HIV and ID Observations

The DOTS randomized clinical trial of dalbavancin versus standard-of-care for Staph aureus bacteremia (SAB) just landed in JAMA, where it undoubtedly will be featured in numerous ID, hospitalist, and medical resident journal clubs over the next several months. Proof:  one of our great second-year ID fellows tagged it immediately for his journal club literally the day it was published.

Led by Drs. Nicholas Turner, Thomas Holland, and a seasoned group of clinical investigators, it didn’t hit superiority on the primary endpoint, but clinical efficacy matched standard therapy.

Here’s why I’m optimistic despite this “negative” study:

• The primary outcome (Desirability of Outcome Ranking at day 70, DOOR) favored dalbavancin 47.7% of the time. That wasn’t statistically superior to standard care, and explains the cautious tone in the paper. But DOOR mixes clinical response, complications, safety, mortality, and quality of life; failing superiority there is not the same as failing clinically.
• Clinical efficacy? Essentially equal. On the prespecified noninferiority secondary endpoint, clinical efficacy at day 70 was 73/100 with dalbavancin versus 72/100 with standard therapy (difference 1.0%, 95% CI −11.5 to 13.5). When you focus on the question “Did the patient get better?”, dalbavancin did fine.
• Think of the comparison — two 1500-mg doses of dalbavancin (days 1 and 8) versus weeks of daily IV therapy. If outcomes are similar and safety is acceptable, this sort of study is exactly how indications and comfort grow for long-acting drugs. No peripherally inserted central catheter (PICC) line! No enrollment in outpatient parenteral antimicrobial therapy (OPAT)! No need for home delivery and storage of medications! No vancomycin levels! Hooray! The accompanying JAMA editorial, by Erin McCreary, PharmD and Dr. Preeti Malani, strikes a similar optimistic tone. Based on many years of hearing patients complain about PICC lines and OPAT, I’m also assuming that the quality of life instrument did not capture the specific tortures of home OPAT we all know and have grown to hate.
• Who participated really matters. Importantly, patients with left-sided endocarditis, CNS infection, retained infected prosthetic material, or severe immunocompromise were excluded. So although “uncomplicated” SAB was excluded, this wasn’t the everything-and-the-kitchen-sink group either — more like “intermediate complicated,” including right-sided endocarditis and other complicated bacteremias after initial clearance.

The study isn’t perfect, of course, with limitations acknowledged by the authors, but importantly none of them negate the findings. It was open-label, but I’d argue by necessity — the standard-of-care regimens were diverse, and exposing someone to the risks of a PICC line for weeks just for study purposes can’t be justified. Also, the benefits of two infusions would be greatly diluted if everyone had to get daily IVs. With only 200 participants, DOTS was relatively small, with enrollment taking over 2 years despite being open at 23 sites — perhaps because it was hard for investigators to thread the needle on the complicated-but-not-too complicated SAB inclusion criterion. Finally, at least some staph bacteremia is now managed with oral therapy, in particular after clinical stability is achieved with IV; this was not part of the comparison in this study.

(I added that one for you, Dr. Brad Spellberg. You’re welcome.)

OK, elephant in room time:  The infrequent use of dalbavancin for inpatients currently is mostly about money, not microbiology. It’s no secret that if dalbavancin weren’t so eye-wateringly expensive, and if inpatient reimbursement weren’t DRG-based, we’d be using it a whole lot more already.

Price estimates hover in the multi-thousand-dollar range per 500-mg vial or per 1500-mg dose, which is painful for DRG-paid hospital stays even if it saves nursing time and averts line complications later. Who wants to be responsible for a pharmacy budget that includes several thousand dollars for a single antibiotic dose? I reached out to the lead study authors; an economic analysis is in progress.

But let’s back up and take a broader view. We recently heard a talk from Dr. Priya Nori about their experience broadening the use of dalbavancin in their healthcare system, with endorsement from their C-suite. They have found that dalbavancin can be a safe OPAT workaround for patients with barriers to long-term IV access, sometimes enabling earlier discharge and fewer complications, both of which substantially offset the cost (especially the early discharges). The fact that the drug is extremely well tolerated gives additional support for its more widespread use.

So yes, DOTS was “negative” on its primary outcome. But it also showed that dalbavancin performs about as well as what we do now, with far less infrastructure: no PICC, no daily infusions, no vancomycin levels, fewer moving parts. That alone should make the economics work, at least in healthcare systems looking at the global aspects of care rather than just an inpatient antimicrobial pharmacy budget.

Interested in what readers think — will these trial results increase use of dalbavancin for Staph aureus bacteremia? Have at it in the comments.