Dalbavancin for Treatment of Staphylococcus aureus Bacteremia: The DOTS Randomized Clinical Trial

Nicholas A Turner; Toshimitsu Hamasaki; Sarah B Doernberg; Thomas P Lodise; Heather A King; Varduhi Ghazaryan; Sara E Cosgrove; Timothy C Jenkins; Catherine Liu; Shrabani Sharma; Smitha Zaharoff; Lana Wahid; Valerie J Renard; Paul Cook; Issam Raad; Ray Hachem; Anne-Marie Chaftari; Matthew Sims; Carmen DeMarco; Loren G Miller; Matthew W McCarthy; Caryn G Morse; Chris Lucasti; Graeme N Forrest; Kartikeya Cherabuddi; Christopher Polk; Tasaduq Fazili; Mark E Rupp; George R Thompson, III; Kami Kim; Luke Strnad; Amanda E Schnee; James A McKinnell; Mayur Ramesh; Fernanda P Silveira; Todd P McCarty; Todd C Lee; Emily G McDonald; Kristopher Paolino; Katie Wiegand; Alison Wall; Todd Riccobene; Rinal Patel; Urania Rappo; Scott Evans; Henry F Chambers; Vance G Fowler, Jr; Thomas L Holland

doi:10.1001/jama.2025.12543

. 2025 Aug 13;334(10):866–877. doi: 10.1001/jama.2025.12543

Dalbavancin for Treatment of Staphylococcus aureus Bacteremia

The DOTS Randomized Clinical Trial

Nicholas A Turner ¹, Toshimitsu Hamasaki ², Sarah B Doernberg ³, Thomas P Lodise ⁴, Heather A King ^5,^6,⁷, Varduhi Ghazaryan ⁸, Sara E Cosgrove ⁹, Timothy C Jenkins ¹⁰, Catherine Liu ¹¹, Shrabani Sharma ¹², Smitha Zaharoff ¹², Lana Wahid ^13,¹⁴, Valerie J Renard ^13,¹⁴, Paul Cook ¹⁵, Issam Raad ¹⁶, Ray Hachem ¹⁶, Anne-Marie Chaftari ¹⁶, Matthew Sims ¹⁷, Carmen DeMarco ¹⁷, Loren G Miller ¹⁸, Matthew W McCarthy ¹⁹, Caryn G Morse ²⁰, Chris Lucasti ²¹, Graeme N Forrest ²², Kartikeya Cherabuddi ^23,²⁴, Christopher Polk ²⁵, Tasaduq Fazili ²⁶, Mark E Rupp ²⁷, George R Thompson III ²⁸, Kami Kim ²⁴, Luke Strnad ²⁹, Amanda E Schnee ³⁰, James A McKinnell ³¹, Mayur Ramesh ³², Fernanda P Silveira ³³, Todd P McCarty ³⁴, Todd C Lee ³⁵, Emily G McDonald ³⁶, Kristopher Paolino ^37,^38,³⁹, Katie Wiegand ⁴⁰, Alison Wall ⁴⁰, Todd Riccobene ⁴¹, Rinal Patel ⁴¹, Urania Rappo ⁴², Scott Evans ², Henry F Chambers ³, Vance G Fowler Jr ^1,¹², Thomas L Holland ^1,^12,^✉, for the Antibacterial Resistance Leadership Group

¹Division of Infectious Diseases, Department of Medicine, Duke University, Durham, North Carolina

²The Biostatistics Center and the Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, George Washington University, Rockville, Maryland

³Division of Infectious Diseases, Department of Medicine, University of California, San Francisco

⁴Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York

⁵Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina

⁶Health Systems Research, Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care System, Durham, North Carolina

⁷Division of General Internal Medicine, Duke University School of Medicine, Durham, North Carolina

⁸Division of Microbiology and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

⁹Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

¹⁰Division of Infectious Diseases, Department of Medicine, Denver Health and University of Colorado, Denver

¹¹Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Division of Allergy and Infectious Diseases, University of Washington, Seattle

¹²Duke Clinical Research Institute, Durham, North Carolina

¹³Department of Hospital Medicine, Duke University Health System, Durham, North Carolina

¹⁴Department of Medicine, Virginia Tech Carilion School of Medicine, Roanoke

¹⁵Division of Infectious Diseases, Department of Medicine, Brody School of Medicine at East Carolina, Greenville, North Carolina

¹⁶Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston

¹⁷Section of Infectious Diseases and International Medicine, Department of Medicine, Corewell Health William Beaumont University Hospital, Royal Oak, Michigan

¹⁸Division of Infectious Diseases, Department of Medicine, Harbor-UCLA Medical Center and Lundquist Institute at Harbor-UCLA, Torrance, California

¹⁹Weill Cornell Medicine, New York, New York

²⁰Division of Infectious Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

²¹South Jersey Infectious Disease, Somers Point, New Jersey

²²Division of Infectious Diseases, Rush University Medical Center, Chicago, Illinois

²³Division of Infectious Diseases, Department of Internal Medicine, University of Florida, Gainesville

²⁴Division of Infectious Disease and International Medicine, University of South Florida and Tampa General Hospital, Tampa

²⁵Atrium Health, Wake Forest School of Medicine, Charlotte, North Carolina

²⁶Division of Infectious Diseases, Department of Medicine, Virginia Tech Carilion School of Medicine, Roanoke

²⁷Division of Infectious Diseases, Department of Internal Medicine, University of Nebraska Medical Center, Omaha

²⁸Division of Infectious Diseases, Department of Internal Medicine, UC-Davis Medical Center, Sacramento, California

²⁹Division of Infectious Diseases, Department of Internal Medicine, Oregon Health and Science University, Portland

³⁰University of South Carolina School of Medicine, Greenville

³¹Torrance Memorial Medical Center, Torrance, California

³²Division of Infectious Diseases, Henry Ford Health, Detroit, Michigan

³³Division of Infectious Diseases, Department of Medicine, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania

³⁴Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham

³⁵Division of Infectious Diseases, Department of Medicine, McGill University, Montreal, Quebec, Canada

³⁶Division of General Internal Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada

³⁷Division of Infectious Disease, SUNY Upstate Medical University, Syracuse, New York

³⁸Department of Medicine, SUNY Upstate Medical University, Syracuse, New York

³⁹Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York

⁴⁰The Emmes Company, Rockville, Maryland

⁴¹AbbVie, Florham Park, New Jersey

⁴²BiomX Inc, Gaithersburg, Maryland

Group Information: The Antibacterial Resistance Leadership Group appears in Supplement 3.

Accepted for Publication: July 5, 2025.

Published Online: August 13, 2025. doi:10.1001/jama.2025.12543

^✉

Corresponding Author: Thomas L. Holland, MD, MSc, Duke University School of Medicine, DUMC 102359, Durham, NC 27710 (thomas.holland@duke.edu).

