2066. Synergistic Bacteriophage-Antibiotic Combinations Against High Inoculum DNS MRSA

• Published in: Open forum infectious diseases 2023-11, Vol.10 (Supplement_2)
• Main Authors: Kunz Coyne, Ashlan J, Stamper, Kyle, Bleick, Callan, Bayer, Arnold S, Lehman, Susan, Rybak, Michael J
• Format: Article
• Language: English
• ISSN: 2328-8957; 2328-8957
• DOI: 10.1093/ofid/ofad500.136

Abstract Background Phage-antibiotic combinations (PAC) have been proposed for high inoculum daptomycin-nonsusceptible (DNS) MRSA infections refractory to conventional therapy. We studied PAC with synergistic activity against two DNS MRSA clinical bloods isolates (C4 and C37; DAP MIC = 4 ug/mL). Methods PAC containing DAP and/or ceftaroline (CPT) (each at ½ MIC) plus a 2-phage cocktail (Intesti13 and Sb-1, at a range of multiplicities of infection [MOI]) were tested at a high MRSA inoculum (109 CFU/mL) using: i) modified checkerboard (CB) minimum inhibitory concentration (MIC); and ii) 24h time-kill assays (TKA). Synergistic activity in CB assays was defined as either: a fractional inhibitory concentration (FIC) index ≤ 0.5 in modified CB assays; or a ≥ 2 log10 CFU/mL reduction by PACs vs the most active single-agent regimen. Significant differences between regimens were assessed by ANOVA with Tukey’s post hoc modification (P < 0.05). Results By CB assay, synergistic activity was demonstrated with Intesti13 + Sb1 (MOI of 10 to 0.01) plus either DAP or DAP + CPT (FIC ≤ 0.5 for each combination). In 24h TKA vs C4, Intest13 + Sb1 (MOI 1 and 0.1) plus either DAP or DAP + CPT demonstrated robust synergistic activity (-Δ7.21 and -Δ7.39 log10 CFU/mL, respectively) vs. the next most effective regimen of CPT + Intesti13+Sb1 (P < 0.05 each). Against C37, Intesti13 + Sb1 (MOI of 1 and 0.1) with CPT or DAP + CPT were equally potent and effective regimens (-Δ7.14 log10 CFU/mL each), but neither were significantly better than the synergistic regimen of DAP + Intesti13 + Sb1 (-Δ6.65 log10 CFU/mL).Figure 1.Bacterial quantification in 24 h high inoculum (10^9 CFU/mL) TKA of DAP and CPT combined with phages Intesti13 and Sb1 against DNS MRSA strain C4. These studies demonstrated positive phage-antibiotic synergy (PAS), with phage cocktail Intesti13 + Sb1 and either DAP or DAP + CPT. Addition of these phages to DAP or DAP + CPT combinations caused bactericidal and synergistic killing vs. CPT + phages. *, P