Abstract
Background: Daptomycin (DAP) is a lipopeptide antibiotic currently used in the treatment of vancomycin-resistant enterococcal infections. The enterococcal LiaFSR three-component regulatory system plays a major role in DAP resistance. Prior work has suggested the absence of LiaF in E. faecalis impairs activation of LiaFSR, leading to increased susceptibility to DAP. The aim of this study was to evaluate the efficacy of DAP against E. faecalis lacking a functional LiaF in a rat endocarditis model.
Methods: Three strains were used in this study: wild-type E. faecalis OG117, a strain lacking functional liaF via addition of four stop codons at amino acid positions 11-14 (OG117liaF*11-14), and a complementation of wild-type LiaF in its chromosomal location (OG117liaF*11-14::liaF). Each strain was evaluated with a previously published endocarditis model using male Sprague-Dawley rats. Subcutaneous DAP was administered for 3 days (45.3 mg/kg every 24 hours) to mimic human dosing (6 mg/kg). Bacterial colony-forming units per gram of vegetation (CFU) were determined for baseline controls prior to therapy (t=0) and at 24 hours after the last DAP dose. Geometric means of bacterial CFU per gram were log-transformed for statistical analysis using unpaired t-tests. The animal protocol (IS00006793) was approved by CMP, HMRI, Methodist Hospital, Houston TX.
Results: The ID90 values for OG117, OG117 liaF*11-14, and OG117 liaF*11-14::liaF were 7.9 × 103, 7.8 × 104, and 7.3 × 104 CFU/g, respectively and bacterial burden at t=0 were similar between each group of animals. All strains showed a significant reduction in CFU with DAP therapy (Table 1). Notably, rats inoculated with OG117liaF*11-14 had significantly lower CFU as compared to OG117 (P < 0.015) and OG117liaF*11-14::liaF (P < 0.005). Among animals inoculated with OG117 liaF*11-14 and treated with DAP, 43% exhibited sterile vegetation, whereas none in the OG117 and OG117 liaF*11-14::liaF groups did.
Conclusion: Loss of functional LiaF resulted in increased efficacy of DAP in a rat model of endocarditis. Targeting and
Methods: Three strains were used in this study: wild-type E. faecalis OG117, a strain lacking functional liaF via addition of four stop codons at amino acid positions 11-14 (OG117liaF*11-14), and a complementation of wild-type LiaF in its chromosomal location (OG117liaF*11-14::liaF). Each strain was evaluated with a previously published endocarditis model using male Sprague-Dawley rats. Subcutaneous DAP was administered for 3 days (45.3 mg/kg every 24 hours) to mimic human dosing (6 mg/kg). Bacterial colony-forming units per gram of vegetation (CFU) were determined for baseline controls prior to therapy (t=0) and at 24 hours after the last DAP dose. Geometric means of bacterial CFU per gram were log-transformed for statistical analysis using unpaired t-tests. The animal protocol (IS00006793) was approved by CMP, HMRI, Methodist Hospital, Houston TX.
Results: The ID90 values for OG117, OG117 liaF*11-14, and OG117 liaF*11-14::liaF were 7.9 × 103, 7.8 × 104, and 7.3 × 104 CFU/g, respectively and bacterial burden at t=0 were similar between each group of animals. All strains showed a significant reduction in CFU with DAP therapy (Table 1). Notably, rats inoculated with OG117liaF*11-14 had significantly lower CFU as compared to OG117 (P < 0.015) and OG117liaF*11-14::liaF (P < 0.005). Among animals inoculated with OG117 liaF*11-14 and treated with DAP, 43% exhibited sterile vegetation, whereas none in the OG117 and OG117 liaF*11-14::liaF groups did.
Conclusion: Loss of functional LiaF resulted in increased efficacy of DAP in a rat model of endocarditis. Targeting and
| Original language | English (US) |
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| State | Unpublished - Apr 29 2024 |
| Event | Congress of the European Society of Clinical Microbiology and Infectious Diseases : ESCMID Global 2024, Barcelona - Barcelona, Barcelona, Spain Duration: Apr 27 2024 → Apr 30 2024 |
Conference
| Conference | Congress of the European Society of Clinical Microbiology and Infectious Diseases |
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| Country/Territory | Spain |
| City | Barcelona |
| Period | 4/27/24 → 4/30/24 |