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

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.

Figure 1:

Recruitment, Randomization and Patient Flow in the DOTS Trial

Figure 2:

Primary Outcome (As Randomized Population) A: Desirability of Outcome Ranking and Components by Treatment Group B: Table of Desirability of Outcome Rankings with Components C: Distribution of Desirability of Outcome Ranking by Treatment Group Desirability of Outcome Ranking with Quality-of-Life (QoL) tie-break represents the DOOR probability that a participant in the dalbavancin group will experience a more favorable outcome compared to a participant in the standard therapy group. In cases where 2 participants achieve the same DOOR, change in QoL is used as a tie-breaker 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% CI (confidence interval) calculated using the Halperin et al. (1989)’s method. If the 95% CI for the probability excluded the point of 50%, the difference in the DOOR endpoint between groups was regarded as significant. The individual components of the DOOR—clinical failure, non-fatal serious adverse events, adverse events leading to discontinuation, and QoL—were analyzed in the same manner as the DOOR. For clinical failure, non-fatal serious adverse events, and adverse events 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 were, therefore these participants were treated as having clinical failure. Rank 1: Alive with no events; Rank 2: Alive with 1 event; Rank 3: Alive with 2 events; Rank 4: Alive with 3 events. Details of adverse events leading to study drug discontinuation and clinical failures can be found in eTables 7 and 8.

Figure 2:

Primary Outcome (As Randomized Population) A: Desirability of Outcome Ranking and Components by Treatment Group B: Table of Desirability of Outcome Rankings with Components C: Distribution of Desirability of Outcome Ranking by Treatment Group Desirability of Outcome Ranking with Quality-of-Life (QoL) tie-break represents the DOOR probability that a participant in the dalbavancin group will experience a more favorable outcome compared to a participant in the standard therapy group. In cases where 2 participants achieve the same DOOR, change in QoL is used as a tie-breaker 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% CI (confidence interval) calculated using the Halperin et al. (1989)’s method. If the 95% CI for the probability excluded the point of 50%, the difference in the DOOR endpoint between groups was regarded as significant. The individual components of the DOOR—clinical failure, non-fatal serious adverse events, adverse events leading to discontinuation, and QoL—were analyzed in the same manner as the DOOR. For clinical failure, non-fatal serious adverse events, and adverse events 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 were, therefore these participants were treated as having clinical failure. Rank 1: Alive with no events; Rank 2: Alive with 1 event; Rank 3: Alive with 2 events; Rank 4: Alive with 3 events. Details of adverse events leading to study drug discontinuation and clinical failures can be found in eTables 7 and 8.

Figure 2:

Primary Outcome (As Randomized Population) A: Desirability of Outcome Ranking and Components by Treatment Group B: Table of Desirability of Outcome Rankings with Components C: Distribution of Desirability of Outcome Ranking by Treatment Group Desirability of Outcome Ranking with Quality-of-Life (QoL) tie-break represents the DOOR probability that a participant in the dalbavancin group will experience a more favorable outcome compared to a participant in the standard therapy group. In cases where 2 participants achieve the same DOOR, change in QoL is used as a tie-breaker 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% CI (confidence interval) calculated using the Halperin et al. (1989)’s method. If the 95% CI for the probability excluded the point of 50%, the difference in the DOOR endpoint between groups was regarded as significant. The individual components of the DOOR—clinical failure, non-fatal serious adverse events, adverse events leading to discontinuation, and QoL—were analyzed in the same manner as the DOOR. For clinical failure, non-fatal serious adverse events, and adverse events 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 were, therefore these participants were treated as having clinical failure. Rank 1: Alive with no events; Rank 2: Alive with 1 event; Rank 3: Alive with 2 events; Rank 4: Alive with 3 events. Details of adverse events leading to study drug discontinuation and clinical failures can be found in eTables 7 and 8.

Figure 2:

Primary Outcome (As Randomized Population) A: Desirability of Outcome Ranking and Components by Treatment Group B: Table of Desirability of Outcome Rankings with Components C: Distribution of Desirability of Outcome Ranking by Treatment Group Desirability of Outcome Ranking with Quality-of-Life (QoL) tie-break represents the DOOR probability that a participant in the dalbavancin group will experience a more favorable outcome compared to a participant in the standard therapy group. In cases where 2 participants achieve the same DOOR, change in QoL is used as a tie-breaker 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% CI (confidence interval) calculated using the Halperin et al. (1989)’s method. If the 95% CI for the probability excluded the point of 50%, the difference in the DOOR endpoint between groups was regarded as significant. The individual components of the DOOR—clinical failure, non-fatal serious adverse events, adverse events leading to discontinuation, and QoL—were analyzed in the same manner as the DOOR. For clinical failure, non-fatal serious adverse events, and adverse events 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 were, therefore these participants were treated as having clinical failure. Rank 1: Alive with no events; Rank 2: Alive with 1 event; Rank 3: Alive with 2 events; Rank 4: Alive with 3 events. Details of adverse events leading to study drug discontinuation and clinical failures can be found in eTables 7 and 8.

Figure 3:

Subgroup Analyses (As Randomized Population) A: Desirability of Outcome Ranking at Day 70 B: Clinical Efficacy at Day 70 A: The numbers display the number of participants by group in each subgroup. The 95% CIs (confidence interval) for the probability were calculated using the Halperin et al. (1989)’s method, except for pulmonary only subgroup. For the pulmonary-only subgroup, the pseudo-score approach based on Halperin et al. (1989) was used to calculate the CI, as the subgroup size was small and unbalanced between the groups. 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 renal abscesses, 1 surgical site infection, 1 inoculation via drug injection, 1 arm infection without specified depth, 1 peritonitis, 1 arteriovenous fistula infection, 1 sacroiliac infection. Any subjects missing a day 70 clinical efficacy assessment were considered clinical failures. B: The numbers display the number of clinical success 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 two-sample proportion. 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 renal abscesses, 1 surgical site infection, 1 inoculation via drug injection, 1 arm infection without specified depth, 1 peritonitis, 1 arteriovenous fistula infection, 1 sacroiliac infection. Any subjects missing a day 70 clinical efficacy assessment were considered clinical failures.