Phage-antibiotic synergy against daptomycin-nonsusceptible MRSA in an ex vivo simulated endocardial pharmacokinetic/pharmacodynamic model

Phage-antibiotic combinations (PAC) offer a potential solution for treating refractory daptomycin-nonsusceptible (DNS) methicillin-resistant (MRSA) infections. We examined PAC activity against two well-characterized DNS MRSA strains (C4 and C37) and . PACs comprising daptomycin (DAP) ± ceftaroline (...

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Vydáno v:Antimicrobial agents and chemotherapy Ročník 68; číslo 4; s. e0138823
Hlavní autoři: Kunz Coyne, Ashlan J, Bleick, Callan, Stamper, Kyle, Kebriaei, Razieh, Bayer, Arnold S, Lehman, Susan M, Rybak, Michael J
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 03.04.2024
Témata:
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Ceftaroline
Cephalosporins - pharmacology
Daptomycin - pharmacology
Methicillin-Resistant Staphylococcus aureus
Microbial Sensitivity Tests
daptomycin-nonsusceptible
synergy
antibiotics
bacteriophage
MRSA
ISSN:1098-6596, 1098-6596
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Shrnutí:Phage-antibiotic combinations (PAC) offer a potential solution for treating refractory daptomycin-nonsusceptible (DNS) methicillin-resistant (MRSA) infections. We examined PAC activity against two well-characterized DNS MRSA strains (C4 and C37) and . PACs comprising daptomycin (DAP) ± ceftaroline (CPT) and a two-phage cocktail (Intesti13 + Sb-1) were evaluated for phage-antibiotic synergy (PAS) against high MRSA inoculum (10 CFU/mL) using (i) modified checkerboards (CB), (ii) 24-h time-kill assays (TKA), and (iii) 168-h simulated endocardial vegetation (SEV) models. PAS was defined as a fractional inhibitory concentration ≤0.5 in CB minimum inhibitory concentration (MIC) or a ≥2 log CFU/mL reduction compared to the next best regimen in time-kill assays and SEV models. Significant differences between regimens were assessed by analysis of variance with Tukey's post hoc modification (α = 0.05). CB assays revealed PAS with Intesti13 + Sb-1 + DAP ± CPT. In 24-h time-kill assays against C4, Intesti13 + Sb-1 + DAP ± CPT demonstrated synergistic activity (-Δ7.21 and -Δ7.39 log CFU/mL, respectively) ( < 0.05 each). Against C37, Intesti13 + Sb-1 + CPT ± DAP was equally effective (-Δ7.14 log CFU/mL each) and not significantly different from DAP + Intesti13 + Sb-1 (-Δ6.65 log CFU/mL). In 168-h SEV models against C4 and C37, DAP ± CPT + the phage cocktail exerted synergistic activities, significantly reducing bio-burdens to the detection limit [2 log CFU/g (-Δ7.07 and -Δ7.11 log CFU/g, respectively)] ( < 0.001). At 168 h, both models maintained stable MICs, and no treatment-emergent phage resistance occurred with DAP or DAP + CPT regimens. The two-phage cocktail demonstrated synergistic activity against two DNS MRSA isolates in combination with DAP + CPT and . Further PAC investigations are needed.
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content type line 23
ISSN:1098-6596
1098-6596
DOI:10.1128/aac.01388-23