Anti-biofilm Approach in Infective Endocarditis Exposes New Treatment Strategies for Improved Outcome.

Christian Johann Lerche,Claus Moser,Niels Høiby,Franziska Schwartz,Emil Loldrup Fosbøl,Marie Theut,Kasper Iversen,Henning Bundgaard

doi:10.3389/fcell.2021.643335

Abstract

Infective endocarditis (IE) is a life-threatening infective disease with increasing incidence worldwide. From early on, in the antibiotic era, it was recognized that high-dose and long-term antibiotic therapy was correlated to improved outcome. In addition, for several of the common microbial IE etiologies, the use of combination antibiotic therapy further improves outcome. IE vegetations on affected heart valves from patients and experimental animal models resemble biofilm infections. Besides the recalcitrant nature of IE, the microorganisms often present in an aggregated form, and gradients of bacterial activity in the vegetations can be observed. Even after appropriate antibiotic therapy, such microbial formations can often be identified in surgically removed, infected heart valves. Therefore, persistent or recurrent cases of IE, after apparent initial infection control, can be related to biofilm formation in the heart valve vegetations. On this background, the present review will describe potentially novel non-antibiotic, antimicrobial approaches in IE, with special focus on anti-thrombotic strategies and hyperbaric oxygen therapy targeting the biofilm formation of the infected heart valves caused by Staphylococcus aureus. The format is translational from preclinical models to actual clinical treatment strategies.

Highlights

Infective endocarditis (IE) is defined as an infection of the inner surface of the heart, the endocardium, most prevalent on the heart valves, or on implanted cardiac devices (Moreillon and Que, 2004)
Vascular endothelial growth factor (VEGF) receptor 2 seemed to be involved in this effect, and we have shown that hyperbaric oxygen therapy (HBOT) was able to reduce vascular endothelial growth factor (VEGF) expression levels in the infected aortic valves using a rat model of left-sided S. aureus IE (Lerche et al, 2017)
The bacterial load in valve vegetations was significantly reduced in dabigatrantreated animals, in parallel with key proinflammatory markers of IE (i.e., IL-8 and IL-6). These findings indicate that dabigatran could be a beneficial non-antibiotic treatment option in acute and severe S. aureus IE

Summary

INTRODUCTION

Infective endocarditis (IE) is defined as an infection of the inner surface of the heart, the endocardium, most prevalent on the heart valves, or on implanted cardiac devices (Moreillon and Que, 2004). The third most common bacterial etiology causing IE on native heart valves is Enterococcus faecalis, especially in patients above 70 years of age (Hoen and Duval, 2013; Østergaard et al, 2019) These three groups of Gram-positive bacteria constitute approximately 80% of all microbial etiologies of IE (Que and Moreillon, 2011; Østergaard et al, 2019). Activated platelets release procoagulant molecules facilitating additional platelet aggregation (Rivera et al, 2009) These essential and protective properties of the hemostatic system are dysregulated in severe infections and further enhanced by virulent Gram-positive bacteria colonizing the valve endothelium facilitating hyperactivation of complex pathways, resulting in vegetational growth and biofilm formation in cardiac valves (Figure 2). A key reason is believed to be the significantly changed physiology of the TABLE 1 | Biofilm characteristics in infective endocarditis (IE)

Limitations

Findings

CONCLUSION