By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A randomized, double-blind, placebo-controlled clinical trial of adults aged 18 years and older found that adjunctive daptomycin did not shorten the duration of methicillin-susceptible Staphylococcus aureus bacteremia compared to monotherapy with an antistaphylococcal beta-lactam antibiotic.

SOURCE: Cheng MP, Lawandi A, Butler-Laporte G, et al. Adjunctive daptomycin in the treatment of methicillin-susceptible Staphylococcus aureus bacteremia: A randomized, controlled trial. Clin Infect Dis 2021;72:e196-e203.

Despite the availability of seemingly effective antibiotics, bacteremia due to methicillin-sensitive Staphylococcus aureus (MSSA) still causes significant complications. Although the incidence of methicillin-resistant S. aureus (MRSA) bacteremia has been declining in the United States, MSSA bacteremia has been increasing. Thus, the evaluation of promising treatment regimens remains a priority. Cheng and colleagues sought to determine whether the addition of daptomycin to standard-of-care therapy (i.e., cefazolin or cloxacillin) would shorten the duration of MSSA bacteremia through the Daptomycin as Adjunctive Therapy for Staphylococcus aureus Bacteremia in Hospital (DASH) study.

DASH was a randomized, double-blind, placebo-controlled trial conducted at two medical centers in Montreal, Canada. The inclusion criteria were age 18 years or older, documented monomicrobial bloodstream infection (BSI) due to MSSA, and enrollment within 72 hours from the first positive blood culture. Exclusion criteria were a polymicrobial infection, an expectation that the patient would die within five days, inability to receive an antistaphylococcal beta-lactam (ASBL) drug or daptomycin, receipt of additional antibiotic therapy, or a known type I hypersensitivity reaction to any of the antibiotics in the study.

The choice of the ASBL (cefazolin or cloxacillin) was up to the treating clinician. The subjects were randomized to receive either 6 mg/kg of intravenous (IV) daptomycin once daily for five days or a matching placebo, along with an ASBL. Two sets of blood cultures were obtained daily for five days or until the bacteremia cleared. The primary outcome was the total duration of MSSA bacteremia. A sensitivity analysis determined that to achieve 80% power for the primary outcome, at least 102 subjects would be needed to detect a one-day difference in duration of bacteremia at a significance of 5%.

One hundred fifteen patients were enrolled in the study, with 104 included in the final intention-to-treat (ITT) population. Fifty-one patients received placebo and 53 received daptomycin. The median age was 67 years (range, 56-73 years) and 36 (34.6%) were women. The median Charlson comorbidity index was 5. The most common sources of MSSA bacteremia were endovascular (39.4%), skin and soft tissue infections (24.0%), osteomyelitis (7.7%), and pneumonia (6.7%). Most patients received cefazolin (73.1%). The follow-up rate was 100% for all outcomes, including 90-day mortality.

The median duration of MSSA bacteremia was 3.1 days in the daptomycin group vs. 3.0 days in the placebo group in the modified intention-to-treat population, and 2.04 days in the daptomycin group vs. 1.65 days in the placebo group in the entire intention-to-treat population. The all-cause mortality at 90 days was 18.9% in the daptomycin group and 17.7% in the placebo group (odds ratio, 1.08; 95% confidence interval, 0.36-3.35; P = 1.0). There were two relapses in both groups at 90 days. More patients in the placebo group died from MSSA-related complications, but the difference was not statistically significant (P = 0.15). Finally, there were no significant differences in toxicities (i.e., renal failure, hepatotoxicity, or rhabdomyolysis) between the two groups.

COMMENTARY 

Despite decades of antibiotic use, the optimal management of MSSA bacteremia remains unclear. Combination therapy in the absence of endocarditis has been controversial, with some studies showing a benefit, while many others have not.1 Moreover, daptomycin previously was found to have in vitro synergy when combined with an ASBL. The study by Cheng and colleagues adds to this body of evidence by showing that the addition of daptomycin to an ASBL does not reduce the duration of MSSA bacteremia. Thus, daptomycin should not be prescribed concurrently with an ASBL for MSSA bacteremia outside of a clinical trial.

There were a few limitations to the study worth mentioning. First, although it did achieve the predefined sample size to reach 80% power, the number of patients enrolled was relatively small for a clinical trial. Second, the authors did not compare outcomes between the two ASBLs used in the study, although the small number of patients (n = 51) likely would have made such an analysis unreliable. Third, 65% of the patients were male, but it seems unlikely the results would have been different had the ratio of males to females been more equal. Finally, whether patients received antibiotic therapy after the study was finished was not controlled for and could have affected the 90-day mortality, although this value was similar in both groups.

So what is the impact of this study on the broader scientific agenda examining combination therapy for MSSA bacteremia? Other agents also have been found to not be useful in combination with a beta-lactam, including gentamicin and rifampin. Indeed, it is becoming increasing clear that “less is more” regarding antibiotics and MSSA bacteremia. Further clinical trials are needed to clarify the optimal agent (e.g., antistaphylococcal penicillins vs. cefazolin) along with its duration, dosing regimen, and ways to mitigate toxicities, especially when used for prolonged periods. 

REFERENCE

  1. Giannella M, Bartoletti M, Gatti M, Viale P. Advances in the therapy of bacterial bloodstream infections. Clin Microbiol Infect 2020;26:158-167.