Author Contributions: Drs Holland and Turner had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Turner, Hamasaki, Doernberg, King, Ghazaryan, Zaharoff, McCarthy, Lucasti, Riccobene, Patel, Rappo, Evans, Chambers, Fowler, Holland.

Acquisition, analysis, or interpretation of data: Turner, Hamasaki, Doernberg, Lodise, Ghazaryan, Cosgrove, Jenkins, Liu, Sharma, Wahid, Renard, Cook, Raad, Hachem, Chaftari, Sims, DeMarco, Miller, Morse, Lucasti, Forrest, Cherabuddi, Polk, Fazili, Rupp, Thompson, Kim, Strnad, Schnee, McKinnell, Ramesh, Silveira, McCarty, Lee, McDonald, Paolino, Wiegand, Wall, Evans, Chambers, Fowler, Holland.

Drafting of the manuscript: Turner, Hamasaki, Ghazaryan, Miller, Morse, Lucasti, Fazili, Thompson, Lee, McDonald, Fowler, Holland.

Critical review of the manuscript for important intellectual content: Turner, Hamasaki, Doernberg, Lodise, King, Ghazaryan, Cosgrove, Jenkins, Liu, Sharma, Zaharoff, Wahid, Renard, Cook, Raad, Hachem, Chaftari, Sims, DeMarco, McCarthy, Morse, Lucasti, Forrest, Cherabuddi, Polk, Fazili, Rupp, Thompson, Kim, Strnad, Schnee, McKinnell, Ramesh, Silveira, McCarty, Lee, McDonald, Paolino, Wiegand, Wall, Riccobene, Patel, Rappo, Evans, Chambers, Fowler, Holland.

Statistical analysis: Hamasaki, McCarthy, Thompson, Wall, Evans.

Obtained funding: Evans, Chambers, Fowler, Holland.

Administrative, technical, or material support: Turner, King, Sharma, Zaharoff, Cook, Raad, Hachem, Chaftari, Sims, DeMarco, Miller, Morse, Forrest, Rupp, Thompson, Strnad, Schnee, Ramesh, McCarty, Lee, McDonald, Riccobene, Patel, Rappo.

Supervision: Turner, Sharma, Zaharoff, Miller, Lucasti, Polk, Rupp, Thompson, Kim, Strnad, McKinnell, Ramesh, Silveira, McCarty, Rappo, Fowler, Holland.

Other—technical knowledge: McKinnell.

Other—data management: Wiegand.

Other—clinical events committee participation: Jenkins, Liu.

Other—project leadership and operational oversight: Zaharoff.

Other—contributed to clinical trial operations and logistics: Wahid.

Conflict of Interest Disclosures: Dr Turner reported grants from the Centers for Disease Control and Prevention, a clinical trial adjudication contract from Basilea, a research contract from PDI, a research contract from Purio, and a double-blind pharmaceutical consultation from Techspert outside the submitted work. Dr Doernberg reported grants from Pfizer, F2G Ltd, Chan Zuckerberg Initiative, Patient-Centered Outcomes Research Institute; Shionogi for clinical adjudication of a COVID-19 clinical trial; Basilea for clinical adjudication of a Staphylococcus aureus clinical trial; and personal fees from AstraZeneca outside the submitted work. Dr Lodise reported being an invited speaker for Paladin Pharma Inc during the conduct of the study. Dr King reported grants from Veterans Affairs (VA), National Institutes of Health (NIH), and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc outside the submitted work; Dr King is also supported by the Durham Center of Innovation to Accelerate Discovery and Practice Transformation (CIN 13-410) at the Durham VA Health Care System. Dr Cosgrove reported personal fees from Duke Clinical Research Institute outside the submitted work. Dr Cook reported grants from East Carolina University during the conduct of the study and grants from Pfizer, Gilead, AbbVie, and Janssen outside the submitted work. Dr Raad reported personal fees from Citius for serving on its scientific advisory board pertaining to a novel antimicrobial lock solution for the salvage of central catheters in the setting of bacteremia outside the submitted work; in addition, Dr Raad had a patent for Minolok antimicrobial catheter lock solution with royalties paid from Citius and a patent for NiCE issued as a co-inventor on an MD Anderson technology pertaining to a novel antimicrobial lock solution for the prevention of central catheter–related bacteremia. Dr Chaftari reported grants from Citius Pharmaceuticals Inc outside the submitted work. Dr Sims reported grants from Seres, Pfizer, QIAGEN, Adaptive Phage Therapeutics, OpGen, Leonard-Meron Biosciences, Prenosis, Janssen, Applied Biocode, PhAST Corp, Locus Biosciences, Affinity Biosensors, Vedanta Biosciences, and AstraZeneca and personal fees from InflaaRx outside the submitted work; in addition, Dr Sims had a patent for methods of diagnosing increased risk of developing MRSA or CA-MRSA issued held by Corewell Health Research Institute. Dr Miller reported grants from Paratek, Merck, Contrafect, Armata, and GSK outside the submitted work. Dr Polk reported being employed by ViiV Healthcare. Dr Rupp reported personal fees from Citius Pharmaceuticals, MedPace, and Teleflex outside the submitted work. Dr Thompson reported grants from Astellas, Basilea, GSK, F2G, Elion, and Scynexis outside the submitted work. Dr Kim reported personal fees from Shionogi and grants from Regeneron, Duke/Antibacterial Resistance Leadership Group, AstraZeneca, NIH, Department of Defense, and Armata outside the submitted work. Dr Strnad reported membership on Infectious Diseases Society of American/European Society of Clinical Microbiology and Infectious Diseases Staphylococcus aureus bacteremia guideline writing panel (guideline in development); Dr Strnad’s work on this guideline had no involvement to date regarding any content related to the study drug (dalbavancin) or its comparison with any standard-of-care antimicrobial therapy. Dr McKinnell reported consulting for Premier Home Health and Infusion and Expert Stewardship and personal fees from ThermoFisher Scientific, Nestle Health Science, and AbbVie and grants from AstraZeneca and CalciMedica outside the submitted work. Dr Lee reported research salary support from Fonds de Recherche Quebec Santé during the conduct of the study. Dr McDonald reported research salary support from the Fonds de Recherche du Québec Santé. Dr Paolino reported personal fees from Sanofi Institut Pasteur paid to perform this work during the conduct of the study. Dr Riccobene reported being employed by and owning stock in AbbVie. Dr Patel reported being employed by and owning stock in AbbVie. Dr Rappo reported personal fees from Allergan during the conduct of the study. Dr Evans reported grants from National Institute of Allergy and Infectious Diseases (NIAID)/NIH during the conduct of the study. Dr Fowler reported grants from NIH during the conduct of the study and grants from Contrafect, Merck, Karius, Genentech, Basilea, Janssen, and AstraZeneca; EDE research grants to his institution; personal fees from Debiopharm, Genentech, Basilea, Contrafect, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, Armata, AstraZeneca, Akagera, Aridis, Roche, GSK, and MicuRx; stock options from ValanBio; and royalties from UpToDate outside the submitted work. In addition, Dr Fowler had a patent for sepsis diagnostic pending. Dr Holland reported personal fees from Basilea Pharmaceutica, Astellas Pharma, Concert, Karius, PSI, Affinivax, Advarra, Aridis, and UpToDate; and serving on the data and safety monitoring board for Spero outside the submitted work. No other disclosures were reported.

