Biofilms in the Medical Field

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Introduction

Biofilms were first observed on medical devices in the early 1980’s through the use of electron microscopy (14). Since then, they have been associated with a significant portion of nosocomial infections and subsequent deaths (8). Therefore, understanding the structure of medically significant biofilms, and how to prevent them, are important sectors of current research in the microbiological field.

What is a biofilm?

In an aqueous environment, bacteria may form an organized community that is attached to a solid surface at the liquid interface; this is known as a biofilm (1). Bacteria that form biofilms must be able to adhere to a surface, as well as accumulate to form multilayered cell clusters through intracellular adhesion (2, 3).

Formation of the biofilm. In this diagram, reversible attachment and irreversible attachment are two different steps.

Within a biofilm, bacterial cells express different gene sets depending on their location (4). A key aspect of biofilms is the matrix of extracellular polymeric substance (EPS) that is secreted by, and encases the bacteria (1). The formation of a biofilm involves a four step process: attachment of bacterial cells to a surface, accumulation of bacterial cells forming multiple layers, maturation of the biofilm, and release of some bacteria in the planktonic state, which can attach to a new surface and form another biofilm (6). These sessile communities offer protected growth from the environment (4), and have a heightened resistance to antimicrobials as well as to the host immune responses (5).

Biofilms of Staphylococcus species

Biofilm composed of S. auereus.

In respect to medical devices, Staphylococcus epidermidis and Staphylococcus aureus are the most common organism to form a biofilm and cause an infection (3, 6). Because S. epidermidis is normally a harmless part of human flora, it is considered an opportunistic pathogen when it causes an infection (2). A key aspect of Staphylococcus biofilms is the polysaccharide intercellular adhesion (PIA) (2). The bacteria cells are embedded in the PIA and it is thought that this substance provides resistance against host immune responses as well as antibiotic-resistance (2).


Importance of Biofilms in the Medical Field

Nosocomial infections (infections acquired at a hospital) are the fourth leading cause of death in the United States, and about 65% of these infections are due to biofilms on an implanted medical device such as an intravenous catheter (8, 9). One reason biofilms differ from an infection of planktonic bacteria is due to the exopolysaccharide matrix of the biofilm, which is important in cell adhesion and aggregation. This EPS matrix also impedes the normal functions of antibodies and the phagocytic cells of the host’s immune system (10). Another key factor that makes biofilms particularly difficult in medical situations is their heightened resistance to antibiotics. There are three proposed methods for why biofilms are more resistant to the action of antibiotics.

1. The antibiotic may not be able to penetrate past the surface layers of the biofilm, or it is deactivated more quickly than it can diffuse (11).

2. The different chemical environments throughout the biofilm can affect the action of the antibiotic (11). Also because of the low level of nutrients in the lower layers of the biofilm, some bacteria may exist in a non-growing state (11). Many antibiotics, such as the cell-wall targeting penicillin antibiotics, require the bacteria to be growing in order for it to kill the bacteria (11).

3. About 1% of the population may exhibit a highly protected, phenotypic state, which persists under continued exposure to an antibiotic, even when the biofilm is too thin to inhibit diffusion of the antibiotic or of nutrients (11).

Because of these properties, cells that exist in biofilms can be 1000 times more resistant to antimicrobial agents than the same cells in planktonic form (9). Cells at the surface of the biofilm can detach from the matrix and infect the host (12). Therefore, biofilms on inserted medical devices can act as a reservoir of protected bacteria that can often persist until the removal of the infected device (9, 12).

Prevention of biofilm related nosocomial infections

Because of the detrimental impact of biofilms for the individual as well as for healthcare facilities, research is being conducted to figure out how to fight biofilm related infections. There are three strategies to fight these infections: inhibiting bacterial cells from binding to the surface, interfering with biofilm development, and killing the bacteria within a biofilm either directly or through the disaggregation of the biofilm matrix (7).

Diagram showing three methods to fight biofilm infections.

1. Inhibiting bacteria from binding to a device can be done by creating a surface that the bacteria cannot physically bind to, or by coating the surfaces with antimicrobial agents (7). For example, Hook, A. et al discovered that silicon, when coated with materials containing ester and cyclic hydrocarbon moieties showed a 96.7% reduction of the surface area with attached bacteria when compared to silicon coated with silver hydrogel coating (5). One of the most important points about using a material that inherently blocks bacterial binding, rather than one coated in antimicrobial agents, is that there is no selective pressure for organisms to develop antimicrobial resistance (5).

