Kebriaei, RaziehRice, Seth A.Singh, Kavindra V.Stamper, Kyle C.Dinh, An Q.Rios, RafaelDíaz, LorenaMurray, Bárbara E.Munita, JoséTran, Truc T.Arias, Cesar A.Rybak, Michael J.2022-05-302022-05-302018Citation 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.https://doi.org/10 .1128/AAC.00315-18.http://hdl.handle.net/11447/6159Enterococcus 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.enPK/PDVREfmCombination therapyDaptomycinArticle