Catheter-Related Infections: It's All About Biofilm

Marcia A. Ryder, PhD, MS, RN

Disclosures

Topics in Advanced Practice Nursing eJournal. 2005;5(3) 

In This Article

Biofilm Recalcitrance to Antimicrobials

The hallmark characteristic of biofilm microbes is their innate resistance to antimicrobial agents and host immune defenses. Phagocytic cells poorly penetrate the physical barrier of the biofilm matrix. Those phagocytes that do penetrate are unable to engulf the biofilm bacteria and are rendered useless by premature release of lysozymes.[23]

Systemic dosing levels of antibiotics, which were developed according to the pharmacodynamics and pharmacokinetics of planktonic organisms, are relatively ineffective against biofilm micro-organisms. Biofilm micro-organisms have been shown to be 100-1000 times less susceptible to antibiotics than their planktonic counterparts.[24] At least 4 mechanisms are attributed to this resistance: (1) restricted penetration of the antibiotic through the biofilm; (2) nutrient limitation, altered microenvironment, and slow growth of biofilm cells; (3) adaptive responses; and (4) genetic alteration to "persister" cells.

Once the biofilm forms, delivery of nutrients to the cells is dependent on diffusion through the EPS. The substances in the EPS act as a diffusion barrier, either by limiting the rate of molecule transport to the biofilm interior or by chemically reacting with the molecules themselves.[25] Restricted diffusion protects the cells from large molecules such as complement. Biofilms are mostly water, so solutes the size of antibiotics will readily diffuse through the biofilm matrix.[26] However, the negatively charged EPS restricts permeation of positively charged molecules of antibiotics, such as aminoglycosides, by chemical interaction or molecular binding.[27] If the antibiotic is inactivated or ionically bound in the surface layers, its delivery to the depths of the biofilm can be profoundly retarded.[28] Microbial biofilms formed in conditioning films present an even greater problem, because antimicrobials poorly penetrate fibrin or host protein complexes.

Limited diffusion of nutrients and oxygen generates physiological gradients throughout the biofilm. Cells in the outer microns close to the flowing liquid have ready access to nutrients and oxygen. These cells are metabolically active, normal in size, and similar to planktonic organisms.

The near complete consumption of oxygen and glucose in the surface layers creates anaerobic niches in the depths of the biofilm where the cells downregulate into an extremely slow-growing or nongrowing state in order to survive.[23] Growth rate is one of the factors that changes bacterial cells' susceptibility to antimicrobial agents, along with temperature, pH, and prior exposure to subeffective concentrations of antibiotics.[17] Subsequently, those antibiotics readily diffused through the biofilm are ineffective in killing the slow and nongrowing cells in the anaerobic regions of the biofilm.

The age of the biofilm also affects its susceptibility to antibiotics. Older (10-day-old) biofilms are significantly more resistant than 2-day-old biofilms.[25] This emphasizes the need for prompt diagnosis and treatment.

Biofilm cells adapt to environmental fluctuations in temperature, pH, osmolarity, and nutrient availability, through the expression of multiple stress-response genes. The genetic alteration not only ensures survival in community living but also affords protection from the host immune system, environmental toxins, and antimicrobials.[28,29,30] Antibiotic resistance is further enhanced by the horizontal exchange of resistant plasmids. Plasmids are extrachromosomal circles of DNA that may encode resistance to antimicrobial agents, including beta-lactams, erythromycin, aminoglycosides, tetracycline, glycopeptides, trimethoprim, and sulfonamides.[4,31] The high cell densities and greater probability of contact between the cells in the biofilm clusters favor the higher rates of horizontal transfer of plasmid DNA. This phenomenon has contributed to the dramatic increase of antimicrobial resistance among nosocomial pathogens.[32]

The majority of cells in the upper regions of the biofilm are susceptible to prolonged exposure to antibiotics. Most die rapidly when treated with a cidal antibiotic such as ciprofloxacin that effectively kills slow-growing cells. It is now thought that the presence of a subpopulation of "persister" cells within the biofilm may account for the profound resistance to complete eradication of biform bacteria. Persisters are phenotypic variants of wild-type cells that neither grow nor die in the presence of bactericidal agents and that exhibit multidrug tolerance.[33]

The population of persister cells has been estimated to reach about 0.1% to 10% of all cells in a biofilm.[34] Their purpose is to ensure the survival of the population in the presence of lethal factors and to reseed the community in the event of catastrophic killing. This subpopulation persists even during prolonged exposure or escalated concentrations of antimicrobial agents. When antimicrobial therapy is discontinued, the unaffected persister cells reverse the phenotype and become metabolically viable to regrow the biofilm. Infection may reoccur at a later time or may linger for months, years, or even a lifetime, or until the colonized device is removed.[35]

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