The Journal of infectious diseases · 2020
Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus β-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium.
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Kebriaei Razieh, Stamper Kyle C, Singh Kavindra V, Khan Ayesha, Rice Seth A, Dinh An Q, Tran Truc T, Murray Barbara E, Arias Cesar A, Rybak Michael J
Аннотация
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.
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.
Предметные рубрики MeSH
AmpicillinAnimalsAnti-Bacterial AgentsCephalosporinsDaptomycinDisease Models, AnimalDrug Resistance, BacterialDrug Therapy, CombinationEndocarditis, BacterialEnterococcus faeciumErtapenemGram-Positive Bacterial InfectionsMicrobial Sensitivity TestsRatsSequence AlignmentTranscriptomebeta-LactamsCeftaroline