Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with -Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions
Date
2018
Type:
Article
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Abstract
Enterococcus faecium isolates that harbor LiaFSR substitutions but are
phenotypically susceptible to daptomycin (DAP) by current breakpoints are problem-
atic, since predisposition to resistance may lead to therapeutic failure. Using a simu-
lated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model,
we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as mono-
therapy 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 resis-
tant 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 in-
oculum effect was confirmed in a rat model using humanized DAP exposures. Com-
binations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and re-
duced 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.
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Citation
Citation Kebriaei R, Rice SA, Singh KV, Stamper KC, Dinh AQ, Rios R, Diaz L, Murray BE, Munita JM, Tran TT, Arias CA, Rybak MJ. 2018. Influence of inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-lactams against daptomycin- susceptible Enterococcus faecium harboring LiaSR substitutions. Antimicrob Agents Chemother 62:e00315-18. https://doi.org/10 .1128/AAC.00315-18.
Keywords
PK/PD, VREfm, Combination therapy, Daptomycin