Mechanistic insights into the differential efficacy of Daptomycin Plus β-Lactam combinations against Daptomycin-Resistant Enterococcus faecium

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.

• Autores: Kebriaei, Razieh; Stamper, Kyle; Singh, Kavindra; Khan, Ayesha; Rice, Seth A.; Dinh, An Q; Tran, Truc T.; Murray, Barbara E.; Arias, César A.; Rybak, Michael Joseph
• Tipo de recurso: Article of journal
• Fecha de publicación: 2020
• Institución: Universidad El Bosque
• Repositorio: Repositorio U. El Bosque
• Idioma: eng
• OAI Identifier: oai:repositorio.unbosque.edu.co:20.500.12495/5317
• Acceso en línea: http://hdl.handle.net/20.500.12495/5317; https://doi.org/10.1093/infdis/jiaa319
• Palabra clave: Vancomycin-resistant E. faecium; E. faecium; Daptomycin, β-lactam; PBP
• Rights: openAccess
• License: Acceso abierto