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    Influence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutions

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    TY - GEN T1 - Influence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutions UR - http://hdl.handle.net/20.500.12495/2320 PB - American Society for Microbiology AB - ER - @misc{20.500.12495_2320, author = {}, title = {Influence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutions}, year = {}, abstract = {}, url = {http://hdl.handle.net/20.500.12495/2320} }RT Generic T1 Influence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutions LK http://hdl.handle.net/20.500.12495/2320 PB American Society for Microbiology AB OL Spanish (121)
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    Author
    Kebriaei, Razieh 
    Rice, Seth A.
    Singh, Kavindra V.
    Stamper, Kyle C.
    Rafael Rios
    Diaz, Lorena 
    Dinh, An Q.
    Murray, Barbara 
    Munita, Jose M. 
    Arias, Cesar A 
    Rybak, Michael 
    Tran, Truc T.
    Date
    2018
    Published in
    Antimicrobial agents and chemotherapy, 1098-6596, Vol. 62, Nro. 8, 2018, p. 1-12
    Published for
    American Society for Microbiology
    URI
    http://hdl.handle.net/20.500.12495/2320
    Source's URL
    https://aac.asm.org/content/62/8/e00315-18.long
    DOI
    https://doi.org/10.1128/AAC.00315-18

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    Abstract
    Enterococcus faecium isolates that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problematic, since predisposition to resistance may lead to therapeutic failure. Using a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as monotherapy and in combination with ampicillin (AMP), ceftaroline (CPT), or ertapenem (ERT) against E. faecium HOU503, a DAP-susceptible strain that harbors common LiaS and LiaR substitutions found in clinical isolates (T120S and W73C, respectively). Of interest, the efficacy of DAP monotherapy, at any dose regimen, was dependent on the size of the inoculum. At an inoculum of ∼109 CFU/g, DAP doses of 6 to 8 mg/kg/day were not effective and led to significant regrowth with emergence of resistant derivatives. In contrast, at an inoculum of ∼107 CFU/g, marked reductions in bacterial counts were observed with DAP at 6 mg/kg/day, with no resistance. The inoculum effect was confirmed in a rat model using humanized DAP exposures. Combinations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and reduced potential for resistance, allowing de-escalation of the DAP dose. Persistence of the LiaRS substitutions was identified in DAP-resistant isolates recovered from the SEV model and in DAP-resistant derivatives of an initially DAP-susceptible clinical isolate of E. faecium (HOU668) harboring LiaSR substitutions that was recovered from a patient with a recurrent bloodstream infection. Our results provide novel data for the use of DAP monotherapy and combinations for recalcitrant E. faecium infections and pave the way for testing these approaches in humans.
    Keywords
    Combination therapy
    Daptomycin
    PK/PD
    VREfm
    Topics
    Enterococcus faecium
    Ácido pirúvico
    Enterococos resistentes a la vancomicina
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