Dalbavancin shows promise for complicated SAB management

Findings from the DOTS trial presented at ESCMID Global 2024 underpin the potential of dalbavancin, a long-acting lipoglycopeptide, for the management of complicated Staphylococcus (S.) aureus bacteraemia (SAB) without requiring long-term vascular access.

“We chose Desirability of Outcome Ranking (DOOR) at day 70 as our primary outcome of interest analysed by intention to treat. DOOR is a validated outcome for [SAB] that better reflects the full spectrum of outcomes experienced by patients,” explained Dr Nicholas Turner from Duke University, Durham, North Carolina, US, during his presentation at ESCMID Global 2024.

“Overall, DOOR probability represents the chances [of having a superior DOOR] by a subject who received dalbavancin compared to a randomly drawn subject from the SoC arm,” said Turner.

“[In our study,] it was 47.7 percent, with the confidence interval (CI) overlapping 50 percent. Notably, that overlaps the equivalence mark. [Therefore,] dalbavancin was not superior by DOOR; [rather,] it had similar benefits and risks compared to SoC,” he continued.

Looking at the DOOR components at day 70, mortality rates were similar in both arms at 4 percent, yielding a DOOR probability of 50 percent. Other DOOR components that were similar between the dalbavancin and SoC arms were the rates of clinical failure (20 percent vs 22 percent; DOOR probability, 51 percent) and infectious complications (13 percent vs 12 percent; DOOR probability, 49.5 percent).

The dalbavancin arm had fewer adverse events (AEs) leading to discontinuation than the SoC arm (3 percent vs 12 percent; DOOR probability, 54.5 percent) but a slightly higher rate of serious AEs (40 percent vs 34 percent; DOOR probability, 47 percent). [ESCMID Global 2024, abstract O0812]

“[Taken together, there were] similar rates of survival and clinical success, with slightly fewer AEs leading to dalbavancin discontinuation,” said Turner.

Looking at the secondary outcome in the more traditional noninferiority analysis, clinical efficacy at day 70 was 73 percent for dalbavancin and 72 percent for SoC. “Looking at the margin of difference, the lower end of the CI was -12 percent, which was within our prespecified margin for noninferiority. Thus, dalbavancin was noninferior to SoC by traditional clinical efficacy,” he said.

Serious AEs were relatively common in both the dalbavancin and SoC arms (n=43 and 37) which, according to Turner, is “not surprising for a bacteraemia trial.” AEs deemed treatment-related were reassuringly rare with the former vs the latter (n=2 and 4). AEs leading to treatment discontinuation followed a similar pattern (n=3 and 12).

High complication rates with prolonged IV antibiotics

S. aureus remains a leading cause of death by bloodstream infection globally. [Clin Microbiol Infect 2022;28:1076-1084] Treatment traditionally involves prolonged IV antibiotics, but these are associated with high complication rates, underlined Turner, hence the need for better treatment alternatives.

“Dalbavancin provides a particularly appealing option, given its long half-life in potent S. aureus activity, including against MRSA*. Dalbavancin is FDA- and EMA-approved for acute skin and soft tissue infections with an established safety track record under these indications,” he said.

Turner added that dalbavancin is already used increasingly off-label for endocarditis and bacteraemia, with evidence indicating high clinical success rates. He however noted occasional reports of treatment-emergent resistance and failure.

In DOTS, 200 patients (mean age 54 years, 69 percent men) who cleared bacteraemia after ≥72 hours but ≤10 days of induction antibacterial therapy were randomized 1:1 to receive either two doses of IV dalbavancin 1,500 mg (days 1 and 8) or a conventional antibiotic for MSSA** (cefazolin or nafcillin) or MRSA (vancomycin or daptomycin).

Two-thirds of the overall cohort had MSSA. A majority of participants had skin or soft tissue infections (31 percent) and osteoarticular infections (31 percent), around 20 percent had endovascular infections, while the rest had pulmonary infections.

A viable Tx alternative

Although dalbavancin did not achieve superiority over SoC, it showed a benefit-risk profile that was similar to SoC by DOOR and achieved noninferiority to SoC by traditional clinical efficacy endpoints for complicated SAB.

“[Hence,] dalbavancin is a viable treatment option for the management of complicated SAB without requiring prolonged IV access,” Turner concluded.