2. Quorum sensing, which involves communication between cells using autoinducers (small diffusible signal molecules), is an important factor in the creation of biofilms (7). The use of molecules to inhibit the signal generator, the signal molecule, or the signal receptor is an important step the prevention of biofilm formation (13).

3. In order to effectively kill the bacteria in a biofilm, many times a combination of different antibiotics along with biofilm matrix-degrading substances must be used (7). Degradation of the biofilm matrix is important in order to expose all of the sessile microbial cells to both the host’s immune defenses as well as antibiotics (7). Dispersin B is an important molecule that can degrade the ESB of many bacteria including S. epidermidis (7). Dispersin B can also be expressed by modified bacteriophages, which is useful for dissolving the biofilm matrix as well as killing the bacterial cells that form the biofilm (7).


References

(1) Davies, D. “Understanding Biofilm Resistance to Antibacterial Agents.” Nature Reviews Drug Discovery, 2003. DOI: 10.1038/nrd1008

(2) Götz, F. “Staphylococcus and Biofilms.” Molecular Microbiology, 2002. DOI: 10.1046/j.1365-2958.2002.02827.x

(3) von Eiff, C., Jansen, B., Kohnen, W., Becker, K. “Infections Associated with Medical Devices: Pathogenesis, Management and Prophylaxis.” Drugs, 2005. DOI:10.2165/00003495-200565020-00003

(4) Costerton, J., Stewart, P., Greenberg, E. “Bacterial Biofilms: A Common Cause of Persistent Infections.” Science, 1999. DOI:10.1126/science.284.5418.1318

(5) Hook, A., Chang, C., Yang, J., Luckett, J., Cockayne, A., Atkinson, S., Mei, Y., Bayston, R., Irvine, D., Langer, R., Anderson, D., Williams, P., Davies, M., Alexander, M. “Combinatorial Discover of Polymers Resistant to Bacterial Attachment.” Nature Biotechnology, 2012. DOI:10.1038/nbt.2316

(6) Arciola, C., Campoccia, D., Speziale, P., Montanaro, L., Costerton, J. “Biofilm formation in Staphylococcus Implant Infections. A Review of Molecular Mechanisms and Implications for Biofilm-Resistant Materials.” Biomaterials, 2012. DOI:10.1016/j.biomaterials.2012.05.031

(7) Francolini, I., Donelli, G. “Prevention and Control of Biofilm-Based Medical-Device-Related Infections.” FEMS Immunology & Medical Microbiology, 2010. DOI:10.1111/j.1574-695X.2010.00665.x

(8) Bryers, J. “Medical Biofilms.” Biotechnology and Bioengineering. 2008. DOI: 10.1002/bit.21838

(9) Mah, T., O’Toole, G., “Mechanisms of Biofilm Resistance to Antimicrobial Agents.” Trends in Microbiology, 2001. DOI:10.1016/S0966-842X(00)01913-2

(10) Gristina, A., Hobgood, C., Webb, L., Myrvik, Q. “Adhesive Colonization of Biomaterials and Antibiotic Resistance.” Biomaterials, 1987. DOI:10.1016/0142-9612(87)90077-9

(11) Stewart, P., Costerton, J. “Antibiotic Resistance of Bacteria in Biofilms.” The Lancet, 2001. DOI:10.1016/S0140-6736(01)05321-1

(12) Talsma, S. “Biofilms on Medical Devices.” Home Healthcare Nurse: The Journal for the Home Care and Hospice Professional, 2007. DOI:10.1097/01.NHH.0000296117.87061.14

(13) Rasmussen, T., Givskov, M. “Quorum-Sensing Inhibitors as Anti-Pathogenic Drugs.” International Journal of Medical Microbiology, 2006. DOI:10.1016/j.ijmm.2006.02.005

(14) Hall-Stoodley, L., Costerton, J., Stoodley, P., “Bacterial Biofilms: From the Natural Environment to Infectious Diseases.” Nature Reviews Microbiology, 2004. DOI:10.1038/nrmicro821