered in the acute setting but can be problematic during Outpatient Parenteral Antimicrobial Therapy (OPAT). Oxacillin and Nafcillin may need to be dosed 6 times per day while Cefazolin is dosed 3 times per day leading to problems with patient adherence. Additionally, side effects encountered with these agents include allergic reactions, myelosuppression, interstitial nephritis, and hepatitis. Ceftriaxone, a parenteral agent with a good safety profile that can be dosed quickly once daily, has an FDA label that includes MSSA bacteremia, but its use has been hampered by concerns regarding adequate drug exposure in serious infection.2

In January 2024, Hamad and colleagues published a retrospective cohort study to compare Nafcillin/Oxacillin/Cefazolin with Ceftriaxone as outpatient therapy for MSSA bacteremia.3 Data was derived from an administrative claims database for patients treated at home with Cefazolin/Oxacillin/Nafcillin or Ceftriaxone within 7 days of hospital discharge. The primary endpoint was readmission within 90 days for the same index infection category with a secondary endpoint of readmission for any reason within 90 days. Propensity scoring was performed to account for potential imbalances in cofounding variables that could affect outcomes. A total of 1435 (76%) of patients received Oxacillin/Nafcillin/Cefazolin while 460 (24%) patients received Ceftriaxone. The most common infection site was skin and soft tissue at 40%. Far more patients received Oxacillin/Nafcillin/Cefazolin than Ceftriaxone for endocarditis and epidural abscess while those with pneumonia were more likely to receive Ceftriaxone.

In terms of results there was no difference in outcomes in the Ceftriaxone group vs Oxacillin/Nafcillin/Ceftriaxone for any of the endpoints examined. A total of 78/460 (17%) met the primary outcome in the Ceftriaxone group vs. 288/1435 (20%) in the Oxacillin/Nafcillin/Ceftriaxone group; aOR 0.89 (95%CI 0.67-1.18). No difference was seen in readmission rates at 90 days for any reason between treatment strategies. These results were unchanged following propensity scoring. In the small subgroup with endocarditis there was also no difference in treatment groups in the primary outcome.

This study, while large, has a number of limitations which the authors acknowledge. It is retrospective in nature allowing the possibility of confounding variables affecting outcomes despite propensity scoring. The trial did not include several important patient groups with MSSA bacteremia including those > 64 years of age, those treated in skilled nursing facilities or nursing homes, and those with renal impairment. Additionally, the population with endocarditis was small at 276 patients with only 47 receiving Ceftriaxone. Finally, important outcomes such as 30-day and 90-day mortality and the occurrence of adverse events were not examined.

It is important to view the recent study in the content of the available literature on the subject. The largest source of data comes from a meta-analysis published by Alsowaida et al in 2022.4 This analysis involved 12 studies, all retrospective, encompassing 1037 patients receiving Ceftriaxone and 2088 patients receiving other standard of care (SOC) antibiotics. No differences in outcomes between groups were seen in clinical or microbiologic cure rate, 30 and 90-day mortality or adverse drug reactions. Importantly, the subgroup with endocarditis was small at 11.5% precluding the ability to draw conclusions. The only prospective study performed was part of the IDISA study.5 This non-randomized study compared duration of bacteremia and 30-day mortality related to MSSA bacteremia in 267 patients in three treatment groups, those receiving Flucloxacillin, Cefuroxime or Ceftriaxone. No difference in outcomes was seen in either of the cephalosporin arms compared with flucloxacillin.

So, where does the current paper from Hamad and colleagues leave us in light of the previous literature? It reinforces the notion that an adequately sized randomized clinical trial should be performed including all pertinent patient subgroups including those with the most serious complications of MSSA bacteremia including endocarditis and epidural abscess. This trial should include all meaningful endpoints including mortality and should also have an adequate safety analysis. In the meantime, Ceftriaxone could be considered as OPAT for MSSA bacteremia in those who are stable with primary sites of infection including skin and soft tissue and pneumonia.


  1. van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11.
  2. Heffernan AJ, Sime FB, Lim SMS, et al. Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option? Int J Antimicrob Agents. 2022 Mar;59(3):106537. doi: 10.1016/j.ijantimicag.2022.106537.
  3. Hamad Y, Nickel KB, Olsen MA, George IA. Outcomes of Ceftriaxone Compared With Cefazolin or Nafcillin/Oxacillin for Outpatient Therapy for Methicillin-Sensitive Staphylococcus aureus Bloodstream Infections: Results From a Large United States Claims Database. Open Forum Infect Dis. 2024 Jan 12;11(2):ofad662. doi: 10.1093/ofid/ofad662.
  4. Buis DTP, van der Vaart TW, Prins JM, et al. Comparative effectiveness of β-lactams for empirical treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective cohort study. J Antimicrob Chemother. 2023 May 3;78(5):1175-1181. doi: 10.1093/jac/dkad057. Erratum in: J Antimicrob Chemother. 2023 May 23;: Erratum in: J Antimicrob Chemother. 2024 Feb 1;79(2):476. PMID: 36897327; PMCID: PMC10154124.
  5. Alsowaida YS, Benitez G, Bin Saleh K, et al. Effectiveness and Safety of Ceftriaxone Compared to Standard of Care for Treatment of Bloodstream Infections Due to Methicillin-Susceptible Staphylococcus aureus: A Systematic Review and Meta-Analysis. Antibiotics (Basel). 2022 Mar 10;11(3):375. doi: 10.3390/antibiotics11030375.

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