Combination Therapy for MRSA Bloodstream Infections: Still a Question Mark

The addition of a β-lactam to a daptomycin regimen for patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections was associated with significantly reduced odds of clinical failure in a retrospective, comparative cohort study. But acute kidney injury was more common in the combination arm, indicating that additional research is still necessary.

The question of combination therapy versus monotherapy for MRSA bloodstream infections is one that is widely debated. In this new analysis, a team of investigators from Wayne State University and the University of California at San Francisco conducted research at 2 academic medical centers between 2008 and 2018. The results were published recently in Clinical Infectious Diseases.

“Combination of vancomycin or daptomycin with a β-lactam has been shown in vitro to be synergistic and has the potential to decrease the emergence of resistance in S aureus,” Michael J. Rybak, PharmD, MPH, PhD, professor of pharmacy & medicine at the Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy & Health Sciences at Wayne State University, and co-author on the study, told Contagion® of the motivation behind the research.

“Most clinical studies to date have shown a benefit in shortening the days of bacteremia, however, there is limited evidence thus far that combination therapy has improved outcomes such as mortality or recurrence of infection,” he said.

In this trial, participants included 229 adults with MRSA bloodstream infections who were treated with daptomycin >72 hours and for whom treatment was initiated within 5 days of culture collection. Participants in the daptomycin/β-lactam (DAP+BL) group received a β-lactam for ≥24 hours and initiated within 24 hours of daptomycin.

The primary outcome in the study was composite clinical failure (60-day all-cause mortality and/or 60-day recurrence), and the analysis was adjusted for confounding using inverse probability of treatment weighting.

A total of 72 participants were included in the DAP+BL group, compared with 157 participants in the daptomycin group. The combination arm was associated with improved clinical outcomes (odds ratio [OR] 0.362, 95% confidence interval [CI] 0.164, 0.801; adjusted OR 0.386, 95% CI 0.175, 0.853).

“DAP plus β-lactam therapy was associated with reduced composite definition for clinical failure (mortality and recurrence of infection). There was no difference in days of bacteremia,” Rybak, a member of the Contagion® Editorial Advisory Board, explained. “There was a higher rate of nephrotoxicity in the combination compared with the monotherapy group (10.8% vs. 2.9%; P = 0.046), and rates of Clostridioides difficile-associated diarrhea were higher vs. the monotherapy group but not statistically significant (1.3 vs. 5.6%).”

The team was surprised that the days of bacteremia were not shorter in the combination therapy arm.

“While the combination of daptomycin plus a β-lactam looks promising as a treatment option for serious MRSA infections, further research in well-controlled clinical trials are needed,” Rybak concluded.

In an accompanying editorial by Thomas L. Holland, MD, assistant professor of medicine at Duke University School of Medicine, and Joshua S. Davis, MBBS, FRACP, DTM&H, PhD, of the Menzies School of Health Research at Charles Darwin University in Australia, highlighted the significance of the new study’s findings in the larger context.

“We now have a relative abundance of small studies suggesting that β-lactam therapy is of net benefit for MRSAB. What about larger clinical trials?” they wrote. “There’s the rub—for when we remove selection bias and expose adjunctive treatments to the whips and scorns of adequately powered randomized trials, unexpected truths may emerge.”