Funding/Support: This work was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under NIAID award No. 5UM1Al104681. The study drug was provided by AbbVie.

Role of the Funder/Sponsor: Employees of AbbVie had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and decision to submit the manuscript for publication but did have a role in the preparation, review, and approval of the manuscript. The NIH established an independent data and safety monitoring board to monitor safety.

Group Information: The Antibacterial Resistance Leadership Group members are listed in Supplement 3.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, Duke University, the US Department of Veterans Affairs, or the US government.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank Michael W. Dunne, MD (Iterum Therapeutics); Sailaja Puttagunta, MD (Durata Therapeutics); and David Melnick, MD (D&K Pharma Consulting), all of whom contributed to earlier protocol drafts and had been employed by Allergan during the development of dalbavancin. They did not receive compensation related to this work. Members of the Antibacterial Resistance Leadership Group (arlg.org) were responsible for design and conduct of the study. The Emmes Company was responsible for collection, management, and analysis of data.

^✉

Corresponding author.

PMCID: PMC12351474 NIHMSID: NIHMS2100545 PMID: 40802264

Key Points

Question

Is dalbavancin a superior treatment option for complicated Staphylococcus aureus bacteremia compared with standard care?

Findings

In this randomized clinical trial that included 200 adults completing therapy for complicated S aureus bacteremia, the probability of a more desirable outcome at day 70 with dalbavancin vs standard therapy was 47.7%, which did not achieve the prespecified criterion for superiority.

Meaning

Among participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy for achieving a more desirable outcome at day 70.

Abstract

Importance

Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.

Objective

To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.

Design, Setting, and Participants

Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus bacteremia who achieved blood culture clearance following at least 72 hours but no more than 10 days of initial antibacterial therapy were included. Participants were excluded if they had central nervous system infection, retained infected prosthetic material, left-sided endocarditis, or severe immune compromise.

Interventions

Participants were randomly assigned to receive either 2 doses of intravenous dalbavancin (n = 100; 1500 mg on days 1 and 8) or 4 to 8 total weeks of standard intravenous therapy (n = 100; cefazolin or antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant).

Main Outcomes and Measures

The primary outcome was the desirability of outcome ranking (DOOR) at day 70, which involved 5 components (clinical success, infectious complications, safety complications, mortality, and health-related quality of life) and was assessed for superiority (achieved if the 95% CI for the probability of dalbavancin having a superior DOOR was >50%). Secondary outcomes included clinical efficacy at day 70 (prespecified noninferiority margin of 20%) and safety.

Results

Of 200 participants randomized (mean [SD] age, 56 [16.2] years; 62 females [31%]), 167 (84%) survived to day 70 and had an efficacy assessment. Participants without a day 70 efficacy assessment were treated as clinical failures in the analyses. The probability of a more desirable day 70 outcome with dalbavancin vs standard therapy was 47.7% (95% CI, 39.8% to 55.7%). Regarding secondary outcomes, clinical efficacy was documented in 73 of 100 for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, −11.5% to 13.5%]), meeting the noninferiority criterion. Serious adverse events were reported in 40 of 100 participants who received dalbavancin and 34 of 100 participants who received standard therapy; treatment-related adverse events were uncommon in both groups.

Conclusions and Relevance

Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes these findings may help inform use of dalbavancin in clinical practice.

Trial Registration

ClinicalTrials.gov Identifier: NCT04775953

This clinical trial compares the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated Staphylococcus aureus bacteremia in hospitalized patients.

Introduction

Staphylococcus aureus is the leading bacterial cause of death due to bloodstream infection worldwide,¹ and randomized clinical trials informing the management of S aureus bacteremia are limited.^2,3,4 Treatment generally requires prolonged administration of intravenous antibiotics, which can be associated with complications such as catheter-associated thrombosis or secondary infection.^5,6

Dalbavancin is an appealing treatment option given its long terminal half-life of 14 days and potent in vitro activity against S aureus (including methicillin-resistant S aureus [MRSA]).⁷ Pharmacokinetic modeling predicts that 2 weekly 1500-mg infusions provide plasma drug levels well above S aureus’ minimum inhibitory concentration for more than 6 weeks.⁸ The 55 participants enrolled in previous randomized trials assessing dalbavancin for other indications who were subsequently found to have S aureus bacteremia achieved microbiologic success.^{9,10,11,12,13} Several case series of dalbavancin for endocarditis and bacteremia have also reported high clinical success rates.^14,15,16,17 However, failures of dalbavancin therapy for complicated S aureus infections have also been reported, highlighting the need for high-quality data to guide clinicians.^18,19,20 The current study reports the results of a randomized clinical trial assessing the efficacy and safety of dalbavancin among hospitalized participants with complicated S aureus bacteremia or right-sided endocarditis. To reflect anticipated real-world use, participants were randomized after they had achieved blood culture clearance with initial therapy (ie, dalbavancin was compared with standard therapy during the consolidation phase of treatment).

Methods

Trial Design and Oversight

Dalbavancin as an Option for Treatment of Staphylococcus aureus Bacteremia (DOTS) was an open-label, assessor-masked, randomized, superiority trial conducted at 23 medical centers in the US and Canada from April 2021 to December 2023 (Supplement 1). A central institutional review board approved the protocol, with assent from each participating center’s local institutional review board. All participants provided written informed consent. The study protocol was previously published.²¹ An independent data and safety monitoring board supervised the trial. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed.²²

Participants

Hospitalized adults (≥18 years of age) with complicated S aureus bacteremia were eligible if they achieved blood culture clearance and resolution of fever. Participants received at least 72 hours but no more than 10 days of initial antibacterial therapy prior to randomization. For study purposes, complicated bacteremia was defined as any case not meeting criteria for uncomplicated bacteremia per 2011 Infectious Diseases Society of America guidelines (Supplement 1 and eMethods in Supplement 2). These guidelines defined uncomplicated bacteremia as infections in which endocarditis had been excluded, there are no implanted prostheses, follow-up blood cultures 2 to 4 days after initial blood cultures do not grow S aureus, defervescence has occurred within 72 hours of initiating effective therapy, and there is no evidence of metastatic sites of infection.²³ Race and ethnicity of participants were self-reported according to multiple prefixed categories and were included to adequately describe the study population.

