TY - JOUR
T1 - Phage-Antibiotic Cocktail Rescues Daptomycin and Phage Susceptibility against Daptomycin-Nonsusceptible Enterococcus faecium in a Simulated Endocardial Vegetation Ex Vivo Model
AU - Coyne, Ashlan J.Kunz
AU - Stamper, Kyle C.
AU - El Ghali , Amer
AU - Kebriaei, Razieh
AU - Biswas, Biswajit
AU - Wilson, Melanie
AU - Deschenes, Michael V.
AU - Tran, Cecilia
AU - Arias, Cesar A.
AU - Rybak, Michael J.
N1 - Funding Information:
This research received no external funding. M.J.R. is supported by NIH grant R21 AI163726. C.A.A. is supported by NIH grants K24AI121296, R01AI134637, R01AI48342, and P01AI152999.
Funding Information:
A.J.K.C., K.S., A.E.G., R.K., B.B., M.W., M.V.D., T.T.T., C.A.A. and M.J.R. have nothing to declare. M.J.R. has received grant support and has consulted or spoken on behalf of Allergan, Melinta, Merck, Paratek, Shionogi, Spero, and Tetraphase. C.A.A. has received grant support from Merck Pharmaceuticals, Entasis Pharmaceuticals and MeMed Diagnostics and is a cofounder and Entasis Therapeutics shareholder of Ancilia Biosciences.
Publisher Copyright:
© 2023 American Society for Microbiology. All rights reserved.
PY - 2023/8/17
Y1 - 2023/8/17
N2 - Enterococcus faecium is a difficult-to-treat pathogen with emerging resistance to most clinically available antibiotics. Daptomycin (DAP) is the standard of care, but even high DAP doses (12 mg/kg body weight/day) failed to eradicate some vancomycin-resistant strains. Combination DAP-ceftaroline (CPT) may increase β-lactam affinity for target penicillin binding proteins (PBP); however, in a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, DAP-CPT did not achieve therapeutic efficacy against a DAP-nonsusceptible (DNS) vancomycin-resistant E. faecium (VRE) isolate. Phage-antibiotic combinations (PAC) have been proposed for resistant high-inoculum infections. We aimed to identify PAC with maximum bactericidal activity and prevention/reversal of phage and antibiotic resistance in an SEV PK/PD model against DNS isolate R497. Phage-antibiotic synergy (PAS) was evaluated with modified checkerboard MIC and 24-h time-kill analyses (TKA). Human-simulated antibiotic doses of DAP and CPT with phages NV-497 and NV-503-01 were then evaluated in 96-h SEV PK/PD models against R497. Synergistic and bactericidal activity was identified with the PAC of DAP-CPT combined with phage cocktail NV-497-NV-503-01, demonstrating a significant reduction in viability down to 3-log
10 CFU/g (-Δ, 5.77-log
10 CFU/g;
P < 0.001). This combination also demonstrated isolate resensitization to DAP. Evaluation of phage resistance post-SEV demonstrated prevention of phage resistance for PACs containing DAP-CPT. Our results provide novel data highlighting bactericidal and synergistic activity of PAC against a DNS E. faecium isolate in a high-inoculum
ex vivo SEV PK/PD model with subsequent DAP resensitization and prevention of phage resistance.
IMPORTANCE Our study supports the additional benefit of standard-of-care antibiotics combined with a phage cocktail compared to antibiotic alone against a daptomycin-nonsusceptible (DNS) E. faecium isolate in a high-inoculum simulated endocardial vegetation
ex vivo PK/PD model. E. faecium is a leading cause of hospital-acquired infections and is associated with significant morbidity and mortality. Daptomycin is considered the first-line therapy for vancomycin-resistant E. faecium (VRE), but the highest published doses have failed to eradicate some VRE isolates. The addition of a β-lactam to daptomycin may result in synergistic activity, but previous
in vitro data demonstrate that daptomycin plus ceftaroline failed to eradicate a VRE isolate. Phage therapy as an adjunct to antibiotic therapy has been proposed as a salvage therapy for high-inoculum infections; however, pragmatic clinical comparison trials for endocarditis are lacking and difficult to design, reinforcing the timeliness of such analysis.
AB - Enterococcus faecium is a difficult-to-treat pathogen with emerging resistance to most clinically available antibiotics. Daptomycin (DAP) is the standard of care, but even high DAP doses (12 mg/kg body weight/day) failed to eradicate some vancomycin-resistant strains. Combination DAP-ceftaroline (CPT) may increase β-lactam affinity for target penicillin binding proteins (PBP); however, in a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, DAP-CPT did not achieve therapeutic efficacy against a DAP-nonsusceptible (DNS) vancomycin-resistant E. faecium (VRE) isolate. Phage-antibiotic combinations (PAC) have been proposed for resistant high-inoculum infections. We aimed to identify PAC with maximum bactericidal activity and prevention/reversal of phage and antibiotic resistance in an SEV PK/PD model against DNS isolate R497. Phage-antibiotic synergy (PAS) was evaluated with modified checkerboard MIC and 24-h time-kill analyses (TKA). Human-simulated antibiotic doses of DAP and CPT with phages NV-497 and NV-503-01 were then evaluated in 96-h SEV PK/PD models against R497. Synergistic and bactericidal activity was identified with the PAC of DAP-CPT combined with phage cocktail NV-497-NV-503-01, demonstrating a significant reduction in viability down to 3-log
10 CFU/g (-Δ, 5.77-log
10 CFU/g;
P < 0.001). This combination also demonstrated isolate resensitization to DAP. Evaluation of phage resistance post-SEV demonstrated prevention of phage resistance for PACs containing DAP-CPT. Our results provide novel data highlighting bactericidal and synergistic activity of PAC against a DNS E. faecium isolate in a high-inoculum
ex vivo SEV PK/PD model with subsequent DAP resensitization and prevention of phage resistance.
IMPORTANCE Our study supports the additional benefit of standard-of-care antibiotics combined with a phage cocktail compared to antibiotic alone against a daptomycin-nonsusceptible (DNS) E. faecium isolate in a high-inoculum simulated endocardial vegetation
ex vivo PK/PD model. E. faecium is a leading cause of hospital-acquired infections and is associated with significant morbidity and mortality. Daptomycin is considered the first-line therapy for vancomycin-resistant E. faecium (VRE), but the highest published doses have failed to eradicate some VRE isolates. The addition of a β-lactam to daptomycin may result in synergistic activity, but previous
in vitro data demonstrate that daptomycin plus ceftaroline failed to eradicate a VRE isolate. Phage therapy as an adjunct to antibiotic therapy has been proposed as a salvage therapy for high-inoculum infections; however, pragmatic clinical comparison trials for endocarditis are lacking and difficult to design, reinforcing the timeliness of such analysis.
KW - Enterococcus
KW - infective endocarditis
KW - antibiotic resistance
KW - bacteriophage
KW - Microbial Sensitivity Tests
KW - Enterococcus faecium
KW - beta-Lactams/pharmacology
KW - Daptomycin/pharmacology
KW - Humans
KW - Vancomycin/pharmacology
KW - Anti-Bacterial Agents/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85168256637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168256637&partnerID=8YFLogxK
U2 - 10.1128/spectrum.00340-23
DO - 10.1128/spectrum.00340-23
M3 - Article
C2 - 37338375
SN - 2165-0497
VL - 11
SP - e0034023
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 4
ER -