According to Paulo, Wolfgang, and Gilmore (1), infections caused by fungal or bacterial biofilms have become a major public health concern not only in the developing nations but also the developed countries around the world. The biofilm infections are often immune both to the host immune defenses and antibiotics, making them very dangerous. Conlon, Rowe, and Lewis (2) define bacterial biofilm as “a structured community of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface.” These bacteria communities start by joining to form a small protective matrix on a given surface. In the beginning, these bacteria are joined by weak van der Waals forces that can easily be destroyed. They need an aqueous environment to start their community. If left uninterrupted, they start excreting a slimy substance that is glue-like which helps them to anchor on any material such as metals, soil particles, plastics, medical equipment, and animal or human tissues. These bacterial then form permanent bonds using what Fang (3) refer to as cell adhesion molecules. The molecules and proteins in nature and the cell formed are often referred to as adhesion cells.
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The bacterial pioneers that form the initial biofilms create a perfect environment that facilitates entry of other pathogens. They pathogens are provided with diverse adhesion sites. The pathogens quickly form a colony, and if it happens within the body of a human being or an animal, it can cause serious disease that may not be easy to treat. A study by Shi and Ryan (4) found out that success of the bacterial or fungal biofilms within various surfaces is enhanced by a phenomenon they refer to as quorum sensing. In this paper, the researcher sees to conduct a review of the literature on the current state of knowledge of the role of bacterial biofilms in medical infections.
Review of the Literature
O’Toole, Kaplan, and Kolter (5) define biofilm is a system consisting of a bacterial aggregate and associated with extracellular bacteria polymer matrix. According to Ciofua et al. (6), the formation of biofilms is a critical step in the progression of cystic fibrosis. The bacteria find its way into the intestines and use it as a breeding ground. If detected and treated early, the host often survives because the weak van der Waals forces can be easily destroyed using antibiotics. However, the problem is that, in most of the cases, the host may not exhibit early symptoms of infection. It allows the bacteria time to form strong biofilms that allow them to colonize the intestines. At such advanced stages, it is easy for the host to succumb to the disease because of the resistance to the immune system and multiple antibiotics. As stated by Lewis (7), it may be provoked by the presence of specific persistent in biofilms that are characterized by inhibited metabolism. The increased metabolic inertia inherent with such cells results in a greater level of survival in contacts with antibiotic agents.
According to Ghannoum, Roilides, Katragkou, Petraitis, and Walsh (8), the bonds which are created in the biofilms are often strong because they are anchored to a surface they colonize with the help of glue-like slimy substance that they create. Lee et al. (9) mention that the initial attachment of bacterial cells to the surface of a substrate is mediated through the process of non-specific adhesion which, in its turn, is defined by the non-specific interactions between adhesin proteins or bacterial lectins and receptors or particular areas of membrane surface of a target cell. The mechanism of adhesion may be supported by different elements in different types of bacteria, e.g., Polysaccharide Intercellular Adhesin in staphylococci adhesion (10) and type IV pili or flagella in some gram-negative organisms (11). As stated by Craig, Pique, and Tainer (11) flagella movements promote the formation of a cellular monolayer on a substrate, and type IV pili are involved in cell aggregation through the lectin interaction. As a result of bacteria multiplication, the cells adhere to the surface more firmly, differentiate, and exchange genes. This process increases their antibiotic resistance.
The figure below shows a bacterial biofilm that has developed in a catheter.
Organisms Common and Uncommon Causes of Biofilm‐Related Infections
According to Rybtke, Hultqvist, Givskov, and Nielsen (13), in order to effective deal with this problem, it is important to start by understanding causes of biofilm-related infections. There are a number of organisms believed to be common causes of biofilm-related infection.
Staphylococcus aureus biofilm is one of the main biofilm-related bacterial infections which are responsible for some diseases. The growth of Staphylococcus aureus biofilm is closely controlled by very complex generic factors (14). If this occurs within the intestines, the community can develop into a biofilm within a very short time. The bacterium is very dangerous within the body and can cause death within a very short time (15). One of the unique characteristics of biofilm is their ability to coordinate and systematically leave the body of one host to find a new host to colonize. This characteristic makes it very dangerous in environments where sanitation is very poor.
Neisseria gonorrhoeae, an organism that causes gonorrhea is also a common cause of biofilm-related infection. Palese (16) note that the bacteria finds its way into a surface within the reproductive system. If detected in a timely manner, the bacteria can easily be destroyed without having a devastating impact on the host. However, if left untreated, it can cause serious damage to the reproductive system. The organism can easily move from a host to a new host when there is an exchange of body fluids. Some people can even acquire the disease when using washrooms that had been previously used by an infected person but poorly maintained (17). Escherichia coli, commonly known as E. coli, Clostridium difficile, Campylobacter, and Shigella are other common organisms that cause biofilm-related infections (18). Diarrhea is often caused by these bacteria in an environment where hygiene is poor. Dysentery, another common disease in the developing countries, is also associated with biofilm-related organisms such as Campylobacter and Shigella.
