Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis/oralis in an Ex Vivo Simulated Endocarditis Vegetation Model.

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 β-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-β-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.

• Authors: 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 6 (06 2019) ISSN: 1098-6596 [Electronic] United States
• PMID: 30962347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• beta-Lactams
• Vancomycin
• Ceftriaxone
• Daptomycin

Topics

• Anti-Bacterial Agents (administration & dosage)
• Ceftriaxone (administration & dosage)
• Daptomycin (administration & dosage)
• Drug Resistance, Bacterial (drug effects)
• Drug Therapy, Combination (methods)
• Endocarditis (drug therapy, microbiology)
• Endocarditis, Bacterial (drug therapy, microbiology)
• Humans
• Microbial Sensitivity Tests (methods)
• Streptococcus mitis (drug effects, metabolism)
• Streptococcus oralis (drug effects, metabolism)
• Vancomycin (administration & dosage)
• beta-Lactams (metabolism)