A National Institutes of Health (NIH)-supported clinical trial has found that the outcome of treating complicated Staphylococcus aureus bloodstream infections with two intravenous (IV) doses of the antibiotic dalbavancin seven days apart is just as good as daily IV doses of conventional antibiotics over four to six weeks. Nearly 120,000 S. aureus bloodstream infections and 20,000 associated deaths occurred in the United States in 2017. The study results provide the clearest evidence to date for the safety and effectiveness of dalbavancin therapy for complicated S. aureus bloodstream infections, expanding the number of antimicrobial treatment options for clinicians and patients. The findings were published today in the Journal of the American Medical Association.
"Given the small number of antimicrobial drugs available to treat Staphylococcus aureus bloodstream infections and the bacteria's growing drug resistance, establishing dalbavancin as a beneficial therapy for these severe infections gives us a vital new alternative to treat them," said John Beigel, M.D., the acting director of the Division of Microbiology and Infectious Diseases at NIH's National Institute of Allergy and Infectious Diseases (NIAID), which sponsored and funded the trial.
Standard therapy for complicated S. aureus bloodstream infections, or bacteremia, typically involves inserting a long IV line known as a peripherally inserted central catheter (PICC) into a vein, usually in the arm, to deliver antibiotics through the blood for many weeks. The PICC line remains in place for the full duration of treatment, and people with a PICC line have many limitations on their activity to avoid damaging the line. Its long-term presence and use can lead to complications such as blood clots and additional infections. By contrast, dalbavancin therapy requires temporarily inserting a short catheter into a vein in the hand or arm twice for only an hour at a time. Given these differences, the investigators who designed the trial hypothesized that study participants who received dalbavancin therapy would have fewer side effects, higher rates of treatment completion, and a better quality of life than those who received standard therapy.
The Phase 2b trial enrolled 200 hospitalized adults with complicated S. aureus bacteremia at 23 medical centers in the United States and Canada from 2021 to 2023. The participants initially received three to 10 days of preliminary treatment with a broad-spectrum antibiotic, had no fever, and lacked detectable S. aureus in their blood when it was cultured in a laboratory. The bacteria could still be present below the limit of detection, however. For study purposes, complicated bacteremia was defined as any case not meeting criteria for uncomplicated bacteremia according to the Infectious Diseases Society of America's 2011 guidelines.
Participants were assigned at random to receive either dalbavancin 1500 mg intravenously on days one and eight, or standard therapy for four to eight weeks. The antibiotics used as standard therapy were cefazolin or an anti-Staphylococcal penicillin for methicillin-susceptible S. aureus and vancomycin or daptomycin for methicillin-resistant S. aureus (MRSA), with the amount and frequency of dosing determined by each study site.
The study team evaluated the likelihood that a participant randomly selected from the dalbavancin group would have a better overall treatment outcome than a participant randomly selected from the standard therapy group. The components of overall outcome were clinical success (survival with resolution of bacteremia), infectious complications, safety complications, death, and health-related quality of life. In measuring outcomes this way, the researchers aimed to capture not only the end result of antibiotic therapy, but also participants' treatment-related experiences during therapy. A committee of four infectious disease experts ranked study participants based on the desirability of their overall treatment outcome after 70 days of therapy. To avoid risk of bias, the committee did not know which treatment the participants received.
The study team also did a more conventional analysis comparing the efficacy and safety of dalbavancin therapy to standard therapy.
Investigators found that a participant randomly selected from the dalbavancin group was 47.7% likely to have a better overall treatment outcome than a participant randomly selected from the standard therapy group, meaning dalbavancin was not superior to standard therapy. However, the individual components of overall outcome, such as clinical success, were similar for the two groups, suggesting that dalbavancin therapy and standard therapy were equally good. This was reinforced by the finding from the conventional analysis that dalbavancin and standard therapy were similarly safe and effective.
"Our findings give patients and healthcare providers the data to support an extra choice when deciding on treatment for complicated S. aureus bacteremia," said Nicholas A. Turner, M.D., assistant professor of medicine at Duke University School of Medicine in Durham, North Carolina, and first author of the study.
To the investigators' surprise, study participants in the two groups reported a similar health-related quality of life. It is unclear whether this is because the quality-of-life survey given to participants at each study visit failed to capture relevant differences between the groups, or because the way the antibiotics were delivered had little effect on participants' treatment experiences.
As expected, the rate of side effects leading to treatment discontinuation and of complications such as catheter-associated blood clots were greater in the standard therapy group than the dalbavancin therapy group. Yet the overarching similarities in the components of overall outcome diluted these differences.
To further compare the two types of therapy for complicated S. aureus bacteremia, the investigators are analyzing their cost effectiveness.
Called "Dalbavancin as an Option for Treatment of S. aureus Bacteremia" (DOTS), the study was conducted by the NIH's Antibacterial Resistance Leadership Group under the leadership of Thomas L. Holland, M.D. Dr. Holland is a professor of medicine at the Duke University School of Medicine and a member of the Duke Clinical Research Institute in Durham, North Carolina.