Pseudomonas aeruginosa is a major causative agent in the development of opportunistic infections. It causes about 10% of all nosocomial infections (19). The major feature of Pseudomonas infections is their chronic nature; in cases when the infection reaches a certain level of development in patients with reduced immune defenses, lifelong antibiotic therapy is recommended because the complete elimination of the causative agent in such cases is not possible. Researchers reveal that Pseudomonas is associated with intracellular parasitism, i.e., the process in which the cells of the host organism used as a reservoir for bacteria (19). In Ps. aeruginosa this type of infestation is usually observed in epithelial cells during the urogenital tract infection, typically, near the entrance gate of infection where the concentration of the pathogen is particularly large.
Possible Sources of Infection and Clinical Outcomes in Different Patient Groups
In a hospital setting, there is a great number of possible sources of infections that nurses and other clinical staff must understand and come up with ways of dealing with effectively. The operations and surgical equipment and surfaces are often a good environment for the formation of fungal and bacterial biofilms. It is a requirement that after these equipment and surfaces are used, there must be a standard way of cleaning them to ensure that they are safe for future use. However, Wu, Moser, Wang, Høiby, and Song (20) note that sometimes those trusted with this responsibility fail to follow the set standards when cleaning and sterilizing such environment. Poor level of hygiene in the surgical environment may expose a patient to bacterial and fungal infections. The outcome of surgical-related biofilm infection may vary from one patient to another depending on one’s immune system and the magnitude of the infection. When the internal organs are infected, the impact can be dire, and it may force the patient to undergo a similar procedure to correct the mistake (21). In other cases, the patient may be subjected to serious medication to deal with the infection.
Wounds such as surgical cuts, burns, ulcers, and accident wounds provide a perfect ground for bacterial and fungal biofilm infections. The aqueous environment in surgical cuts and wounds is a characteristic that is perfect for the development of the biofilms. Hengzhuanga et al. (22) state that the important feature of such infections is that the developed biofilm can bear any physical conditions: it is highly resistant to drying, and it is actively evolve in the moist environments (e.g., in the closed bandages). Moreover, in the conditions of the closed bandages, the risks for the reproduction of the anaerobic infection agents. When such wounds get infected, it becomes almost impossible for them to heal, which means that they may turn chronic. Especially enduring chronic biofilm-related infections may be observed in patients with the reduced immune status.
Due to the capacity of the biofilms to survive in different types of environments, they can persist in the hospital environment even if it is thoroughly and regularly serialized. Thus, there is a high risk for the occurrence of hospital-acquired infections especially in long-stay patients. Although anti-microbial medicines are the common methods of treatment in such situations, the excessive use of antibiotics can only increase bacterial persistence (14). It happens because of the presence of the dormant cells in biofilms. These non-active cells may activate mechanisms of the adaptive mutagenesis such as the multidrug resistance. Under these conditions, antibiotics may destroy the majority of independent planctonic cells of pathogen in the macroorganism, as well as most of the sesnsitive microorganisms in a biofilm. The innate immune system then gets rid of the residuals of the planctonic cells. However, persister cells localized in biofilms are unavailable for the immune system and, as soon as the antibiotic treatment is ceased, those cells commence reproduction again and provoke the repeated outbreak of an infectious process (14). Biofilms are formed on almost all types of invasive medical devices: catheters, prostheses, etc. Therefore, the issues of bacterial persistence is of great significance in the modern medicine.
What is known of the structure of biofilms
Biofilm structure is formed in a consistent manner, starting with two or more bacteria or fungi being joined through the weak van der Waals forces. The bacteria or fungi will need an aqueous environment that can enable them to float in a free manner and be easily reproduced. The organisms start by reproducing on a given surface. They then start excreting, forming a protective cover over the bacterial community. For instance, in E. coli biofilm matrix, curli fibers develop to help in creating a strong bond between one bacterium and another. The early structure then attaches itself to a given surface. In the case of E. coli, their preferred surface is often the intestine where they reproduce very fast. The weak van der Waals forces are then replaced by very strong molecular forces that create permanent attachment among the cells and with the surface colonized. The bacteria spread to other parts of the cells from the point of infection as they continue to increase in number. The figure below shows the known structure of biofilm.
