Medical device infections (MDI) caused by vancomycin resistant Enterococcus (VRE) are associated with a high rate of treatment failure and increased mortality. Infections due to vancomycin-resistant Enterococcus faecium (VREF) are more problematic than any other species of enterococci since these organisms are associated with the highest rate of vancomycin resistance and are often multi-drug resistant making treatment more difficult due to the limited available antimicrobial options. MDI are one of the most difficult infections to treat because of the high association with biofilm producing pathogens, which represents a significant barrier for effective antibiotic therapy. Daptomycin, a novel lipopeptide antibiotic, rapidly penetrates biofilms and exerts bactericidal activity against metabolically active or arrested enterococci, including VREF. The daptomycin dose for VRE to optimize patient outcomes and prevent the emergence of resistance during MDI, however, is currently unknown. In addition, there is little to no information regarding the optimal daptomycin drug combination to treat VRE MDI. Therefore, there are two potential strategies to optimize daptomycin therapy for VRE MDI. One is daptomycin dose optimization and the other strategy is the use of combination therapy. The long-term goal is to optimize patient outcomes and preserve daptomycin therapy for VRE MDI infections through utilization of the ideal dose exposure to prevent daptomycin resistance in enterococci. The overall objective for this study is to define the dose-exposure breakpoint (pharmacokinetic/pharmacodynamic [PK/PD] breakpoint) for daptomycin resistance prevention in biofilm embedded VREF and the correlating breakpoint when daptomycin is combined with other antimicrobials. The central hypothesis is that higher daptomycin dose exposures alone or in antibiotic combination are needed against biofilm embedded VREF to prevent the emergence of resistance compared to dose exposures using planktonic VREF. The rationale behind the proposed research is that data on the daptomycin dose relationship with biofilm embedded enterococci will lead to clinical dose optimization, improved patient outcomes, reduced emergence of resistance, and preservation of daptomycin as a viable antibiotic for clinical use. The central hypothesis will be tested by pursuing two Specific Aims: 1) Determine the dose-exposure breakpoints for daptomycin resistance using biofilm embedded molecularly defined and clinical strains of VREF to determine the optimal dose;and 2) Identify the optimal dose-exposure of daptomycin in combination with ampicillin or rifampin that is associated with the prevention of the development of VREF resistance. The proposed research is innovative because we will utilize an in vitro biofilm PK/PD model that simulates drug exposures in humans. This technique allows for frequent assessment of antibiotic activity as well as observation of changes in the organism susceptibility as it relates to specific drug exposures over time. The research proposed in this application is significant because it is expected to provide the knowledge needed to understand the resistance characteristics of biofilm embedded enterococci and their relationship to daptomycin dose exposure that will lead to dose optimization resulting in improved patient outcomes, and preservation of daptomycin as a viable therapeutic option for the treatment of enterococcal MDI.

Public Health Relevance

The preservation of available antibiotics to treat multidrug resistant bacterial infections is a vital public health initiative. Medical device infections (MDI)due to biofilm producing vancomycin resistant enterococci are associated with increased mortality and limited treatment options. The overall goal of this project is to determine the optimal dose of daptomycin alone or in combination with other antibiotics for MDI due to enterococci which will allow for better understanding and treatment of this infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI109266-01
Application #
8620019
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Huntley, Clayton C
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wayne State University
Department
Public Health & Prev Medicine
Type
Schools of Pharmacy
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Zasowski, Evan J; Murray, Kyle P; Trinh, Trang D et al. (2018) Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin. Antimicrob Agents Chemother 62:
Garcia-de-la-Maria, C; Xiong, Y Q; Pericas, J M et al. (2017) Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis. Antimicrob Agents Chemother 61:
Mishra, Nagendra N; Tran, Truc T; Seepersaud, Ravin et al. (2017) Perturbations of Phosphatidate Cytidylyltransferase (CdsA) Mediate Daptomycin Resistance in Streptococcus mitis/oralis by a Novel Mechanism. Antimicrob Agents Chemother 61:
Finch, Natalie A; Zasowski, Evan J; Murray, Kyle P et al. (2017) A Quasi-Experiment To Study the Impact of Vancomycin Area under the Concentration-Time Curve-Guided Dosing on Vancomycin-Associated Nephrotoxicity. Antimicrob Agents Chemother 61:
Zasowski, Evan J; Trinh, Trang D; Claeys, Kimberly C et al. (2017) Multicenter Observational Study of Ceftaroline Fosamil for Methicillin-Resistant Staphylococcus aureus Bloodstream Infections. Antimicrob Agents Chemother 61:
Hall Snyder, Ashley D; Werth, Brian J; Nonejuie, Poochit et al. (2016) Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model. Antimicrob Agents Chemother 60:5716-23
Karino, Shigehiko; Kaye, Keith S; Navalkele, Bhagyashri et al. (2016) Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship. Antimicrob Agents Chemother 60:3743-50
Zasowski, Evan J; Claeys, Kimberly C; Lagnf, Abdalhamid M et al. (2016) Time Is of the Essence: The Impact of Delayed Antibiotic Therapy on Patient Outcomes in Hospital-Onset Enterococcal Bloodstream Infections. Clin Infect Dis 62:1242-1250
Brade, Karrine D; Rybak, Jeffrey M; Rybak, Michael J (2016) Oritavancin: A New Lipoglycopeptide Antibiotic in the Treatment of Gram-Positive Infections. Infect Dis Ther 5:1-15
Claeys, Kimberly C; Zasowski, Evan J; Casapao, Anthony M et al. (2016) Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections. Antimicrob Agents Chemother 60:5841-8

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