Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus β-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium. (8th June 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of infectious diseases. Volume 222:Number 9(2020)
• Page Start: 1531
• Page End: 1539
• Publication Date: 2020-06-08
• Subjects: Vancomycin-resistant E. faecium -- E. faecium -- Daptomycin -- β-lactam -- PBP; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiaa319
• Languages: English
• ISSNs: 0022-1899

Abstract

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. Abstract : We present evidence that the success of daptomycin–β-lactam combination therapy against multidrug-resistant Enterococcus faecium with LiaFSR substitutions is likely dependent on β-lactam interactions with penicillin-binding proteins. Our findings open a possible new approach to severe enterococcal infections.