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

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.

Bacteriophages Combined With Subtherapeutic Doses of Flucloxacillin Act Synergistically Against Staphylococcus aureus Experimental Infective Endocarditis

“…For IE applications, S. aureus phages would not be given as monotherapy but rather in combination with antibiotics. 41 , 42 Indeed, phages may accelerate bacterial load reduction at infection sites at the start of therapy. This type of intervention may improve infection‐related cardiac dysfunction in general, 43 potentially truncating the period of systemic embolization risk, and thus, ultimately, shortening the duration of antibiotic therapy needed.…”

Potential Advances of Adjunctive Hyperbaric Oxygen Therapy in Infective Endocarditis

“…This change in virulence was observed in the HBOT treated group, by significantly better clinical performance status compared to the control group (Lerche et al, 2017). This observation would also be relevant in a clinical protocol of HBOT in IE, highlighting the need to treat IE with a secondary antibiotic, which do not have an oxygen-dependent killing mechanism (i.e., rifampicin and linezolid), to prevent SCVs and with a good efficacy against biofilm (Lerche et al, 2021). This potential drawback of HBOT selecting these resistant bacterial phenotypes could, however, be limited by strategies by combining antibiotics with different modes of action.…”

“…In the intact vasculature most platelets never undergo firm adhesion; however, upon vessel wall injury they rapidly adhere to the exposed extracellular matrix (ECM), become activated and form a platelet plug, thereby preventing blood loss and capillary leakage. In IE the same process can lead to excessive platelet aggregation on the valves contributing to expansion of vegetations (Lerche et al, 2019;Lerche et al, 2021).…”

“…IE is a serious acute infection characterized by bacterial vegetation formation composed of endothelial cells, platelets, monocytes and neutrophils, as well as extracellular components including fibrin, fibrinogen and collagen. Bacterial adherences to the damaged endothelial cells or sterile vegetation promote a cascade of interactions between host cells and colonizing pathogen (Werdan et al, 2014;Moser et al, 2017;Lerche et al, 2021).…”

Infectious Uveitis in Horses and New Insights in Its Leptospiral Biofilm-Related Pathogenesis

“…Other biofilm-associated diseases include wound infections [496,497], infected implants and bone sequestrum formation [498], osteomyelitis [499][500][501], chronic otitis [449,502], infectious endocarditis [503], and borreliosis [504][505][506]. Whenever possible, mechanical or surgical removal of the biofilm is considered the most effective therapy to eliminate the infection [481,507,508].…”