Editorial Commentary: Linezolid vs Daptomycin for Vancomycin-Resistant Enterococci: The Evidence Gap Between Trials and Clinical Experience

Bloodstream infections due to vancomycinresistant enterococcal species (VRE-BSI) can be a lethal complication for hospitalized patients. VRE-BSI principally affects vulnerable patient populations, including complex postsurgical and internal medicine patients withmultiple comorbid conditions [1–6]. VRE-BSI has particularly high attributable mortality in hematopoietic stem cell transplant recipients, liver transplant recipients, oncology patients, and other critically ill hospitalized populations [5–13]. Despite the high human and economic burden of VRE-BSI, the optimal treatment for these infectionshasnotbeenestablished, and due to the fact that most enterococcal isolates (ie, E. faecium) aremultidrug-resistant, clinicians are often faced with no reliable therapeutic options in critically ill patients. Linezolid is the only drug specifically approved by the Food and Drug Administration (FDA) for the treatment of VRE-BSI. However, studies leading to approval were based on limited data in an erawhere even fewer treatment options were available [6,7].Two phase-III clinical trials for VRE-BSI were started but were subsequently aborted due to enrollment difficulties [14, 15]. Additionally, there have been concerns that linezolid may not be optimal in deep-seated VRE infections. Linezolid is a bacteriostatic agent, and its activity may not be ideal for patients with severe VRE infections including those with infective endocarditis and other endovascular infections. Furthermore, linezolid toxicity when administered for prolonged courses may limit its use in VRE endocarditis. Due to the above issues and despite lacking FDA approval for VRE infections, daptomycin (DAP, a lipopeptide antibiotic with in vitro bactericidal activity against VRE) has become a first-line agent to treat severe VRE infections. Although robust clinical evidence for the use of daptomycin for this indication is lacking, its in vitro profile and perceived clinical success [16] has made DAP attractive for clinicians. However, the use of DAP for these infections have several caveats including, (i) emergence of resistance during therapy, (ii) the presence of mutations associated with DAP-resistance in isolates that are currently reported as DAP “susceptible” (minimum inhibitory concentrations [MICs] 3–4 μg/mL, breakpoint 4 μg/mL) that may jeopardize DAP clinical utility as monotherapy, and (iii) the optimal DAP dosing for VRE infections has not been established with some in vitro data suggesting that doses of 10–12 mg/kg should be used to prevent development of resistance [17], a notion that is also supported by some clinical data indicating better outcomes with higher doses [18, 19]. There have been 3 independent systematic reviews of the literature with meta-analysis that sought to compare DAP or linezolid for treatment of VREBSI [20–22]. Although the studies differed in some regards, all 3 meta-analysis suggested a survival benefit of linezolid over DAP.What was perhapsmore impressive than the meta-analysis results was the fact that all 3 investigations found significant methodological limitations to the Received 27 May 2015; accepted 1 June 2015; electronically published 10 June 2015. Correspondence: James A. McKinnell, MD, Infectious Disease Clinical Outcomes Research Unit (ID-CORE), LA-Biomed Research Institute at Harbor-UCLA, 1124 West Carson St, Box 466, Torrance, CA 90502 ([email protected]). Clinical Infectious Diseases 2015;61(6):879–82 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of thework, in anymedium, provided theoriginalwork is not altered or transformed in anyway, and that thework is properly cited. For commercial re-use, please contact journals.permissions@oup. com. DOI: 10.1093/cid/civ449