Simplifying the Complex: Dalbavancin as an Option for Treatment of Staphylococcus aureus Bacteremia

Staphylococcus aureus bacteremia (SAB) remains a leading bacterial cause of mortality. Randomized clinical trials informing SAB management are limited, and treatment generally consists of prolonged courses of intravenous antibiotics.^1-3 Although outpatient parenteral antimicrobial therapy (OPAT) has shifted the treatment of infections from inpatient to outpatient, clinicians should remain alert to OPAT-associated complications, including vascular access complications, such as vascular occlusion, catheter-associated thrombosis, or line-associated infection.^4,5

Dalbavancin, a long-acting lipoglycopeptide with a terminal half-life of 14 days, is an attractive agent in our arsenal for the treatment of gram-positive infections.⁶ When administered as a 2-dose, 1500-mg weekly regimen, pharmacokinetic modeling reveals plasma therapeutic concentrations above S aureus’ minimum inhibitory concentration sustained for 6 weeks or longer.⁷ Although clinical success with dalbavancin has been demonstrated in skin and soft tissue infections, bone and joint infections, and endocarditis,^8-16 failures have also been reported,^17-19 highlighting the need for quality data.

The DOTS: Dalbavancin as an Option for Treatment of Staphylococcus aureus Bacteremia trial (NCT04775953) was an open-label, randomized, superiority clinical trial conducted at 23 medical centers in the US and Canada from April 2021 to December 2023.²⁰ This trial aimed to assess the efficacy and safety of dalbavancin among inpatients with complicated SAB or right-sided endocarditis. Patients 18 years or older with complicated SAB with blood culture clearance and resolution of fever were included. These patients received at least 72 hours but no longer than 10 days of initial antibiotic therapy prior to random assignment. Complicated bacteremia was defined as any case that did not meet the criteria for uncomplicated bacteremia. The Infectious Diseases Society of America’s 2011 clinical practice guidelines defined uncomplicated bacteremia as positive blood culture results and the following: exclusion of endocarditis, no implanted prosthetic material, cleared blood cultures 2 to 4 days after initial blood cultures, defervescence within 72 hours of effective therapy, and lack of metastatic infection. Patients were excluded if they had central nervous system infections, known or suspected left-sided endocarditis or perivalvular abscess; presence of prosthetic material, cardiac device, or vascular graft unless there were plans for removal; receipt of dalbavancin or oritavancin 60 days prior; severe immunosuppression; and pregnancy. Vancomycin susceptibility was utilized to inform dalbavancin susceptibility.

Patients were randomly assigned 1:1 to receive dalbavancin or standard therapy (restricted to monotherapy with cefazolin, antistaphylococcal penicillin, vancomycin, or daptomycin, tailored to methicillin susceptibility). Dalbavancin dosing consisted of 1500 mg intravenously on days 1 and 8 (adjusted to 1125 mg if creatinine clearance was less than 30 mL/min). Standard therapy duration was limited to at least 4 weeks but less than 8 weeks total, with final duration decided by the treating clinician. The primary outcome was desirability of outcome ranking (DOOR) at day 70 after random assignment, which consisted of clinical success (survival with resolution of signs/symptoms of SAB) with DOOR greater than 50% establishing superiority, infectious complications (new sites of infection, relapse of SAB, or need for unplanned source control), safety (serious adverse events or adverse events leading to discontinuation), mortality, and health-related quality of life. Secondary outcomes included clinical efficacy (composite of lack of clinical failure, infectious complications, or mortality) and safety.

Two hundred patients were included in the study, with 100 patients randomly assigned to each group. Both study arms were well-balanced. The median age was 56 years in both groups, with the majority of patients in both groups being White men, followed by Black or African American (20% in the dalbavancin group vs 29% in the standard therapy group) and Hispanic or Latino (11% vs 14%, respectively) individuals. Body mass index was also similar between groups at approximately 27. Common comorbidities included diabetes in over 40%, immunosuppressed status in approximately 30%, and chronic kidney disease in approximately 20% of patients in both groups. More patients in the dalbavancin group had implanted prosthetic materials (12% vs 4%). Methicillin-resistant S aureus isolation was similar between groups (34% in the dalbavancin group vs 32% in the standard therapy group), with sources of bacteremia being predominantly soft tissue (40% vs 30%, respectively), followed by nonvertebral osteomyelitis (17% vs 19%), septic arthritis (12% vs 14%), and septic thrombophlebitis (10% vs 14%). Of interest, prosthetic joint infection was noted in 1 patient in both groups and cardiac device infections were noted in 4 patients in the dalbavancin group vs 2 patients in the standard therapy group. Over 50% in both groups had deep-seated infections, with duration of bacteremia predominantly being less than 2 days (77% vs 64%, respectively). Duration of therapy prior to random assignment was similar at 8 days for dalbavancin and 7 days for standard therapy. Source control was observed in 27% and 23%, respectively. Median length of stay was 3 days in the dalbavancin group and 4 days in the standard therapy group.

Dalbavancin failed to demonstrate superiority, as evidenced by DOOR of 47.7% (95% CI, 39.8%-55.7%). Dalbavancin demonstrated noninferiority, with clinical efficacy documented in 73% of patients treated with dalbavancin vs 72% treated with standard therapy. Serious adverse effects were similar in both groups, with adverse effects leading to drug discontinuation being less common at 3% with dalbavancin vs 12% with standard therapy.

Although dalbavancin did not demonstrate overall superiority to standard therapy, it demonstrated similar efficacy when considering each component of the DOOR end points, which provide a holistic approach to individual SAB treatment courses. Dalbavancin remains a reasonable option in select patients due to its noninferior efficacy, favorable safety profile, and ease of administration. The ability to provide prolonged coverage with just 2 doses of dalbavancin could significantly reduce health care utilization by avoiding central access placement and associated complications and improving quality of life, without compromising safety and efficacy. Dalbavancin is an attractive agent for patients with limited access to standard OPAT who are at high risk of complications and are not able to remain hospitalized for a prolonged period or be at an extended care facility.

References

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