Abstract
Infective endocarditis (IE) is associated with high morbidity and mortality rates. The predominant bacteria causing IE is Staphylococcus aureus (S. aureus), which can bind to existing thrombi on heart valves and generate vegetations (biofilms). In this in vitro flow study, we evaluated sonobactericide as a novel strategy to treat IE, using ultrasound and an ultrasound contrast agent with or without other therapeutics. We developed a model of IE biofilm using human whole-blood clots infected with patient-derived S. aureus (infected clots). Histology and live-cell imaging revealed a biofilm layer of fibrin-embedded living Staphylococci around a dense erythrocyte core. Infected clots were treated under flow for 30 minutes and degradation was assessed by time-lapse microscopy imaging. Treatments consisted of either continuous plasma flow alone or with different combinations of therapeutics: oxacillin (antibiotic), recombinant tissue plasminogen activator (rt-PA; thrombolytic), intermittent continuous-wave low-frequency ultrasound (120-kHz, 0.44 MPa peak-to-peak pressure), and an ultrasound contrast agent (Definity). Infected clots exposed to the combination of oxacillin, rt-PA, ultrasound, and Definity achieved 99.3 ± 1.7% loss, which was greater than the other treatment arms. Effluent size measurements suggested low likelihood of emboli formation. These results support the continued investigation of sonobactericide as a therapeutic strategy for IE.
Highlights
Infective endocarditis (IE) is a life-threatening microbial infection of the heart valves and surrounding tissue, including endocardial prosthetic material
We report the results of a translatable, proof-of-principle study for treating S. aureus IE biofilms in an in vitro flow model
It has been previously demonstrated that the results of in vitro simulated endocarditis biofilms are comparable to the in vivo rabbit model of endocarditis for the study of fluoroquinolone efficacy, to include pharmacokinetics[68]. In this proof-of-principle study, infected clots were developed as a translatable model of IE biofilm and the efficacy of sonobactericide, the use of US and an ultrasound contrast agents (UCAs) in combination with or without an antibiotic and thrombolytic was evaluated in vitro under flow
Summary
Infective endocarditis (IE) is a life-threatening microbial infection of the heart valves and surrounding tissue, including endocardial prosthetic material. Staphylococcus aureus (S. aureus) has been reported to have the single highest prevalence (30–31%) in IE1 and is associated with the highest mortality and worst prognosis These bacteria initiate colonization by adhering to microthrombi present on valves, caused either by endothelial inflammation, mechanical damage, or spontaneous formation on intact valvular surfaces[1,5,7]. Acoustic cavitation and streaming have been identified as the dominant mechanisms for what appears as an increase in antibiotic efficacy and penetration into biofilms. These studies have employed high acoustic pressures to induce inertial cavitation, which could induce undesirable bioeffects[15]. These studies have not evaluated the potential to enhance treatment of IE biofilms either by US, or US with UCAs
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