Exclusion criteria included (1) infectious central nervous system involvement; (2) known or suspected left-sided endocarditis or perivalvular abscess; (3) planned right-sided valve replacement surgery; (4) presence of a prosthetic heart valve, cardiac device, or intravascular graft unless removal was planned; (5) presence of infected prosthetic joint or other infected extravascular hardware unless removal was planned; (6) polymicrobial bacteremia; (7) significant hepatic insufficiency; (8) severe immunosuppression; (9) known hypersensitivity to dalbavancin; (10) receipt of dalbavancin or oritavancin in the preceding 60 days; (11) pregnant or breastfeeding females; or (12) infections in which S aureus is not susceptible to dalbavancin. Dalbavancin susceptibility was inferred from vancomycin susceptibility.^24,25 Full inclusion and exclusion criteria are listed in the previously published protocol, Supplement 1, and eMethods in Supplement 2.

Trial Groups and Randomization

Eligible participants were randomly assigned in a 1:1 ratio to receive either dalbavancin, 1500 mg, intravenously on day 1 and day 8 from randomization (with dose adjustment to 1125 mg for participants with creatinine clearance <30 mL/min/1.73 m² [to convert to mL/s/m², multiply by 0.0167] and not receiving dialysis) or standard therapy. Standard therapy was restricted to a single agent: cefazolin or an antistaphylococcal penicillin for methicillin-susceptible S aureus (MSSA) and vancomycin or daptomycin for MRSA. Exceptions were permitted for medication allergy or other contraindication. Standard therapy agents were dosed according to local practice of each site. Treatment duration in the standard therapy group was left to the discretion of the treating clinician, but limited to at least 4 but no more than 8 weeks total.

Primary and Secondary Outcomes

The primary outcome was desirability of outcome ranking (DOOR) at day 70 after randomization, assessed by an independent committee of 4 infectious diseases experts who were masked to treatment assignment. The DOOR end point was selected because it better reflects clinical decision-making: in contrast to binary efficacy outcomes, DOOR explicitly integrates efficacy, safety, and quality of life to inform the optimal treatment for a patient. The DOOR end point was specifically developed and validated for bacteremia and consisted of 5 components: clinical success (defined as survival with resolution of signs and symptoms of S aureus bacteremia), infectious complications (development of new sites of infection, relapse of bacteremia, or requirement for additional unplanned source control procedures), safety complications (serious adverse events or adverse events leading to study drug discontinuation), mortality, and health-related quality of life.^26,27,28 Note that clinical success is a summary assessment at the time of follow-up visit, whereas infectious complications are cumulative events that occur throughout study participation. Thus, it is possible for a patient to achieve clinical success in the end despite experiencing infectious complications along the way. The highest DOOR rank included participants who experienced treatment success without infectious or safety complications, whereas the lowest rank included participants who died. Intermediate ranks included participants who survived but with treatment failure or complications (Supplement 1 and eMethods in Supplement 2).²⁷ The day 70 follow-up interval was selected because most participants were anticipated to complete treatment by day 42 and the majority of S aureus bacteremia relapses occur within 30 days of treatment completion.²⁹

Health-related quality of life was assessed at each visit using the Patient-Reported Outcomes Measurement Information System (PROMIS) physical function short form, a subset of a survey derived from PROMIS, which has been specifically evaluated for tracking patient-centered outcomes in S aureus bacteremia (Supplement 1).^26,28 For surviving participants with identical DOOR, change in health-related quality of life from baseline to day 70 served as a tiebreaker.²⁷

Secondary outcomes included clinical efficacy (defined as a composite of the lack of clinical failure, infectious complications, or mortality) and safety (incidence of serious adverse events or adverse events leading to study drug discontinuation). For safety purposes, acute kidney injury was defined as an increase in creatinine to 1.5 times the upper limit of normal or 1.5 times the baseline creatinine. Exploratory outcomes included microbiologic success (defined as no postrandomization growth of the baseline pathogen from blood cultures or other usually sterile body sites), additional safety measures (adverse events categorized by type, severity, and relationship to treatment), and osteomyelitis recurrence by day 180 among participants with osteomyelitis at randomization. The prolonged follow-up interval for participants with osteomyelitis was selected because relapsed infection commonly presents several months after the end of treatment.^30,31

Statistical Analysis

Primary and secondary clinical efficacy outcomes were assessed as randomized. The safety analysis was conducted in the safety population, defined as any participants receiving at least 1 dose of study-directed antibiotics after randomization and allocated according to treatment received. Clinical efficacy was adjudicated by the same treatment-blinded independent review committee as the primary outcome. If the adjudication committee lacked sufficient data to determine clinical efficacy (a component of both DOOR and clinical efficacy outcomes), the patient’s outcome was classified as a clinical failure.

The study was powered to evaluate for superiority by DOOR. Assuming a 65% probability that the dalbavancin group would have a superior DOOR while accounting for up to 12% loss to follow-up, we calculated that 200 participants would need to be enrolled to achieve 90% power with a 1-sided α of .025. Similar power was estimated for the secondary clinical efficacy outcome (87%-94%) with a 1-sided α of .025 and a prespecified 20% noninferiority margin (Supplement 1).

For the primary outcome, the DOOR probability was estimated using the Wilcoxon Mann-Whitney U statistic with the corresponding 95% confidence interval (CI) calculated using the Halperin method.³² Superiority of dalbavancin could be concluded if the 95% CI for the probability of dalbavancin having a superior DOOR was greater than 50%. For the secondary clinical efficacy outcome, difference in clinical efficacy (dalbavancin group minus standard therapy group) was determined and a 2-sided 95% CI for the difference calculated using linear regression. The noninferiority test for clinical efficacy was based on the lower bound of the CI being within a prespecified noninferiority margin of 20% and the upper bound containing 0%. The selected 20% noninferiority margin aligns with the margin used in other contemporary infection trials,^4,33 and also reflects the trade-off in efficacy clinicians and participants might be willing to accept given dalbavancin’s hypothesized advantages over prolonged intravenous therapies. For example, survey data indicate that many clinicians would consider a 20% margin acceptable if the alternative treatment provided some beneficial trade-off,³⁴ such as shorter duration or improved safety. Moreover, dalbavancin avoids the estimated 18% to 22% complication risk associated with prolonged intravenous access.^5,6

No formal hypothesis testing was conducted for exploratory outcomes, subgroup analyses, or other analysis populations. For subgroup analyses, only point estimates with 95% CIs were reported. Widths of the subgroup analyses’ CIs were not adjusted for multiplicity and should not be used to infer definitive treatment effects.

Results

Participant Characteristics

Between April 2021 and December 2023, 200 participants were enrolled from 23 sites in the US and Canada (Figure 1; eTable 1 in Supplement 2); 100 were randomly assigned to dalbavancin and 100 to standard therapy. All participants received at least 1 study drug dose. In the dalbavancin group, 4 participants did not receive the second dose due to death (n = 2), adverse event (n = 1), or loss to follow-up (n = 1). eTables 2 and 3 in Supplement 2 provide a summary of antibiotic selection and duration for participants receiving standard therapy. eTable 4 in Supplement 2 provides source control procedures.

