Dataset Information

Effect of the Lysin Exebacase on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis as Determined by Echocardiography.

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) poses significant therapeutic challenges related to its frequency in clinical infections, innate virulence properties, and propensity for multiantibiotic resistance. MRSA is among the most common causes of endovascular infections, including infective endocarditis (IE). Our objective was to employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE. TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (versus daptomycin alone). Primary intravegetation outcomes were maximum size, weights at sacrifice, and MRSA counts at infection baseline versus after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment day 1). A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase plus daptomycin versus the daptomycin alone therapy groups (P = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower than those of the daptomycin alone group (P < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (P = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower than those of untreated controls (P < 0.0001) and the daptomycin alone group (P < 0.0001). This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size, and weight. Moreover, TTE appears to be an efficient noninvasive tool to assess therapeutic efficacies in experimental MRSA IE.

SUBMITTER: Shah SU

PROVIDER: S-EPMC7317998 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Effect of the Lysin Exebacase on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis as Determined by Echocardiography.

Shah Sonia U SU Xiong Yan Q YQ Abdelhady Wessam W Iwaz James J Pak Youngju Y Schuch Raymond R Cassino Cara C Lehoux Dario D Bayer Arnold S AS

Antimicrobial agents and chemotherapy 20200623 7

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) poses significant therapeutic challenges related to its frequency in clinical infections, innate virulence properties, and propensity for multiantibiotic resistance. MRSA is among the most common causes of endovascular infections, including infective endocarditis (IE). Our objective was to employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE. TTE ...[more]

PMID: 32340988

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Project description:Lysins (peptidoglycan hydrolases) are promising new protein-based antimicrobial candidates under development to address rising antibiotic resistance encountered among pathogenic bacteria. Exebacase is an antistaphylococcal lysin and the first member of the lysin class to have entered clinical trials in the United States. In this study, the bacteriolytic activity of exebacase was characterized with time-kill assays, turbidity reduction assays, and microscopy. Three methicillin-susceptible Staphylococcus aureus and three methicillin-resistant S. aureus isolates were tested in time-kill assays over a range of concentrations from 0.25 to 8 × MIC. Exebacase demonstrated a concentration-dependent killing and showed bactericidal activity (≥3 log10 kill achieved relative to the starting inoculum) within 3 h at 1 × MIC against all strains tested. Dose-dependent lysis by exebacase was, furthermore, observed in the turbidity reduction assay, wherein decreases in initial OD600 of 50% were observed within ~15 min at concentrations as low as 4 µg/mL. Membrane dissolution, loss of cytoplasmic material, and lysis were confirmed by video and electron microscopy. The demonstrated rapid bacteriolytic effect of exebacase is an important distinguishing feature of this novel modality. IMPORTANCE To guide the development of an investigational new antibacterial entity, microbiological data are required to evaluate the killing kinetics against target organism(s). Exebacase is a lysin (peptidoglycan hydrolase) that represents a novel antimicrobial modality based on degradation of the cell wall of Staphylococcus aureus. Killing by exebacase was determined in multiple assay formats including time-kill assays, wherein reductions of viability of ≥3 log10 colony-forming units/mL were observed within 3 h for multiple different isolates tested, consistent with very rapid bactericidal activity. Rapid reductions in optical density were likewise observed in exebacase-treated cultures, which were visually consistent with microscopic observations of rapid lysis. Overall, exebacase provides a novel antimicrobial modality against S. aureus, characterized by a rapid cidal and lytic activity.

Project description:ImportanceInfective endocarditis (IE) caused by Staphylococcus aureus is associated with high mortality, approximately 20% to 30%, mostly in the first month, with no improvement in recent decades. Current opinion is that antistaphylococcal penicillin and cefazolin are equally effective in treating methicillin-susceptible S aureus (MSSA) IE, and both are recommended as possible first-line treatments. Most MSSA strains carry the β-lactamase blaZ gene, and some blaZ-positive strains exhibit an inoculum effect, meaning increased minimum inhibitory concentrations at high inoculum. This reduced susceptibility to an antibiotic at high bacterial inoculum may be particularly relevant in IE, where vegetations have very high bacterial densities.ObjectiveTo evaluate the association between phenotypic characteristics of S aureus isolates, β-lactam used, and outcome in patients with MSSA IE.Design, settings, and participantsThis retrospective case series included MSSA cases treated at 3 French university hospitals between February 2016 and February 2022. The study included patients who had clinical isolates available and had definite or possible S aureus IE that involved native or prosthetic valves. Data were analyzed from July 2023 to June 2024.Main outcomes and measuresMSSA isolates were tested for the presence of blaZ and for inoculum effects to cefazolin and oxacillin. The association between first-month mortality and the β-lactam used, the presence of blaZ, and the presence of an inoculum effect to the treatment received was evaluated.ResultsThis study included 216 patients with MSSA IE (median [IQR] age, 65 [49-73] years; 152 [70.4%] male) who were treated with antistaphylococcal penicillin (139 [64.4%]) or cefazolin (77 [35.6%]). One-month mortality of left-sided IE was 44 of 180 patients (24.4%), with no overall difference between patients treated with antistaphylococcal penicillin or cefazolin. However, 1-month mortality was higher in patients infected with blaZ-positive strains than with blaZ-negative strains (38 of 129 [29.5%] vs 6 of 51 [11.8%]; P = .01), and with strains with an inoculum effect to the β-lactam received than with strains without an inoculum effect (25 of 62 [40.3%] vs 13 of 67 [19.4%]; P = .005). On multivariable analysis, the presence of an inoculum effect was independently associated with first-month mortality (HR, 2.84; 95% CI, 1.28-6.30; P = .01).Conclusions and relevanceIn this case series of MSSA IE, the presence of an inoculum effect to the β-lactam received was a risk factor for death in the first month. Phenotyping MSSA isolates for inoculum effect may guide β-lactam choice and improve outcomes.

Dataset Information

Effect of the Lysin Exebacase on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis as Determined by Echocardiography.

Publications

Effect of the Lysin Exebacase on Cardiac Vegetation Progression in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis as Determined by Echocardiography.

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