Antibiotic Tolerance of Staphylococcus aureus Biofilm in Periprosthetic Joint Infections and Antibiofilm Strategies

Abstract

The need for bone and joint prostheses is currently growing due to population aging, leading to an increase in prosthetic joint infection cases. Biofilms represent an adaptive and quite common bacterial response to several stress factors which confer an important protection to bacteria. Biofilm formation starts with bacterial adhesion on a surface, such as an orthopedic prosthesis, further reinforced by matrix synthesis. The biofilm formation and structure depend on the immediate environment of the bacteria. In the case of infection, the periprosthetic joint environment represents a particular interface between bacteria, host cells, and the implant, favoring biofilm initiation and maturation. Treating such an infection represents a huge challenge because of the biofilm-specific high tolerance to antibiotics and its ability to evade the immune system. It is crucial to understand these mechanisms in order to find new and adapted strategies to prevent and eradicate implant-associated infections. Therefore, adapted models mimicking the infectious site are of utmost importance to recreate a relevant environment in order to test potential antibiofilm molecules. In periprosthetic joint infections, Staphylococcus aureus is mainly involved because of its high adaptation to the human physiology. The current review deals with the mechanisms involved in the antibiotic resistance and tolerance of Staphylococcus aureus in the particular periprosthetic joint infection context, and exposes different strategies to manage these infections.

Keywords: Staphylococcus aureus; antibiotic; biofilms; periprosthetic joint infections; resistance; tolerance.

Figure 1

Scanning electron microscopy acquisition of S. aureus biofilm in vitro. Scale bar = 1 μm.

Figure 2

Representation of Periprosthetic Joint Infection involving S. aureus biofilm and the mechanisms of persistence. (1) Following surgery, traumatized bone releases several factors such as magnesium, inducing a specific microenvironment where S. aureus biofilm can develop. (2) Biofilm is composed of bacteria under various metabolisms and embedded in a matrix essentially composed of exopolysaccharides, extracellular DNA (eDNA), and proteins. (3) Antibacterial action of all types of immune cells is obstructed by the biofilm. (4) Biofilms’ semi-permeable structure induces the formation of diffusion gradients of nutrients and oxygen, found in higher concentrations on the upper layers of the biofilm, and an opposite gradient of metabolic wastes that accumulates in the deeper layers. (5). Communication signals (quorum sensing) are produced and captured by bacteria. In addition to stress factors, these signals regulate the metabolism activity, the production of virulence factors, and other bacterial responses. It results in metabolic heterogeneities within the biofilm. (6) Antibiotics partially penetrate into the biofilm, resulting in a high concentration in the upper parts and progressively lower concentrations in deeper parts. While active bacteria in the upper parts are efficiently killed, the sub-Minimum Inhibitory Concentrations of antibiotics in the inner parts allow bacteria to survive, especially those with slow metabolisms, such as persisters. (7) Even when surgery is performed, S. aureus can persists under abscess communities in the surrounding tissues of the bone or (8) by internalizing within bone cells such as osteoblasts, or even by colonizing the osteocyte lacuno-canalicular network (OLCN). These strategies allow bacteria to escape or hide from the immune system and can act as sources for future reinfections.

Figure 3

Summary of different ways to fight biofilm during its lifecycle.