As shown in the above structure, the bacteria or fungi within a biofilm are more concentrated in the inner part of the biofilm, making it difficult for the immune system and the medication administered to destroy them. The cellulose cover, shown in the figure above, also protects the bacteria found in the inner region of the cells. The flagella help in the movement of the pathogens from one part of the cells to the other or even to the external environment. It is believed that curli fibers, the amyloid proteins that help bacteria to attach to surfaces, play a critical role in enabling communication among the pathogens. Curli fibers are involved in bacteria’s adhesion to surfaces, aggregation, and development of biofilm. As stated by Barnhart and Chapman (24), they also “mediate host cell adhesion and invasion, and they are potent inducers of the host inflammatory response” (p. 131).
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The figure above also shows different stages of cell division of the pathogens as they progressively increase in numbers and spread to various parts of the body. When the pathogens on the outer age are destroyed, because they lack protection offered by the cellulose, they are often replaced quickly through the rapid reproduction of other cells in the inner region. The mechanism of reproduction used by the pathogen, and the cellulose protection formed when the biofilm develops, makes it difficult to treat some of these bacterial and fungal diseases. According to Núñez and Hancock (25), nowadays, the majority of anti-biofilm peptides used in medical practice are composed of L-amino acids which are ineffective in the treatment of biofilm-related infections as they are easily recognized by bacteria or host proteases. It results in the reduced biological activity of peptides. However, the researchers (25) suggest designing and using D-enantiomeric peptides because their activity is likely not to be inhibited and, in this way, they may be more potent in treatment those diseases.
Known Factors That Are Used By Bacteria to Attach To Surfaces to Establish Biofilms
In the analysis of biofilm conducted above, it is clear the pattern taken by bacteria to form the van der Waals forces that enable them to stick together. However, to survive as a colony, these bacteria or fungi must be strongly attached to a surface. As explained above, the surface may be metallic, plastic, wooden, body cells or soil particles. The best environment for the attachment of the molecules is aqueous in nature.
The figure below shows biofilm’s life cycle:
The figure demonstrates that it is easy to destroy the biofilm at the initial stages. However, when it is fully developed, it creates a defense mechanism that cannot be easily destroyed by the immune system.
Overall, the process of biofilm formation can be divided into three stages. The first one is the reversible attachment to the surface. As O’Toole, Kaplan and Kolter (5) state, frequently microorganisms exist as free-swimming masses or sporadic (e.g., planktonic) colonies. But normally, the majority of organisms tend to attach to surfaces and, as a result, form biofilm. At the next stage which can be called as the permanent attachment, bacteria adhere to surface more strongly. Moreover, at this stage differentiation and gene exchange – the processes that ensure bacterial survival, – occur. Finally, bacteria form the protective mucilaginous matrix. As soon as the adhesive process is completed, bacteria start to develop the extracellular polymeric substance or EPS-matrix comprised of proteins, glycoproteins, and glycolipids and which determines “the immediate conditions of life of biofilm cells living in this microenvironment by affecting porosity, density, water content, charge, sorption properties, hydrophobicity, and mechanical stability” (27, p. 7945). Then, the small bacterial colonies start to form the initial biofilm.
The formed matrix cannot be easily destroyed by the immune system or use of antibiotics. However, these pathogens have the capacity to detach themselves from a given surface when they want to move to a new environment.
The figure below shows bacteria attached to the intestinal surface to establish biofilm:
How biofilm formation permits micro‐organisms to evade the immune system
According to Swidsinski, Loening, and Swidsinski (29), treating bacterial and fungal biofilms is not easy, especially when it has reached advanced stages of development because of the layer that it develops to protect it against antibodies. As more of this substance is produce, a layer of the polysaccharide is developed that covers the microorganisms within the colony as shown in figure 2. It acts as a barrier to the immune system. Phagocytes (i.e., neutrophils, macrophages, etc.), the key effectors of the innate immune system in the protection against bacterial infection, detect microorganisms as pathogens that need immediate elimination (30). However, the extracellular matrix of biofilms (regardless of the taxonomic affiliation or forms of microbes) contains structures weakening the phagocytic reactions. The polysaccharide intercellular adhesion (PIA) decreases the activation of phagocytes by inhibiting the phagocytic clearance of biofilm bacteria. Moreover, it can increase the resistance of bacteria to human antibiotic peptides (30).
PIA can be so strong that even antibiotic medication cannot destroy it. According to Uppua et al. (31) who had analyzed the properties of biofilm in A. baumannii, the biofilms may contain some resting and uncultivable forms of bacteria. Their presence in the bacterial aggregate protected from the external influences is important to the protection of the species and survival of microorganisms in the changing and extreme environments. The cells in different physiological condition may trigger the mechanism of adaptive mutagenesis that can be complemented by the interchange of metabolic products and horizontal transfer of genetic information. These processes activate microevolutionary mechanisms including the realization of antibiotic resistance (7). The empirical evidence obtained by the researchers (31) makes it clear that to solve the topical issue of bacterial persistence, and especially in those types of microorganisms which can survive on the artificial surfaces for a long time, it is possible to use polymer substances. It is observed that polymers may be highly toxic to bacteria while being less toxic to mammal cells. Polymers’ efficacy is defined by their capacity to influence the chemical structure of bacteria: depolarize membrane, and deplete energy. In this way, polymers can be recommended for the treatment of clinical device surfaces.
