No abstract

No abstract

We utilized the rabbit model of aortic valve infective endocarditis to examine the combined efficacy of the lysin, LSVT-1701, plus daptomycin. The combination of LSVT-1701 plus daptomycin was highly effective at reducing target tissue MRSA counts. When given for four daily doses, both lysin dose-regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as adjunctive therapy for the treatment of invasive MRSA infections.

Farber disease is an ultra-rare lysosomal storage disorder where a deficiency of acid ceramidase activity leads to the accumulation of ceramide and the formation of granulomas which, in conjunction with a chronic inflammatory state, likely results in tissue damage. A rapidly progressive murine knock-in Asah1P361R/P361R model of Farber disease recapitulates many aspects of the human disease, including an increase in ceramide and pronounced tissue inflammation. The focus of this study was to describe the aberrant immune cells in this disease model. Blood, livers, lungs, and spleens were collected from 4- to 8-week old litter-matched Farber and wild-type mice for characterization by flow cytometry. Characterization of the monocyte population revealed a marked increase in the frequency of MHCII−CD11bhiLy6C+ cells (3–6 fold vs WT). These cells were highly activated as evidenced by CD86 expression, and skewed toward a pro-inflammatory M1 phenotype, based on CD38 expression. A concurrent decrease in CD206+ anti-inflammatory M2 macrophages was identified. In addition to the macrophage compartment, a profound increase in neutrophils in the spleen, liver, and lung was evident by 4 weeks of age (2–7 fold vs. wild-type). Marked differences in the adaptive immune compartment also were noted, with a clear increase in the frequency of plasmablasts (precursors to immunoglobulin-producing plasma cells), likely secondary to the increase in pro-inflammatory monocytes. Importantly, the alterations observed in the tissues were reflected in the blood of Farber mice. In summary, these data expand the characterization of the murine Farber disease model and provide insight into the immuno-phenotype of Farber disease.

Background LSVT-1701, formerly SAL200, is a novel, recombinantly-produced, bacteriophage-encoded lysin that specifically targets staphylococci via cell wall enzymatic hydrolysis. We reported the in vitro activity of LSVT-1701 against clinical isolates of S. aureus and coagulase-negative staphylococci (CoNS) collected worldwide. Methods LSVT-1701 and comparators were tested against 415 S. aureus (n=315) and CoNS (n=100) clinical isolates expressing various resistance phenotypes. The isolates were collected in 2002-2019 from medical centers located in the United States (50 medical centers; 174 isolates; 41.9% overall), Europe (37 medical centers; 140 isolates; 33.7% overall), Asia-Pacific region (15 medical centers; 55 isolates; 13.3% overall), and Latin America (12 medical centers; 46 isolates; 11.1% overall). These isolates originated mostly from the year 2019 (n=323).The isolates were susceptibility tested by the CLSI broth microdilution method. MIC interpretations were based on CLSI and EUCAST criteria where available. Results LSVT-1701 was highly active against S. aureus and CoNS isolates with MIC90 values of 2 mg/L for all S. aureus, methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), and CoNS (Table). The highest LSVT-1701 MIC values were 4 and 8 mg/L among S. aureus and CoNS, respectively. LSVT-1701 retained potent activity against S. aureus isolates showing resistance or decreased susceptibility to oxacillin, vancomycin, teicoplanin, telavancin, linezolid, daptomycin, ceftaroline, or lefamulin; MIC50 values ranged from 0.5 to 1 mg/L and MIC90 values ranged from 1 to 4 mg/L among S. aureus resistant subsets. Summary of LSVT-1701 activity against S. aureus, CoNS and resistant subsets Conclusion LSVT-1701 demonstrated potent in vitro activity against contemporary clinical isolates of S. aureus and CoNS collected from medical centers worldwide and against resistant S. aureus isolates with uncommon resistance phenotypes. The results of this study support further clinical development of LSVT-1701 to treat staphylococcal infections. Disclosures David Huang, MD, PhD, Lysovant (Consultant) Helio S. Sader, MD, PhD, FIDSA, AbbVie (formerly Allergan) (Research Grant or Support)Basilea Pharmaceutica International, Ltd. (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)Department of Health and Human Services (Research Grant or Support, Contract no. HHSO100201600002C)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support) Paul R Rhomberg, Cidara Therapeutics, Inc. (Research Grant or Support)Pfizer, Inc. (Research Grant or Support) Katyna Borroto-Esoda, PhD, Lysovant (Consultant) Eric Gaukel, BS, Lysovant (Employee)