Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus β-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium

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 strai...

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Published in:	The Journal of infectious diseases 2020-10, Vol.222 (9), p.1531-1539
Main 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
Format:	Article
Language:	eng
Subjects:	Ampicillin - administration & dosage Ampicillin - pharmacology Animals Anti-Bacterial Agents - administration & dosage Anti-Bacterial Agents - pharmacology beta-Lactams - administration & dosage beta-Lactams - pharmacology Ceftaroline Cephalosporins - administration & dosage Cephalosporins - therapeutic use Daptomycin - administration & dosage Daptomycin - pharmacology Disease Models, Animal Drug Resistance, Bacterial Drug Therapy, Combination Endocarditis, Bacterial - drug therapy Enterococcus faecium - drug effects Enterococcus faecium - genetics Ertapenem - administration & dosage Ertapenem - pharmacology Gram-Positive Bacterial Infections - drug therapy Major and Brief Reports Microbial Sensitivity Tests Rats Sequence Alignment Transcriptome
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Summary:	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. 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. 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. 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.
ISSN:	0022-1899 1537-6613