Effects of Treatment with Anti‐Microbial
When it is established that one is suffering from a biofilm infection such as Staphylococcus aureus biofilm, an antimicrobial is often administered. Those suffering from bacterial infection are given antibacterial while those suffering from fungal infection are given antifungal medication. At early stages of the development of the biofilm, the anti-microbial medicines may be effective in destroying the weak van der Waal forces, which would result in complete destruction of the pathogens if the patient follows the prescription as a state by the physician. However, if pathogens are surrounded by a well-developed EPS-matrix, the microbial may have no effect on the patient (32). Such medication may only inhibit further development of the biofilm, but may not destroy it. The majority of modern antibiotic medicines target the secretory and regulatory systems of biofilms, i.e., T3SS and QS processes (33). For instance, such macrolide antibiotic as azithromycin can block QS system of Ps. auruginosa, acting as an inhibitor of LasI- RhlI-synthase (34). Macrolides have a therapeutic effect in multiple chronic lung Ps. aeruginosa-related infections (34). One of their active mechanisms is the blockade of formation of bacterial QS-mediators
Nevertheless, Cole and Lee (35) note that frequent use of antibiotics also affects the immune system. It reduces the capacity of the antimicrobial to fight bacteria and fungi within the body in an effective way. It explains why medical experts highly recommend the use of antibiotics only when it is unavoidable. It is necessary to help in reducing cases where bacteria become resistant to the microbial. When the body gets used to regular doses of antimicrobials, this form of medication becomes infective to the body..
Current Treatment Approaches
Biofilm infections such as Staphylococcus aureus biofilm are known to be resistant to come of the common antibiotics that have been in use for the past several years. It has become necessary to find alternative ways of managing this infection. Medical researchers have been conducting studies to come up with ways of destroying well-established biofilms within the body. At first, medical experts tried the use of high dosages of antibiotics to try and kill the bacterial infections. However, it was established that such medications only weaken biofilm but do not destroy it. As such, doctors have tried to come up with surgical methods as the only way of destroying the infections. Lebeaux et al. (36) say that, through research, antimicrobial therapies are being developed to help in the treatment of biofilm infections, Staphylococcus aureus biofilm, instead of using surgical processes. According to Tafina et al. (14), “in conjunction with surgical intervention such as debridement, incision and drainage, indwelling medical device removal, antimicrobial therapy is often prolonged and often takes place in the outpatient setting” (p. 454) Some doctors prefer biofilm infections through a surgical process often referred to as myringotomy, but anti-biofilm peptides are also becoming common form of medication. It involves placing tubes in the eardrum to drain the infectious fluid. The use of the surgical process is becoming popular because of the strong attachment that the biofilm develops with the body surface and the strong protective cover that makes it impossible for antimicrobial to penetrate. It is clear that that the use of small dosage of antimicrobial is still effective in destroying biofilms at early stages of development.
Status of New Treatments or Prevention Strategies That Are in Development
New studies have been conducted to find better ways of treating biofilms or prevent biofilm infections. The best way of dealing with biofilm infection is through prevention (37). Maintaining a high level of hygiene is the only way of eliminating possible cases of infection. It has been confirmed that biofilms thrive in the unhygienic environment. Maintaining high levels of hygiene makes it difficult for the microbial to move from one host to the other. It is highly recommended that one should be very careful about anything being ingested. Food must be cleaned and if possible properly heated to destroy the pathogens before being ingested. It is apparent that medical experts still have a conflicting opinion about the use of an antimicrobial in the treatment of biofilm infection. Given that it always forms a strong adhesive force that strongly attaches it to the surface, one of the ways destroying biofilm is to surgically cut it out (38). The process destroys the outer protective cover, making it possible to successfully use antimicrobial to complete the treatment. The use of anti-biofilm peptides is also becoming popular as an option for treating biofilm infections..
Biofilm infection has been a major problem in the global society for many years. When scientists discovered this colony of pathogens, measures were put in place to find ways of eradicating it. Antimicrobial was discovered as a medication for the bacterial and fungal infection. However, this medication is only effective when the pathogens have not developed a biofilm. The use of surgical procedures that physically destroys the cells and protective cover before administering antimicrobial has long been considered the only way of treating biofilm infections. However, anti-biofilm peptides are also becoming a popular form of treating biofilm infections. It is a new therapeutic approach to managing biofilm infections. If fully developed, the use of anti-biofilm peptides may make a significant milestone towards finding cost-effective ways of managing biofilm infections.
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