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Staph aureus Bloodstream Infections
Wherever the Bloodstream Goes, the Staph aureus Goes, Too

Released: December 31, 2025

Paul E. Sax
Paul E. Sax, MD
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Key Takeaways
  • The most current data from the SNAP study favors cefazolin over semisynthetic penicillins for treatment of Staph aureus bacteremia in terms of both safety and efficacy.
  • Further data from the SNAP study suggests that penicillin was actually more active against penicillin-sensitive staph aureus than the antistaphylococcal penicillins.
  • Results from the DOTS trial indicate that dalbavancin is noninferior to the standard of care in terms of efficacy and may provide advantages in terms of ease of use.

First, let me give you some background information about the importance of Staph aureus bacteremia. It is one of the leading causes of death from bacteremia worldwide, with a case fatality rate of 15% to 30%. As a result, it is incredibly important that we identify it early and treat it aggressively. I sometimes joke that when people are training in infectious diseases (ID), that first year of intensive inpatient ID consultations is almost like a Staphylococcus aureus fellowship because they see so many cases of Staph aureus bacteremia.

One of the things that makes Staph aureus bacteremia so difficult to manage is that it has a high predilection for metastatic infections. The metastatic infections are most commonly endocarditis, where obviously the heart valves and associated structures are involved, but also septic arthritis, vertebral osteomyelitis, spinal epidural abscess, psoas abscesses, splenic abscesses, septic pulmonary emboli, and on and on. Wherever the bloodstream goes, the Staph aureus can, too.

In addition, when people have prosthetic devices, whether it is a prosthetic heart valve or a prosthetic joint or a vascular graft, Staph aureus has a tendency to stick on these and cause the infection to be very, very difficult to eradicate. We now have a little more clarity about how to treat Staph aureus bacteremia because of several recent clinical trials.

The SNAP Study
Two major aspects of the largest clinical trial of Staph aureus bacteremia, the SNAP study, were presented at ESCMID Global. The first aspect examined the question of which antistaphylococcal β-lactam should be first-line treatment for methicillin-susceptible S aureus (MSSA) bloodstream infections? Should it be a semisynthetic penicillin like nafcillin, oxacillin, or flucloxacillin? Or, should it be cefazolin, the first-generation cephalosporin? 

For years, we have known that Staph aureus capable of producing β-lactamase can, in some ways, overcome the stability of cefazolin, and that the semisynthetic penicillins, like oxacillin, were actually more stable in the presence of the β-lactamases. So, it was thought that the semisynthetic penicillins had stronger activity against Staph aureus. On the other hand, we have known for some time that cefazolin is safer. So, this study directly compared them in a randomized clinical trial and showed conclusively that, yes, the semisynthetic penicillins have renal adverse effects. But cefazolin provided comparable activity. So, right now, the first-line regimen for Staph aureus bacteremia would have to be considered cefazolin because this is the highest level of evidence that we have.

Another aspect of the SNAP trial was an open question about penicillin-sensitive Staph aureus. When you learn about antibiotics, you learn that Staph aureus figured out how to develop resistance to penicillin very early on by generating β-lactamase. Well, one of the strange things about this resistance is that it increased to a high proportion, but then it stopped increasing.

This resistance has actually decreased a bit over the last 10-15 years, and now there is more penicillin-susceptible Staph aureus than there used to be. So, the question was, should we use antistaphylococcal penicillin, even if the infection is penicillin sensitive, or should we use penicillin? Here, the data suggest that penicillin was actually more active against penicillin-sensitive Staph aureus than was the antistaphylococcal penicillins.

So, these are 2 very important findings from the SNAP trial, the most important being that cefazolin is now the agent of choice for this condition.

The DOTS Trial
Now that I have talked about the SNAP trial, I want to talk about the DOTS trial. The DOTS trial was interesting because it looked at people who had complicated, but not too complicated, Staph aureus bacteremia. What I mean by that is the trial excluded people with prosthetic heart valves and left-sided endocarditis, but it did not only enroll people who had just 1 positive blood culture, or transient bacteremia; the trial enrolled people with the real thing—Staph aureus bacteremia. It ended up being a comparison of standard of care and dalbavancin.

Dalbavancin is a long-acting glycopeptide that is very similar to vancomycin, and it can be given as just 2 doses. Here is the amazing thing: The standard of care for treatment of Staph aureus bacteremia, if you are talking about typical cases, would be IV therapy for 4-6 weeks. So, to be able to give dalbavancin on just Day 1and Day 8 is potentially transformative. The results sort of say that it is a negative study, but I want to emphasize that I think this trial had a lot of positive findings.

The reason the results look negative was because the goal was to demonstrate superiority of dalbavancin with something called the DOOR endpoint, that is, the desirability of outcome ranking at Day 70.

DOOR mixes a bunch of different endpoints, including clinical response, complications, safety, mortality and even quality of life. Considering all those things together, the outcome of using either approach was basically the same. But the good news, the silver lining to this “negative study” is that the clinical efficacy was about the same between the standard of care and the dalbavancin arm, that is, 73 of 100 participants receiving dalbavancin were successfully treated vs 72 participants with standard therapy. So, when you focus on the question, “Did the patient get better?” The dalbavancin did just fine.

Imagine you are managing a patient who is now clinically stable, and you are trying to set out what they will get for the rest of their treatment. You could either give them a dose now and a dose in 8 days, or you can give them 4-6 weeks of IV antibiotics. There is no doubt in my mind that given those options, virtually everyone would choose the 2 doses. In fact, I would argue that the quality-of-life instrument used in this study was not specifically tailored to ask about the inconvenience or difficulty of home outpatient parenteral antimicrobial therapy (OPAT) because clearly this is vastly superior to an OPAT.

So, were there any caveats to the study? Of course, it is not a perfect study. There is no such thing as a perfect study. It was open label, which was by necessity because investigators could not give IV placebo for 4-6weeks, and it had only 200 participants, so it was a pretty small study. Investigators also had to screen many participants to find the “Goldilocks, just right” Staph aureus bacteremia. The other caveat is that there are some healthcare professionals now who are managing Staph aureus bacteremia with a “step down to oral antibiotics” method with drugs like linezolid. This study did not include an oral antibiotic strategy, which would be easier yet.

Why aren’t we all marching off and using dalbavancin over everything? The answer is simple. It is because dalbavancin costs a lot of money. If you have a pharmacy budget in your hospital and you are charged with keeping costs down, you might not want to include dalbavancin very often. However, I think it is time that we take a look at pharmacy budgets, not as siloed and separated from all the other costs of patient care, but included as part of the global aspect of patient care. In that context, one could make the argument that dalbavancin has certain cost advantages over home IV therapy, if you think not just about the hospital pharmacy budget, but the global budget of caring for the patients.

So, I would argue that these 2 studies, the SNAP trial and the DOTS trial, are the best advances in management of Staph aureus spectrum we have had in some time.

What About MRSA Bacteremia?
The treatment of choice is still vancomycin. Nothing has come along to knock it off its perch, even though persistent MRSA bacteremia is a clinical problem. Occasionally, you get these cases where you are giving salvage therapy with agents like ceftaroline plus daptomycin, or there is actually interest in using ceftobiprole. But those are fringe cases.

Your Thoughts
How have these studies affected your approach to antibiotic selection for Staph aureus bacteremia? How do the results of the SNAP and DOTS trials affect your decision to use cefazolin vs dalbavancin? Join the conversation by posting below.