Baseline characteristics and infection features were generally balanced, although bacteremia durations longer than 4 days and chronic kidney disease were numerically more common in the standard therapy group while immunosuppression and soft tissue infections were numerically more common in the dalbavancin group (Table 1). Overall, common comorbidities among participants with S aureus bacteremia were well represented in the trial population, including 15.0% of participants with injection drug use and 8.0% with implanted prosthetic materials. Reflecting current epidemiology in the US, 67.0% of isolates were methicillin susceptible and 33.0% were methicillin resistant.³⁵

Table 1. Baseline Characteristics of Participants in the DOTS Trial^a.

Characteristic	Dalbavancin (n = 100)	Standard therapy (n = 100)
Age, median (IQR), y	56 (41-66)	56 (41-68)
Age ≥80, No. (%)	1 (1)	4 (4)
Sex, No. (%)
Male	70 (70)	68 (68)
Female	30 (30)	32 (32)
Race, No. (%)
Asian	5 (5)	1 (1)
American Indian or Alaska Native	2 (2)	0
Black or African American	20 (20)	29 (29)
White	68 (68)	69 (69)
Not reported	5 (5)	1 (1)
Hispanic or Latino, No. (%)	11 (11)	14 (14)
Body mass index, median (IQR)^b	27.6 (24.3-31.7)	26.9 (23.3-33.5)
Persons who inject drugs, No. (%)	16 (16)	13 (13)
Medical comorbidities, No. (%)
Diabetes	44 (44)	48 (48)
Immunosuppressed condition^c	35 (35)	26 (26)
Chronic kidney disease	20 (20)	30 (30)
Heart failure	21 (21)	19 (19)
Cancer	21 (21)	17 (17)
Receiving dialysis	12 (12)	13 (13)
Liver disease	14 (14)	8 (8)
Participants who had implanted prosthetic materials, No. (%)	12 (12)	4 (4)
Methicillin-resistant S aureus, No. (%)	34 (34)	32 (32)
Anatomic site of infection, No. (%)^d
Soft tissue infection	40 (40)	30 (30)
Osteomyelitis, nonvertebral	17 (17)	19 (19)
Septic arthritis	12 (12)	14 (14)
Septic thrombophlebitis	10 (10)	14 (14)
Pneumonia/empyema	11 (11)	5 (5)
Septic pulmonary emboli	8 (8)	7 (7)
Right-sided endocarditis	6 (6)	4 (4)
Vascular graft infection/mycotic aneurysm	4 (4)	6 (6)
Vertebral osteomyelitis	5 (5)	2 (2)
Cardiac device infection	4 (4)	2 (2)
Prosthetic joint infection	1 (1)	1 (1)
Visceral abscess	1 (1)	1 (1)
Deep-seated infection, No. (%)^e	54 (54)	51 (51)
Days of bacteremia, No. (%)
<2	77 (77)	64 (64)
2-4	21 (21)	26 (26)
>4	2 (2)	10 (10)
Transthoracic echocardiography performed, No. (%)	73 (73)	71 (71)
Transesophageal echocardiography performed, No. (%)	27 (27)	29 (29)
Duration of prerandomization therapy, median (IQR), d	8 (6-9)	7 (6-9)
Participants who underwent source control interventions, No. (%)
Surgical debridement	27 (27)	23 (23)
Central venous catheter removal	9 (9)	14 (14)
Amputation	1 (1)	8 (8)
Percutaneous drainage	4 (4)	4 (4)
Cardiac device removal	3 (3)	2 (2)
Other device removal^f	2 (2)	1 (1)
Vascular graft excision	1 (1)	1 (1)
Cardiac valve surgery	1 (1)	0
Percutaneous mechanical aspiration	1 (1)	0
Osteomyelitis^g	22 (22)	20 (20)
Underwent surgical debridement^h	8 (36)	8 (40)

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Abbreviation: DOTS, Dalbavancin as an Option for Treatment of Staphylococcus aureus Bacteremia.

^{^a}

Denominators are the number of randomized participants, unless specified otherwise.

^{^b}

Calculated as weight in kilograms divided by height in meters squared.

^{^c}

Severe immunosuppression was excluded from the trial (see Supplement 1 and eMethods in Supplement 2 for detailed exclusion criteria). Here, immunosuppressed refers to participants with HIV and a CD4+ cell count of >50 to ≤200 cells/mm³, history of transplant >3 months prior and not receiving augmented immune suppression for treatment of rejection, participants receiving steroids equivalent to prednisone, 40 mg, or greater daily, participants receiving immune-suppressive medications for rheumatologic conditions, and participants receiving chemotherapy but without sustained neutropenia below an absolute neutrophil count of 100 cells/mm³.

^{^d}

Anatomic sites of infection may sum to greater than the number of participants in each group as participants could have had more than 1 anatomic site of infection.

^{^e}

Defined as the presence of at least 1 of the following anatomic sites of infection: endocarditis, osteoarticular infection, cardiac device infection, septic thrombophlebitis, or deep (noncutaneous) abscess (eg, psoas abscess, splenic abscess).

^{^f}

Including 1 peritoneal dialysis catheter, 1 external fixation device, and 1 percutaneous nephrostomy tube.

^{^g}

Including participants with osteomyelitis (vertebral or nonvertebral) at baseline.

^{^h}

Denominators are the number of participants who had osteomyelitis at baseline.

Among the 200 participants in the intention-to-treat population, the distribution of infection categories was similar between groups; S aureus bacteremia was related to soft tissue infection in 70 participants (35.0%), osteoarticular infection (including osteomyelitis, septic arthritis, and prosthetic joint infection) in 55 (27.5%), endovascular infection (including septic thrombophlebitis, right-sided endocarditis, cardiac device infection, vascular graft infection, or mycotic aneurysm) in 45 (22.5%), or pulmonary infection (including pneumonia, septic pulmonary emboli, and empyema) in 29 (14.5%). Ten participants had known right-sided endocarditis (6 in the dalbavancin group, 4 in the standard therapy group). The median hospital length of stay after enrollment was 3 days (IQR, 2-7) in the dalbavancin group and 4 days (IQR, 2-8) in the standard therapy group.

Primary Outcome

The probability that a patient randomly selected from the dalbavancin group would have a superior DOOR vs standard therapy group was 47.7% (95% CI, 39.8%-55.7%; Figure 2), which did not demonstrate superiority of dalbavancin treatment. Individual DOOR components were similar between dalbavancin and standard therapy, though adverse events leading to study drug discontinuation were more common with standard therapy compared with dalbavancin (12.0% vs 3.0%; Figure 2A and B; details in eTables 5, 6, 7, and 8 and eFigure 1 in Supplement 2). To address the issue that dalbavancin cannot be discontinued after receipt of the second dose, a post hoc sensitivity analysis was conducted that excluded treatment discontinuation as a DOOR component, with no significant change in overall outcome (eTable 9 in Supplement 2).

