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Biofilm infections related to medical devices

Gram-positive bacteria

In humans, Gram-positive bacterial infections and biofilms, which are more prevalent than Gram-negative infections, have been demonstrated to be facilitated by human blood components. The extracellular matrix formation mechanisms seem to be strongly related to surface proteins and carbohydrate-rich structures; moreover, it has been indicated that extracellular DNA is also involved in the attachment of bacteria. Associated with endocarditis, chronic otitis, gastrointestinal ulcers, lung and urinary tract infections, osteomyelitis, caries, and periodontitis, the most common infections are caused by Staphylococcus, Streptococcus, and Enterococcus species (Heilmann and Gotz, 2009).

Staphylococci are common commensals of the epithelium and mucous membranes both in humans and in animals. Nonetheless, in humans, Staphylococcus aureus is the leading cause of Gram-positive-related nosocomial infections. Among the staphylococcal species, most often associated with foreign body-related infection (prosthetic heart valves and joints, artificial pacemakers, and intravascular catheters) is S. epider- midis, while S. aureus usually causes host tissue colonizations. Extracellular DNA, a negatively charged macromolecule, is considered a crucial component of the matrices of many bacterial species: S. pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis. Despite not being a mediator itself, extracellular DNA contributes to the development of S. aureus biofilm by interacting with positively charged molecules (polymers), enhancing the development of a glue-like structure. The formation of staphylococcal biofilms is not always mediated by surface proteins as it can also be associated with polysaccharides (Heilmann and Gotz, 2009).

Biofilm detachment is a phenomenon that can occur naturally leading to metastatic infections caused by the colonization of new sites by the fragments that are disintegrated. There are numerous factors that can cause this, including imperfect strategies meant to annihilate the infections. However, enzymes can abruptly lead to the disintegration of the matrices, under conditions that are intensively studied, with poor results, though. According to the nature of the compounds that mediate adhesion, different types of enzymes can be operating: glycosyl hydrolases, which degrades polysaccharide intercellular adhesins (PIA); proteases, which react to protein compounds (such as Aap/SasG or Bap/Bhp), and nucleases, which degrade the extracellular DNA (Heilmann and Gotz, 2009).

Some investigations highlight the fact that the biofilm matrix of an important part of biofilm-forming staphylococcal strains is made of teichoic acids and proteins, rather than PIA. In these situations, protease treatment is able to disintegrate the biofilms, usually incompletely. In S. aureus, protease-mediated biofilm detachment is controlled by quorum sensing (QS) signaling system. Another approach to generate the detachment of the biofilm relies on the production and release of small peptides (phenol-soluble modulins (PSMs), which were first described as proinflammatory agents in S. epidermidis (Heilmann and Gotz, 2009).

Less common but dangerous, Finegoldia magna is a Gram-positive species involved in numerous infections of skin, bone, and joint tissues, grafts/prostheses, as well as synthetic valves. Normally found in the gastrointestinal and urinary tract as a major commensal, it can also cause meningitis and necrotizing pneumonia (Rosenthal et al., 2012; Murphy et al., 2014). The ability of this species to form biofilms on the surface of implanted devices was associated with the presence of pili on the exterior of its cell wall (Murphy et al., 2014).

Pili are elongated, proteic structures, first observed on the surface of Gram-negative bacteria. Corynebacterium renale was the first Gram-positive bacteria where pili were reported. Pili have been discovered in many Gram-positive species, but their investigation is often slowed due to their nanometric or under-nanometric dimensions. For colonization, the cell employs its surface proteins that behave as adhesives; the presence of pili that increase the contact surface contribute to the formation of a prebiofilm intricate network, which is a key aspect of a successful infection (Danne and Dramsi, 2012).

Antibacterial biofilm formation strategies have been developed since the infections can manifest violently and lead to complications and even death. The most common approach is the classic antibiotic medication route. Moreover, numerous newly synthesized compounds are employed in preclinical/clinical studies or are already commercially available, such as novel class of lipoglycopeptides, including Tela- vancin, Oritavancin, Dalbavancin, Ceftobiprole, new anti-MRSA cephalosporins, new oxazolidinones, and Tedizolid. Unfortunately, despite the promising results in simple infections, bacterial biofilms are usually resistant to antibiotics (Morata et al., 2015).

The modern path in designing more efficient strategies to fight biofilms is based on nanotechnology. The advantages of employed nanostructured “remedies” lie in the likelihood that the biofilm can first be prevented from developing and if it already develops, nanoparticles could behave as toxic agents toward the microorganisms embedded in biofilms (Patil et al., 2015).

Nanosilver is one of the most used inorganic agent employed in biomedical applications due to the high rate of success in the fight against bacteria and also due to its generally neutral behavior toward the host tissues (Goswami et al., 2015). Quantum dots caught attention due to their versatility and their in vitro proven antibacterial effect. ZnO- and CdTe-conjugated nanostructures have proven efficient against Gram-positive Bacillus subtilis (Patil et al., 2015).

On the other hand, biofilms developed by the probiotic Gram-positive bacteria can also manifest beneficial functions, as reported by Aoudia et al. Strains of Lactobacillus plantarum and L. fermentum isolated from human feces and saliva were grown on abiotic surfaces under mimicked anaerobic conditions. The experiment consisted of developing rich cultures of the two strains on polystyrene plates and monitoring their kinetics in order to test the ability of the bacterial biofilms to antagonize the adhesion and proliferation of other bacterial pathogens. Following in vitro tests, it was concluded that the Lactobacillus strains are able to discourage pathogen development due to their immunomodulatory properties, which can be beneficial for future tissue engineering applications (Aoudia et al., 2016).

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