Daptomycin dose-ranging evaluation with single-dose versus multidose ceftriaxone combinations against streptococcus mitis/ oralis in an ex vivo simulated endocarditis vegetation model

Razieh Kebriaei, Seth A. Rice, Kyle C. Stamper, Ravin Seepersaud, Cristina Garcia-De-la-Maria, Nagendra N. Mishra, Jose M. Miro, Cesar A. Arias, Truc T. Tran, Paul M. Sullam, Arnold S. Bayer, Michael J. Rybak

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The viridans group streptococci (VGS) are a heterogeneous group of organisms which are important components of the normal human oral flora. Among the VGS, the Streptococcus mitis/oralis subgroup is one of the most common causes of infective endocarditis (IE). Daptomycin (DAP) is a potential alternative therapeutic option for invasive S. mitis infections, given high rates of -lactam resistance and vancomycin tolerance in such strains. However, the ability of these strains to rapidly evolve high-level and durable DAP resistance (DAP-R) is problematic. Recent data suggest that combination DAP-lactam therapy circumvents this issue. Human-simulated dose-escalating DAP-alone dose regimens (6, 8, 10, or 12 mg/kg/day times 4 days) versus DAP (6 mg/kg/day) plus ceftriaxone (CRO) (2 g once daily times 4 days or 0.5 g, single dose) were assessed against two prototypical DAP-susceptible (DAP-S) S. mitis/oralis strains (SF100 and 351), as measured by a pharmacokinetic/ pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). No DAP-alone regimen was effective, with regrowth of high-level DAP-R isolates observed for both strains over 96-h exposures. Combinations of DAP-CRO with either single- or multidose regimens yielded significant reductions in log10 CFU/g amounts within SEVs for both strains (6 log10 CFU/g) within 24 h. In addition, no DAP-R strains were detected in either DAP-CRO combination regimens over the 96-h exposure. In contrast to prior in vitro studies, no perturbations in two key cardiolipin biosynthetic genes (cdsA and pgsA) were identified in DAP-R SEV isolates emerging from strain 351, despite defective phospholipid production. The combination of DAP-CRO warrants further investigation for treatment of IE due to S. mitis/oralis.

Original languageEnglish (US)
Article numbere00386-19
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • Ceftriaxone
  • Daptomycin
  • SEVs

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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