Mechanistic Insights into the Differential Efficacy of Daptomycin plus β-Lactam Combinations against Daptomycin-Resistant Enterococcus faecium

Razieh Kebriaei, Kyle C. Stamper, Kavindra Singh, Ayesha Khan, Seth A. Rice, An Q. Dinh, Truc T. Tran, Barbara E. Murray, Cesar A. Arias, Michael J. Rybak

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: The combination of daptomycin (DAP) plus ampicillin (AMP), ertapenem (ERT), or ceftaroline has been demonstrated to be efficacious against a DAP-tolerant Enterococcus faecium strain (HOU503). However, the mechanism for the efficacy of these combinations against DAP-resistant (DAP-R) E. faecium strains is unknown. Methods: We investigated the efficacy of DAP in combination with AMP, ERT, ceftaroline, ceftriaxone, or amoxicillin against DAP-R E. faecium R497 using established in vitro and in vivo models. We evaluated pbp expression, levels of penicillin-binding protein (PBP) 5 (PBP5) and β-lactam binding affinity in HOU503 versus R497. Results: DAP plus AMP was the only efficacious regimen against DAP-R R497 and prevented emergence of resistance. DAP at 8, 6, and 4 mg/kg in combination with AMP was efficacious but showed delayed killing compared with 10 mg/kg. PBP5 of HOU503 exhibited amino acid substitutions in the penicillin-binding domain relative to R497. No difference in pbp mRNA or PBP5 levels was detected between HOU503 and R497. labeling of PBPs with Bocillin FL, a fluorescent penicillin derivative, showed increased β-lactam binding affinity of PBP5 of HOU503 compared with that of R497. Conclusions: Only DAP (10 mg/kg) plus AMP or amoxicillin was efficacious against a DAP-R E. faecium strain, and pbp5 alleles may be important contributors to efficacy of DAP plus β-lactam therapy.

Original languageEnglish (US)
Pages (from-to)1531-1539
Number of pages9
JournalJournal of Infectious Diseases
Volume222
Issue number9
DOIs
StatePublished - Nov 1 2020

Keywords

  • Daptomycin
  • E. faecium
  • PBP
  • Vancomycin-resistant E. faecium
  • β-lactam

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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