A randomized phase 2B trial of vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations - results of a prematurely terminated study

Abstract

Background: Studies have suggested the reduced effectiveness of vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections with high vancomycin minimum inhibitory concentrations. Alternative agents such as daptomycin may be considered. We conducted a randomized controlled study comparing daptomycin against vancomycin in the treatment of MRSA bloodstream infections with high vancomycin minimum inhibitory concentrations.

Methods: Patients were randomized to receive vancomycin or daptomycin for a minimum of 14 days. The primary end point was the rate of all-cause mortality at day 60.

Results: A total of 14 patients were randomized in this study, with 7 patients in each treatment arm. The study was terminated early due to slow patient accrual. At day 60, there was one death in the vancomycin arm and none in the daptomycin arm. The median time to microbiological clearance was 4 days in both arms (IQR 3-5 days in the vancomycin arm and 3-7 days in daptomycin arm). Only one patient in the vancomycin arm had recurrence of bacteremia. Rates of adverse events were similar in both arms. There was one case of musculoskeletal toxicity and one case of drug-related nephrotoxicity - both events occurred in the daptomycin arm. None of the patients in either treatment arm required cessation of study treatment or addition of a second anti-MRSA agent because of worsening infection.

Conclusion: Based on the limited number of patients evaluated in this study, it remains unclear if alternative, more expensive agents such as daptomycin are superior to vancomycin in the treatment of high vancomycin minimum inhibitory concentration MRSA bloodstream infections. More studies are urgently needed but investigators may wish to consider employing novel, alternative trial methodologies to ensure a greater chance of success.

Trial registration: ClinicalTrials.gov, NCT01975662 . Registered on 5 November 2013.

Keywords: Bacteremia; Daptomycin; Methicillin-resistant Staphylococcus aureus; Minimum inhibitory concentration; Vancomycin.

Conflict of interest statement

Ethics approval and consent to participate

The trial was granted ethics approval by the Singhealth Centralized Institute Review Board (CIRB) (approval ID 2013/846/E). Written informed consent was obtained from all patients before enrolment into the study.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Patient allocation into the study populations. “Significant conditions” included any condition in the investigator’s opinion that would compromise the patient’s safety in the trial. Reasons for exclusion listed under “others” included inability to comply with study treatments and procedures (n = 2), inability to provide consent (n = 1), prosthetic heart valve in situ (n = 1), creatine kinase (CK) ≥ 1.5 upper limit of normal (n = 1), on treatment with linezolid for more than 96 h prior to enrolment (n = 1), and patient demise prior to consent (n = 2). MRSA, methicillin-resistant Staphyloccus aureus; MIC, minimum inhibitory concentration