Emergence of Resistance during Therapy with Daptomycin for Infections due to Vancomycin-Resistant Enterococci (VRE)

Background: Development of daptomycin resistance in Vancomycin-resistant Enterococci (DR-VRE) during daptomycin therapy is a clinically important but rarely reported phenomenon.  

 

Objective: To describe the clinical and microbiologic characteristics of patients infected with VRE isolates which became non-susceptible to daptomycin during therapy.

Methods: We reviewed clinical records of all patients diagnosed with persistent VRE infections which became daptomycin non-susceptible during daptomycin therapy from 1/2010-11/2010. Isolate minimum inhibitory concentrations (MICs) were determined and susceptibility to daptomycin was interpreted per Clinical and Laboratory Standards Institute (CLSI) criteria. For available isolates, MICs were verified by two methods [MicroScan® (Siemens, Deerfield, IL) and Etest® (AB biomerieux, Solna, Sweden].

 

Results: Five patients developed VRE infections that became daptomycin resistant while receiving therapy. The median age was 60 and all 5 patients were male and immunosuppressed: 4 (80%) had hematologic malignancies and all were neutropenic at the time of VRE infection; 1 had (20%) had liver-kidney transplant. Four patients had vancomycin-resistant E. faecium bloodstream infections. All patients with VRE bloodstream infections had central lines in situ at the time and all of these patients had exchange of their central lines as part of therapy. The VRE in the remaining patient was associated with peritonitis. 3 (60%) patients had prior daptomycin exposure within 6 months prior to the VRE infection of interest. Treatment dose of daptomycin and the MIC of bacterial isolates are found in the Table. Two patients switched to linezolid and cleared the infection; one patient cleared VRE despite no change in therapy. Two (40%) patients died due to underlying disease.

Conclusions: VRE isolates from five immunosuppressed patients developed increased MICs to daptomycin while receiving daptomycin therapy.  This trend is of public health concern due to potential for widespread dissemination, risk of increased morbidity and mortality for patients as well as few therapeutic options that remain active against this pathogen. The exact cause for the emergence of elevated MICs remained unclear – the role of prior exposure to daptomycin needs to be specifically examined. Further studies should include surveillance for daptomycin susceptibility in VRE isolates, population studies to identify presence of daptomycin non-susceptible subpopulations in pre-treatment isolates of VRE as well as cell-wall and molecular characterization of these non-susceptible isolates.