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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dc.contributor.authorKebriaei, Razieh
dc.contributor.authorRice, Seth A.
dc.contributor.authorSingh, Kavindra V.
dc.contributor.authorStamper, Kyle C.
dc.contributor.authorRafael Rios
dc.contributor.authorDiaz, Lorena
dc.contributor.authorDinh, An Q.
dc.contributor.authorMurray, Barbara
dc.contributor.authorMunita, Jose M.
dc.contributor.authorArias, Cesar A
dc.contributor.authorRybak, Michael
dc.contributor.authorTran, Truc T.
dc.date.accessioned2020-04-22T16:29:41Z
dc.date.available2020-04-22T16:29:41Z
dc.date.issued2018
dc.description.abstractenglishEnterococcus 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.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1128/AAC.00315-18
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn1098-6596
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlrepourl:https://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/2320
dc.language.isoeng
dc.publisherAmerican Society for Microbiologyspa
dc.publisher.journalAntimicrobial agents and chemotherapyspa
dc.relation.ispartofseriesAntimicrobial agents and chemotherapy, 1098-6596, Vol. 62, Nro. 8, 2018, p. 1-12spa
dc.relation.urihttps://aac.asm.org/content/62/8/e00315-18.long
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf182
dc.rights.creativecommons2018
dc.rights.localAcceso cerradospa
dc.subject.decsEnterococcus faeciumspa
dc.subject.decsÁcido pirúvicospa
dc.subject.decsEnterococos resistentes a la vancomicinaspa
dc.subject.keywordsCombination therapyspa
dc.subject.keywordsDaptomycinspa
dc.subject.keywordsPK/PDspa
dc.subject.keywordsVREfmspa
dc.titleInfluence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutionsspa
dc.title.translatedInfluence of Inoculum effect on the efficacy of daptomycin monotherapy and in combination with β-Lactams against daptomycin-susceptible enterococcus faecium Harboring LiaSR Substitutions
dc.typearticlespa
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localartículospa

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