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Vancomycin versus daptomycin for the treatment of methicillin-resistant Staphylococcus aureus bacteremia due to isolates with high vancomycin minimum inhibitory concentrations: study protocol for a phase IIB randomized controlled trial

Shirin Kalimuddin1, Rachel Phillips2, Mihir Gandhi23, Nurun Nisa de Souza23, Jenny GH Low1, Sophia Archuleta45, David Lye6 and Thuan Tong Tan1*

Author Affiliations

1 Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore

2 Singapore Clinical Research Institute, 31 Biopolis Way, Singapore 138669, Singapore

3 Centre of Quantitative Medicine, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore

4 Division of Infectious Diseases, University Medicine Cluster, National University Health System, Kent Ridge Road, Singapore 119228, Singapore

5 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge Road, Singapore 119228, Singapore

6 Department of Infectious Diseases, Communicable Disease Centre, Tan Tock Seng Hospital, Moulmein Road, Singapore 308433, Singapore

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Trials 2014, 15:233  doi:10.1186/1745-6215-15-233

Published: 19 June 2014



Vancomycin is the standard first-line treatment for methicillin-resistant Staphylococcus aureus bacteremia. However, recent consensus guidelines recommend that clinicians consider using alternative agents such as daptomycin when the vancomycin minimum inhibitory concentration is greater than 1 ug/ml. To date however, there have been no head-to-head randomized trials comparing the safety and efficacy of daptomycin and vancomycin in the treatment of such infections. The primary aim of our study is to compare the efficacy of daptomycin versus vancomycin in the treatment of bloodstream infections due to methicillin-resistant Staphylococcus aureus isolates with high vancomycin minimum inhibitory concentrations (greater than or equal to 1.5 ug/ml) in terms of reducing all-cause 60-day mortality.


The study is designed as a multicenter prospective open label phase IIB pilot randomized controlled trial. Eligible participants will be inpatients over 21-years-old with a positive blood culture for methicillin-resistant Staphylococcus aureus with vancomycin minimum inhibitory concentration of greater than or equal to 1.5ug/ml. Randomization into intervention or active control arms will be performed with a 1:1 allocation ratio. We aim to recruit 50 participants over a period of two years. Participants randomized to the active control arm will receive vancomycin dose-while those randomized to the intervention arm will receive daptomycin. Participants will receive a minimum of 14 days study treatment.

The primary analysis will be conducted on the intention-to-treat principle. The Fisher’s exact test will be used to compare the 60-day mortality rate from index blood cultures (primary endpoint) between the two treatment arms, and the exact two-sided 95% confidence interval will be calculated using the Clopper and Pearson method. Primary analysis will be conducted using a two sided alpha of 0.05.


If results from this pilot study suggest that daptomycin shows significant efficacy in the treatment of bloodstream infections due to methicillin-resistant Staphylococcus aureus isolates with high vancomycin minimum inhibitory concentrations, we aim to proceed with a larger scale confirmatory study. This would help guide clinicians and inform practice guidelines on the optimal treatment for such infections.

Trial registration

The trial is listed on (NCT01975662, date of registration: 29 October 2013).

MRSA; Bacteremia; Daptomycin; Vancomycin