1399. Efficacy of Daptomycin Combination with ß-lactams for Daptomycin Resistant Enterococcus faecium Harboring LiaSR Substitutions
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • RO1-1-10-18-17.5.pdf (6.6 MB)
  • Background:

    Daptomycin (DAP) is one of the mainstay treatments for Enterococcus faecium infections. However, development of resistance threatens its continued viability as a treatment option. Although the mechanisms of DAP resistance in enterococci are not fully comprehended, they are associated with alterations in cell envelope phospholipids assembly which leads to repulsion of the drug from cell exterior and diversion from the cell septum. Previous data suggests that combination of DAP with ß-lactams has the potential to improve patient outcomes. In this investigation, we sought to evaluate combinations of DAP with ampicillin (AMP), ceftaroline (CPT), and ertapenem (ERT).

    Methods:

    E. faecium R497 harboring liaSFR mutations (DAP MIC of 16 mg/L) was evaluated in a simulated endocardial vegetation (SEV) pharmacokinetic and pharmacodynamic model over 336 h at a starting inoculum of 109 log10 CFU/g of SEV. DAP alone at 10 mg/kg/day or DAP (6,8,10 mg/kg/day) in combination with AMP (2 g continuous infusion), CPT 600 mg q 12 h or ERT 1 g q 24 h were evaluated. The emergence of DAP resistance was determined daily over the course of the 14-day experiment.

    Results:

    DAP alone was not bactericidal and high-level DAP resistance was observed (MIC increase from 16 to 256 µg/ml) for all DAP alone regimens. Combination of DAP+AMP offered a significant reduction in log10CFU/g amounts (Up to 7 log10 CFU/g and to detection limits) in 24h in DAP10+AMP model with no further emergence of DAP resistance. Even in DAP 6 mg/kg/d with AMP (2g), dramatic killing with no further emergence of resistance was observed. Neither CPT nor ERT in combination with DAP was effective against this strain. At higher doses of DAP (14 mg/kg/day)+CPT or ERT, a temporary (0-48h) CFU/g reduction was observed followed by regrowth and the further emergence of DAP resistance.

    Conclusion:

    Combination of DAP+ AMP offered the most encouraging results against E. faecium R497. A DAP dose sparring effect was noted with DAP + AMP but not with CPT or ERT. The reason for the discrepancy is unknown and is under further investigation. Further evaluation of DAP plus beta-lactam therapy is warranted to discover the most optimized DAP and ß-lactam therapy to improve patient outcome and prevent the emergence of resistance.

    Razieh Kebriaei, Ph.D.1, Seth Rice, BSc2, Kavindra Singh, Ph.D.3, Kyle Stamper, BSc4, An Dinh, BS5, Rafael Rios, MSc6, Lorena Diaz, PhD6, Barbara Murray, M.D.7, Jose M. Munita, MD8, Truc T. Tran, PharmD5, Cesar Arias, MD, PhD, FIDSA9 and Michael J. Rybak, PharmD, MPH, PhD10, (1)Antiinfective Research Laboratory, Department of Pharmacy Practice, Wayne State University, Eugene Applebaum College of Pharmacy & health Sciences, Detroit, MI, (2)Pharmacy Practice, Wayne State University, Detroit, MI, (3)Center for Antimicrobial Resistance and Microbial Genetics (CARMiG), University of Texas McGovern Medical School, Houston, TX, (4)Wayne State University, Detroit, MI, (5)Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, TX, (6)Molecular Genetics and Antimicrobial Resistance Unit - International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia, (7)Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, TX, (8)Instituto De Ciencias e Innovacion En Medicina (ICIM), Clinica Alemana Universidad del Desarrollo, Santiago, Chile, (9)Microbiology and Molecular Genetics, University of Texas McGovern Medical School, Houston, TX, (10)259 Mack Ave, Suit 4131, Eugene Applebaum College of Pharmacy and Health Sciences Bldg, 259 Mack Ave, Detroit, MI

    Disclosures:

    R. Kebriaei, None

    S. Rice, None

    K. Singh, None

    K. Stamper, None

    A. Dinh, None

    R. Rios, None

    L. Diaz, None

    B. Murray, Paratek pharmaceuticals: Consultant and Scientific Advisor , Consulting fee and Speaker honorarium . Forest/Actavis: Grant Investigator , Grant recipient . Cubist/Merck: Grant Investigator , Grant recipient .

    J. M. Munita, None

    T. T. Tran, None

    C. Arias, Merck & Co., Inc.: Grant Investigator , Research support . MeMed: Grant Investigator , Research support . Allergan: Grant Investigator , Research support .

    M. J. Rybak, Allergan: Consultant , Grant Investigator and Speaker's Bureau , Research grant and Research support . Achaogen: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Bayer: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Melinta: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Merck: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Theravance: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Sunovian: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . Zavante: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support . NIAID: Consultant , Grant Investigator and Speaker's Bureau , Consulting fee , Research grant and Research support .

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