Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial

Abstract

Background: Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population.

Methods: The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients.

Discussion: The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis.

Trial registration: ClinicalTrials.gov, NCT02972983 . Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pdf.

Keywords: Bacteremia; Beta-lactam; Daptomycin; Staphylococcus aureus.

Conflict of interest statement

Ethics approval and consent to participate

The DASH-RCT trial was reviewed and approved by the McGill University Health Center Research Ethics Board. Informed consent will be obtained from all patients recruited to the study prior to study participation.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Time and events scheduled for patients enrolled into the DASH-RCT. *Refers to the first day post-allocation. 1Routine antimicrobial susceptibility testing is performed on the first methicillin-susceptible Staphylococcus aureus isolate of each patient. 2The minimal inhibitory concentration (MIC) to daptomycin is performed by Etest® on the first methicillin-susceptible S. aureus isolate of each patient. 3Two sets of blood cultures are obtained daily for 5 days or until microbiological clearance is documented, whichever is longer. 4Hepatic profile includes aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and total bilirubin. 5Electrolytes include sodium, potassium, chloride, and bicarbonate. 6A symptom questionnaire is administered on day 5 to assess patients for nausea, vomiting, headaches, and myalgia

Fig. 2

Identification algorithm utilized for methicillin-susceptible Staphylococcus aureus