Oritavancin for the Treatment of Daptomycin Nonsusceptible Vancomycin-Resistant Enterococci Osteomyelitis Rachel A. Foster, PharmD, MBA,*† Kingsavanh Paul Philavong, BS,* Sharon Weissman, MD,‡ Xiaonan Tang, PhD,§, and P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP*† Abstract: Vancomycin-resistant enterococci (VRE) are a growing cause of health care–associated infections globally, and limited treatment options exist for invasive VRE infections. Daptomycin is commonly used with modest suc- cess in the treatment of deep-seated infections secondary to VRE; however, there is concern for the emergence of daptomycin nonsusceptible VRE, es- pecially during protracted courses, as required in osteomyelitis. We report the clinical and microbiologic success of a once-weekly, 6-week course of oritavancin with therapeutic drug monitoring in the treatment of daptomycin nonsusceptible VRE osteomyelitis secondary to prosthetic hip replacement. Our data suggest favorable pharmacokinetics and no treatment-related adverse events with once-weekly dosing. This report provides compelling information for future studies of prolonged oritavancin regimens in deep-seated infections. Key Words: daptomycin, pharmacokinetics, prosthesis, oritavancin, osteomyelitis, vancomycin-resistant enterococci (Infect Dis Clin Pract 2017;00: 00–00) V ancomycin-resistant enterococci (VRE) are a growing cause of health care–associated infections globally. 1 According to the National Healthcare Safety Network data, vancomycin resistance was 82.6% among 2118 Enterococcus faecium isolates recovered from bloodstream infections, an overall increase by 2.5% compared with data from 2007–2008. 1 Comparatively, VRE is associated with increased mortality, hospital length of stay, costs, and admissions to long-term-care facilities. 2 Limited treatment options exist for inva- sive VRE infections. Tolerability concerns and the static nature of antibiotics like quinupristin/dalfopristin, tigecycline, and the oxazolidinones limit use of these agents, especially for prolonged durations. Daptomycin is commonly used with modest success in the treatment of deep-seated infections secondary to VRE; however, there is concern for the emergence of daptomycin nonsusceptible (DNS) VRE, especially during protracted courses, as required in osteomyelitis. 3–5 CASE REPORT We report a case of DNS VRE and Pseudomonas aeruginosa femoral osteomyelitis secondary to an ongoing right hip infection in a 57-year-old man complicated by the presence of retained hardware and an extensive orthopedic surgical history. The patient originally suffered a femur fracture following a motor vehicle ac- cident 3 decades prior to the index admission and underwent a to- tal hip arthroplasty and placement of a femoral rod at the time of the accident. Multiple surgical revisions occurred in the years fol- lowing, including placement of antibiotic-impregnated cement (vancomycin and aminoglycosides), multiple washouts, and most recently a partial removal of the hip implant. The patient was admitted for wound dehiscence and serous drainage at the surgical site 4 months after hip implant. The patient underwent incision and drainage with antibiotic bead removal and a proximal resection of osteolytic femoral bone on hospital day (HD) 1 of the index admission. The femoral rod was left in place. No obvious intraoperative signs of infection were present, but the patient was empirically started on daptomycin and ciprofloxacin following surgery. Two intraoperative tissue cultures from the right hip and proximal femur grew E. faecium and P. aeruginosa. The susceptibility profile (VITEK 2, bioMérieux, Inc., Durham, NC) for E. faecium demonstrated the following: intermediate susceptibility to doxycycline (minimum inhibitory concentra- tion [MIC] 8 mg/L) and linezolid (MIC 4 mg/L), resistance to vancomycin (MIC ≥32 mg/L), high-level gentamicin resistance, and an elevated MIC (6 mg/L) to daptomycin by E-test. No com- mercially available in vitro susceptibility testing for oritavancin was available at the time. The patient remained on daptomycin plus ciprofloxacin until HD 21, at which time an infectious diseases specialist was consulted. Daptomycin was discontinued, and ori- tavancin 1200 mg intravenously once weekly was initiated on HD 27 for a target duration of 6 weeks. The ciprofloxacin was continued for an additional 3 weeks from infectious diseases con- sultation, to complete 6 weeks of therapy. The remaining femoral hardware was removed, and daptomycin-impregnated cement was placed during wound closure on HD 33. Oritavancin plasma con- centrations were obtained 48 and 168 hours after administration following the second and third doses and at 3 hours after admin- istration of the second dose to confirm the dosing strategy. Phar- macokinetic parameters are shown in Table 1. Bone cultures from the distal femur obtained in the operating room on HD 33 revealed no growth. The patient tolerated the 6-week oritavancin course, with no adverse events (AEs). Intraop- erative bone cultures were obtained 9.5 months after the comple- tion of oritavancin, which again revealed no growth. No serologic inflammatory markers were obtained during either admission. The patient was deemed to be infection-free and underwent com- pletion of the 2-stage hip revision 9.5 months after the completion of oritavancin. He remains infection-free 5 months following the completion of the revision. DISCUSSION In the current case, the VRE isolate showed elevated MICs for daptomycin and linezolid, prompting the need for alterna- tive antimicrobial therapy. Oritavancin is a US Food and Drug Administration–approved lipoglycopeptide for the treatment of gram-positive acute bacterial skin and skin structure infections From the *Department of Clinical Pharmacy and Outcomes Science, University of South Carolina College of Pharmacy; †Department of Pharmacy, Palmetto Health; and ‡Department of Medicine, Division of Infectious Diseases, University of South Carolina School of Medicine, Columbia, SC; and §Frontage Laboratories Inc, Exton, PA. Correspondence to: P. Brandon Bookstaver, PharmD, FCCP, FIDSA, BCPS, AAHIVP, Department of Clinical Pharmacy & Outcomes Sciences, University of South Carolina College of Pharmacy, 715 Sumter St, Columbia, SC 29208. E‐mail: bookstaver@cop.sc.edu. This study was carried out as part of standard patient care. The data in this study were presented at the South Carolina Society of Health-System Pharmacists Annual Meeting, Hilton Head Island, SC, March 13, 2016 (abstract 1). P.B.B. receives consultation funds from Rockpointe, Inc; research funding from Allergan, Inc; and scientific advisory funds from Allergan, Inc. R.A.F., K.P.P., S.W., and X.T. have no conflicts of interest to disclose. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1056-9103 CASE REPORT Infectious Diseases in Clinical Practice • Volume 00, Number 00, Month 2017 www.infectdis.com 1 Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.