Figure 2. — Desirability of outcome ranking (DOOR) with quality-of-life tiebreak represents the DOOR probability that a participant in the dalbavancin group will experience a more favorable outcome compared with a participant in the standard therapy group. In cases where 2 participants achieve the same DOOR, change in quality of life is used as a tiebreaker to provide a more nuanced distinction between them, except when both participants have died. The probability was estimated using the Wilcoxon-Mann-Whitney statistic, with the corresponding 95% confidence interval (CI) calculated using the Halperin et al³² method. If the 95% CI for the probability excluded the point of 50%, the difference in the DOOR end point between groups was regarded as significant. The individual components of the DOOR—clinical failure, nonfatal serious adverse events (SAEs), adverse events (AEs) leading to discontinuation, and quality of life—were analyzed in the same manner as the DOOR. For clinical failure, nonfatal SAEs, and AEs leading to discontinuation, the number of events and the proportion by group were presented. The adjudication committee did not have sufficient evidence to determine clinical failure for 11 participants in the dalbavancin group and 14 participants in standard therapy group; therefore, these participants were treated as having clinical failure. Details of AEs leading to study drug discontinuation and clinical failures can be found in eTables 7 and 8 in Supplement 2.

Baseline and day 70 quality-of-life measures were similar between dalbavancin and standard therapy (eTable 10 in Supplement 2). Overall DOOR probability was similar whether or not change in health-related quality of life was used as a tiebreaker (Figure 2A).

Secondary Outcomes

A total of 73 of 100 participants in the dalbavancin group and 72 of 100 participants in the standard therapy group had overall clinical success (difference, 1.0% [95% CI, −11.5% to 13.5%]; Table 2).³⁶ The lower bound of the 95% CI was within the prespecified margin of −20%, indicating that dalbavancin met criteria for noninferiority relative to standard therapy.

Table 2. Secondary and Exploratory Efficacy Analyses (As-Randomized Population).

Outcomes	No. (%)		Difference in proportions (95% CI)
Outcomes	Dalbavancin (n = 100)	Standard therapy (n = 100)	Difference in proportions (95% CI)
Secondary outcome
Clinical efficacy at day 70	73 (73)	72 (72)	1.0 (−11.5 to 13.5)^a^,^b
Exploratory outcomes
Microbiologic success at day 70	84/85 (98.8)	79/82 (96.3)	2.5 (−2.2 to 7.3)^c
Osteomyelitis at day 180 recurrence	3/15 (20.0)	1/14 (7.1)	12.9 (−15.7 to 40.3)^d

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^{^a}

Clinical efficacy was defined as lack of clinical failure (lack of resolution in signs or symptoms of S aureus bacteremia such that additional or ongoing antibiotic therapy was required), infectious complications, or mortality at day 70 assessment.

^{^b}

Clinical efficacy was compared using the difference in proportions, and the corresponding 95% confidence interval (CI) was calculated by assuming a normal distribution to approximate the distribution of the difference between the 2-sample proportion. If the lower limit of the CI was larger than the noninferiority margin of −20%, it was considered that noninferiority of the dalbavancin group over the standard therapy group was established.

^{^c}

Microbiologic success was compared using difference in proportions and the corresponding 95% CI, which were estimated using the inverse probability weighting approach to adjust for the missing microbiological outcomes. The weights were calculated using logistic regression, including age, sex, and treatment group as covariates.

^{^d}

For difference in osteomyelitis late recurrence proportions recurrence, and the corresponding 95% CI was calculated by the Miettinen-Nurminen method.³⁶

Exploratory Outcomes

Additional exploratory efficacy outcomes are presented in Table 2. Among evaluable participants, 84 of 85 (98.8%) achieved microbiologic success in the dalbavancin group compared with 79 of 82 (96.3%) in the standard therapy group (difference, 2.5% [95% CI, −2.2% to 7.3%]). Among participants with known osteomyelitis at the time of randomization, recurrence by day 180 occurred in 3 of 15 (20.0%) in the dalbavancin group compared with 1 of 14 (7.1%) in the standard therapy group (difference, 12.9% [95% CI, −15.7% to 40.3]).

Repeating the primary DOOR and secondary clinical efficacy analyses yielded similar outcomes within the clinically evaluable population (excluding those with missing data or major protocol deviations) as for all randomized participants (eTables 11, 12, and 13 and eFigure 2 in Supplement 2).

Safety Outcomes

Serious adverse events were common overall and similar between participants receiving dalbavancin (40 of 100) and standard therapy (34 of 100) (Table 3). Adverse events leading to treatment discontinuation were numerically more frequent with standard therapy (12 of 100) than with dalbavancin (3 of 100) (see eTable 7 in Supplement 2 for summary; all adverse events occurring in >2% of participants are summarized in eTable 14 in Supplement 2). Nine total treatment-related adverse events were reported among 8 participants in the dalbavancin group; 6 participants receiving standard therapy experienced treatment-related adverse events. Among participants receiving dalbavancin, 4 adverse events (44.4%) were grade 1 and 5 (55.6%) were grade 3. Grade 1 adverse events consisted of transient rash or pruritus (2 of 4) or transient mild elevation in aspartate or alanine aminotransferases (2 of 4). Grade 3 adverse events attributed to dalbavancin included an infusion reaction (1 of 5, consisting of transient fever, rigors, and tachycardia), palmar rash (1 of 5), acute kidney injury (1 of 5), and aspartate or alanine aminotransferase elevations (2 of 5 events, occurring within the same participant).

Table 3. Adverse Events Occurring Through Day 70 Follow-Up (Safety Population).

Adverse event	No. (%)
Adverse event	Dalbavancin (n = 100)	Standard therapy (n = 100)
Serious adverse events	40 (40)	34 (34)
Adverse events leading to study drug discontinuation	3 (3)	12 (12)
Grade 3 or higher adverse events	51 (51)	39 (39)
Adverse events of special interest^a	12 (12)	8 (8)
Aspartate aminotransferase/alanine aminotransferase elevation	4 (4)	1 (1)
Central line–associated infection	1 (1)	2 (2)
Acute kidney injury	2 (2)	1 (1)
Rash/pruritus	1 (1)	1 (1)
Catheter-associated thrombosis	0	3 (3)
Infusion site infiltration	2 (2)	0
Infusion reaction	1 (1)	0
Generalized itching	1 (1)	0
Hypotension	0	1 (1)
Treatment-related adverse events^a	8 (8)	6 (6)
Aspartate aminotransferase/alanine aminotransferase elevation	3 (3)	1 (1)
Rash/pruritus	3 (3)	0
Acute kidney injury	1 (1)	1 (1)
Hemolytic anemia	0	1 (1)
Infusion reaction	1 (1)	0
Rhabdomyolysis	0	1 (1)
Peripheral neuropathy	0	1 (1)
Eosinophilic pneumonia	0	1 (1)
Elevated blood creatine phosphokinase	0	1 (1)

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^{^a}

The count of individual patients who experienced at least 1 occurrence of the event. Number of events for a category may sum to greater than the individual event types if a participant experienced more than 1 event within that stated category.

One additional participant experienced hepatic failure approximately 4 weeks after dalbavancin receipt and improved following treatment for possible acetaminophen toxicity. Etiology of hepatic failure was attributed to polysubstance use by the safety monitoring group.

Treatment-emergent resistance occurred in 1 participant from each treatment group. Initial blood cultures from 1 patient with vertebral osteomyelitis randomized to dalbavancin showed vancomycin-susceptible MRSA. Swab cultures collected on day 41 from a nonhealing spinal wound grew MRSA that was vancomycin intermediate and daptomycin nonsusceptible (while specific dalbavancin susceptibilities were not performed, activity can be inferred from vancomycin).²⁴ Initial blood cultures from 1 patient with osteomyelitis receiving daptomycin as standard therapy grew MRSA that was daptomycin susceptible. Operative cultures collected during bone debridement on day 6 subsequently grew MRSA that was not susceptible to daptomycin.

Subgroup Analyses

Treatment effect was consistent for prespecified analyses of DOOR, clinical efficacy, and microbiologic success across baseline pathogen (MSSA vs MRSA), all categories of infection (though there were very few pulmonary infections), by bacteremia duration, among persons who inject drugs, and participants who were immunosuppressed (DOOR and clinical efficacy in Figure 3; microbiologic success in eFigure 3 in Supplement 2).

Figure 3. — A, The numbers display the number of participants by group in each subgroup. The 95% confidence intervals (CIs) for the probability were calculated using the Halperin et al³² method, except for the pulmonary-only subgroup. For the pulmonary-only subgroup, the pseudoscore approach based on Halperin et al was used to calculate the CI, as the subgroup size was small and unbalanced between the groups. B, The numbers display the number of clinical successes and proportion by group in each subgroup. The 95% CIs for difference in proportions were calculated by assuming a normal distribution to approximate the distribution of the difference between the 2-sample proportion. The dashed vertical line indicates the prespecified 20% noninferiority margin.

Other or unknown infections included 9 of unknown source, 5 deep muscle abscesses or myositis, 3 catheter/port-related infections, 3 foot infections, 3 pyelonephritis or urosepsis or kidney abscesses, 1 surgical site infection, 1 inoculation via drug injection, 1 arm infection without specified depth, 1 peritonitis, 1 arteriovenous fistula infection, and 1 sacroiliac infection. Any participants missing a day 70 clinical efficacy assessment were considered clinical failures.

Discussion

In this assessor-masked trial enrolling participants with complicated S aureus bacteremia, dalbavancin was not superior to standard therapy by DOOR. Dalbavancin met prespecified criteria for noninferiority by clinical efficacy, a secondary outcome. These findings remained consistent across all key subgroups, including anatomic site of infection, pathogen (MRSA or MSSA), immunosuppressed status, duration of bacteremia, and among persons who inject drugs. Dalbavancin was well-tolerated, consistent with its prior safety record in the treatment of soft tissue infections.^9,10,37

While prior approvals of daptomycin⁴ and ceftobiprole³ have expanded treatment options for S aureus bacteremia, all treatments currently approved with an indication for bacteremia require prolonged intravenous access. Switching from intravenous to oral therapy has proven successful in participants with bacterial endocarditis or osteomyelitis, but S aureus (especially MRSA) are underrepresented in existing trials with another large trial ongoing.^38,39,40 Consequently, safe and effective treatment options are still needed. Dalbavancin is increasingly used for the management of S aureus bacteremia, particularly in situations where clinicians or patients want to avoid prolonged intravenous access. Published observational data suggest high rates of clinical success with dalbavancin.^14,15,16,17

It was hypothesized that dalbavancin might prove superior to standard therapy by improving treatment completion rates, avoiding complications associated with long-term intravenous access, and improving patient quality of life. In contrast to binary outcomes that focus solely on clinical success or failure, the primary DOOR outcome was selected because it better reflects the full balance of efficacy, safety, and quality-of-life considerations clinicians and participants actually use to determine treatment. Rates of adverse events leading to treatment discontinuation and select adverse events of special interest (eg, catheter-associated thrombosis) were numerically more frequent in the standard therapy group. However, overall DOOR and health-related quality-of-life scores were similar between dalbavancin and standard therapy, suggesting that the captured aspects of patient experience did not substantially differ between treatment groups. This result is consistent with other recent trials that sought to minimize or avoid prolonged intravenous antibiotics. Neither the Oral vs Intravenous Antibiotics (OVIVA) trial, using European Quality of Life 5-Dimension score, nor the Partial Oral vs Intravenous Antibiotic Treatment of Endocarditis (POET) trial, using Short-Form 36, found significant differences in quality of life between parenteral vs oral treatment groups.^38,39,41 It is unclear whether this lack of observed difference indicates that current tools fail to capture relevant differences or that the route of antimicrobial therapy minimally affects patient experience. Notably, while the survey used in this trial was intended to capture general function, it did not directly assess specific measures such as burdens associated with intravenous access, caregiver concerns, or the need for home health visits.

Importantly, treatment-emergent resistance developed in 1 patient within each treatment group. Treatment-emergent resistance to daptomycin has been well-described previously.^32,42 Case reports of treatment-emergent resistance with dalbavancin have described similar susceptibility patterns to those observed in this study, typically daptomycin nonsusceptibility and vancomycin intermediate resistance.^18,19,20 Although infrequent, any instance of treatment-emergent resistance underscores the importance of adequate evaluation and management of deep-seated foci of infection including device removal and/or debridement.

Trial strengths included enrollment of persons who inject drugs (15.0% of participants), a key population at risk of S aureus bacteremia, and infections with MRSA (33.0% of participants). Additionally, a bacteremia-specific DOOR was used as the primary end point, which may better reflect the balance of risks and benefits than simple clinical efficacy outcomes. This primary outcome was paired with a more traditional secondary noninferiority end point. The experimental group tested a simple 2-dose dalbavancin regimen based on pharmacological modeling and designed to reflect anticipated real-world use.^7,8,14,15,17 Loss to follow-up rates for the primary outcome were within the estimates used for power calculations. Participants missing a day 70 assessment were handled conservatively (as clinical failure) and participants adjudicated as failures due to missingness were similar between treatment groups (Figure 1).

Limitations

This study had several key limitations. First, it was open label, which may result in bias, although outcomes were assessed by a treatment-masked clinical adjudications committee. Second, mortality was lower than typically reported with S aureus bacteremia, likely because participants were enrolled after clearance of bacteremia, selecting for a population more likely to survive. Third, inclusion of treatment discontinuation as a DOOR component might favor a long-acting agent because dalbavancin cannot be discontinued after the second dose, although a sensitivity analysis excluding this component was performed and the outcome was unchanged. Fourth, bacteremia duration of longer than 4 days was numerically more common among participants randomly assigned to standard therapy, suggesting that some participants in the standard therapy group may have had more severe infection. Fifth, late recurrence was numerically more common among participants with osteomyelitis receiving dalbavancin, though overall follow-up rates were lower for the prolonged day 180 follow-up and numbers were too small to make a reliable comparison. Sixth, because only a single 2-dose regimen was studied, it remains possible that select patient populations might have benefited from an alternative dosing regimen of dalbavancin. Seventh, discharge disposition was not captured, thus, while dalbavancin recipients had a shorter median length of hospital stay, the study results do not necessarily inform whether this allowed participants to be discharged directly home.

Conclusions

Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes, these findings may help inform use of dalbavancin in clinical practice.

Supplement 1.

Trial Protocol

jama-e2512543-s001.pdf^{(46.4MB, pdf)}

Supplement 2.

eMethods

eTable 1. List of Principal Investigators and Number of Participants Enrolled per Site

eTable 2. Treatment Received for Consolidation in Standard Therapy Group by Pathogen

eTable 3. Treatment Durations in Standard Therapy Group

eTable 4. Source Control Procedures by Presence of Deep-seated Infection

eTable 5. Summary of DOOR Events at Day 70 by Treatment Group

eFigure 1. Detailed Distribution of DOOR Rankings by Treatment Group

eTable 6. Matrix Table Comparing Day 70 Clinical Efficacy Outcome and DOOR Categories

eTable 7. Summary of Adverse Events Leading to Study Drug Discontinuation

eTable 8. Summary of Clinical Failures

eTable 9. Sensitivity Analysis of DOOR Without AE Leading to Study Drug Discontinuation

eTable 10. Summary of Physical Function Short Form Score by Treatment Group

eTable 11. Summary of Protocol Deviations

eTable 12. Clinically Evaluable Population

eFigure 2. Analysis of Day 70 DOOR in Clinically Evaluable Population

eTable 13. Day 70 Clinical Efficacy Analysis in Clinically Evaluable Population

eTable 14. Summary of Adverse Events Occurring in >2% of Participants by Treatment Group

eFigure 3. Subgroup Analysis of Microbiologic Success by Treatment Group

eReferences

jama-e2512543-s002.pdf^{(1MB, pdf)}

Supplement 3.

Nonauthor Collaborators. Antibacterial Resistance Leadership Group

jama-e2512543-s003.pdf^{(134.9KB, pdf)}

Supplement 4.

Data Sharing Statement

jama-e2512543-s004.pdf^{(96KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jama-e2512543-s001.pdf^{(46.4MB, pdf)}

Supplement 2.

eMethods

eTable 1. List of Principal Investigators and Number of Participants Enrolled per Site

eTable 2. Treatment Received for Consolidation in Standard Therapy Group by Pathogen

eTable 3. Treatment Durations in Standard Therapy Group

eTable 4. Source Control Procedures by Presence of Deep-seated Infection

eTable 5. Summary of DOOR Events at Day 70 by Treatment Group

eFigure 1. Detailed Distribution of DOOR Rankings by Treatment Group

eTable 6. Matrix Table Comparing Day 70 Clinical Efficacy Outcome and DOOR Categories

eTable 7. Summary of Adverse Events Leading to Study Drug Discontinuation

eTable 8. Summary of Clinical Failures

eTable 9. Sensitivity Analysis of DOOR Without AE Leading to Study Drug Discontinuation

eTable 10. Summary of Physical Function Short Form Score by Treatment Group

eTable 11. Summary of Protocol Deviations

eTable 12. Clinically Evaluable Population

eFigure 2. Analysis of Day 70 DOOR in Clinically Evaluable Population

eTable 13. Day 70 Clinical Efficacy Analysis in Clinically Evaluable Population

eTable 14. Summary of Adverse Events Occurring in >2% of Participants by Treatment Group

eFigure 3. Subgroup Analysis of Microbiologic Success by Treatment Group

eReferences

jama-e2512543-s002.pdf^{(1MB, pdf)}

Supplement 3.

Nonauthor Collaborators. Antibacterial Resistance Leadership Group

jama-e2512543-s003.pdf^{(134.9KB, pdf)}

Supplement 4.

Data Sharing Statement

jama-e2512543-s004.pdf^{(96KB, pdf)}

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PERMALINK

Dalbavancin for Treatment of Staphylococcus aureus Bacteremia

Nicholas A Turner, MD, MHSc

Toshimitsu Hamasaki, PhD

Sarah B Doernberg, MD, MAS

Thomas P Lodise, PharmD, PhD

Heather A King, PhD

Varduhi Ghazaryan, MD, MPH

Sara E Cosgrove, MD, MS

Timothy C Jenkins, MD, MSc

Catherine Liu, MD

Shrabani Sharma, MSc

Smitha Zaharoff, PhD

Lana Wahid, MD

Valerie J Renard, AGACNP

Paul Cook, MD

Issam Raad, MD

Ray Hachem, MD

Anne-Marie Chaftari, MD

Matthew Sims, MD, PhD

Carmen DeMarco, MD

Loren G Miller, MD, MPH

Matthew W McCarthy, MD

Caryn G Morse, MD, MPH

Chris Lucasti, MD

Graeme N Forrest, MBBS

Kartikeya Cherabuddi, MD

Christopher Polk, MD

Tasaduq Fazili, MD

Mark E Rupp, MD

George R Thompson III, MD

Kami Kim, MD

Luke Strnad, MD

Amanda E Schnee, MD

James A McKinnell, MD

Mayur Ramesh, MD

Fernanda P Silveira, MD, MS

Todd P McCarty, MD

Todd C Lee, MD, MPH

Emily G McDonald, MD, MSc

Kristopher Paolino, MD, MTM&H

Katie Wiegand, MEng

Alison Wall, MS

Todd Riccobene, PhD

Rinal Patel, PharmD

Urania Rappo, MD

Scott Evans, PhD

Henry F Chambers, MD

Vance G Fowler Jr, MD, MHS

Thomas L Holland, MD, MSc

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Trial Design and Oversight

Participants

Trial Groups and Randomization

Primary and Secondary Outcomes

Statistical Analysis

Results

Participant Characteristics

Figure 1. Recruitment, Randomization, and Patient Flow in the DOTS Trial.

Table 1. Baseline Characteristics of Participants in the DOTS Triala.

Primary Outcome

Figure 2. Primary Outcome (As-Randomized Population).

Secondary Outcomes

Table 2. Secondary and Exploratory Efficacy Analyses (As-Randomized Population).

Exploratory Outcomes

Safety Outcomes

Table 1. Baseline Characteristics of Participants in the DOTS Trial^a.