Battling Biofilm: Surface Science, Antimicrobials Help Combat Medical Device-Related Infections
By Kelly M. Pyrek
The rising number of medical device-related infections and a new emphasis on patient-safety standards are helping fuel the explosion in a scientific discipline known as "surface science."1 The core of this science is the fact that most biological reactions occur at surface level. How cells and proteins interact at the surface is being studied by scientists as the way to analyze and improve the function and durability of the polymers and other materials used to manufacture medical devices. It is also ground zero for understanding the mechanisms of biofilm, the adherence of bacteria and the triggering of infection.
The mechanisms of device-related infections are still not completely understood even though "the tendency of foreign bodies to predispose patients to infection has been recognized since the 14th century," asserts one team of researchers.2 According to researchers at the Centers for Disease Control and Prevention (CDC), microbial biofilms develop when microorganisms adhere to a submerged surface and produce extracellular polymers that facilitate adhesion to a surface that may be inert, nonliving material or living tissue.3 Biofilms can develop on the simplest of medical devices, such as contact lenses, or they can develop on more complex items such as prosthetic joints, mechanical heart valves and pacemakers.
"Microbial biofilms may pose a public health problem for persons requiring indwelling medical devices," writes Rodney M. Donlan of the CDC.4 "The microorganisms in biofilms are difficult or impossible to treat with antimicrobial agents; detachment from the device may result in infection. Although medical devices may differ widely in design and use characteristics, specific factors determine susceptibility of a device to microbial contamination and biofilm formation: duration of use, number and type of organisms to which the device is exposed, flow rate and composition of the medium in or on the device, device material construction and conditioning films on the device."
Biofilms can be composed of gram-positive or gram-negative bacteria, and species most frequently isolated from medical devices include gram-positive Enterococcus faecalis and Staphylococcus aureus, and the gram-negative Escherichia coli, Klebsiella pneumoniae and Pseudemonas aeruginosa. The bacteria can originate from patients' own skin, from the hands of healthcare workers, or from other external sources in the environment. Biofilm is known to be tenacious as well as highly resistant to antimicrobial treatment; however, that isn't stopping researchers from trying to combat it with various antimicrobial coatings.
In an effort to prevent or mitigate bacterial colonization on the surfaces of implants and medical devices, manufacturers are investigating surface modification technologies, specifically surface coatings that are engineered to release bactericidal agents in a controlled manner.
"A variety of methods have been developed to modify the surfaces of polymers or other biomaterials used in the device industry," writes Jon Katz in Medical Plastics and Biomaterials.5 "Examples include conventional coating processes such as spraying or dipping; vacuum deposition techniques; and such surface-modification technologies as diffusion, laser and plasma processes, chemical plating, grafting or bonding, hydrogel encapsulation and bombardment with high-energy particles. Traditionally, the goal was to achieve improved physical or mechanical properties in a component or device, for example, by adding a nonstick coating to a catheter for easier insertion. Increasingly, however, surface modification also aims at inducing a specific desired bioresponse or inhibiting a potentially adverse reaction."
According to researchers at the University of Texas at Arlington, significant research has been invested in the production of bacteria-inhibitory and bactericidal surfaces.6 "Generally speaking, a bacteria-inhibitory surface discourages and/or prevents bacterial colonization and profliferation, and a bactericidal surface elutes bactericides," writes T.L. Lin, et al.
One way to resolve device-related infections is to affix antimicrobial agents directly onto the surface of the device, such as in the case of central venous catheters or urinary catheters, which have been the source of life-threatening bloodstream infections. It has been estimated that central venous catheters account for 90 percent of all nosocomial bloodstream infections.7 Urinary tract infections (UTIs) occur in about 20 percent of patients with Foley catheters in place for more than 10 days, and in more than 40 percent of patients with Foley catheters in place for more than 25 days. There are approximately 500,000 cases of these kinds of infections in U.S. hospitals annually, and most are associated with catheters.8 Nosocomial UTIs reportedly cost hospitals $1.8 billion annually, and urinary catheter use is associated with up to 90 percent of these infections.9
Recent studies have shown that impregnation of catheters with antiseptic or antimicrobial agents is a viable approach to control catheter-associated infections. In a study conducted by Dennis Maki and colleagues,10 use of central venous catheters coated with chlorhexidine-silver sulfadiazine was associated with a 44 percent reduction in catheter colonization and a 79 percent reduction in the rate of catheter-related bloodstream infections. Use of these catheters also showed a significant reduction in the number of organisms colonizing the skin around the catheter-insertion site.
A study by Raad and colleagues11 found that the use of central venous catheters coated with minocycline and rifampin was associated with significant reductions in the rates of catheter colonization and catheter-related bloodstream infections.
These studies show that none of the impregnated catheters was associated with hypersensitivity reactions, toxicity or infections caused by resistant pathogens; however, the researchers add that further study is warranted because the catheters were in situ for an average of six days and assessment for adverse events required more observations. "The studies by Maki and Raad and their colleagues suggest that impregnated catheters, although not a magic bullet, may be an important advance in reducing the rate of central venous catheter-related infections, particularly in critically ill patients with multilumen catheters for the short term and in settings in which rates of central venous catheter-related bloodstream infection remain high despite full adherence to proven infection control measures," write Michele L. Pearson, MD, and Elias Abrutyn, MD, in the Annals of Internal Medicine.12
Silver has long been acknowledged as having antibacterial properties,13 but its role in antimicrobial medical devices is continually debated.
"Silver compounds (silver chloride or silver oxide) are a popular choice for infection-resistant coatings, but many commercially available silver-coated catheters are of marginal effectiveness because the hydrophobic polymer matrix limits the silver ion concentration near the device surface," Jon Katz writes.15 "A process by STS Biopolymers, Inc. has been developed, however, that incorporates silver compounds in a nonreactive hydrogel polymer system that provides greater aqueous diffusion from the coating and thus a greater concentration of silver ions at and just above the device surface. The coatings can be formulated for short-, intermediate-, or long-term effects; offer controllable lubricity and elution; can be applied inside lumens; and demonstrate superior adhesion, durability and flexibility."
"Our coating is a permanent polymer coating that binds molecules of the antimicrobial agent into a hydrophilic matrix," says John Lanzafame, director of sales and marketing for STS Biopolymers, Inc. "The agents are eluted over time by diffusion into the surrounding bodily fluids, and our technology allows for control of the degree of hydrophilicity of the coating, which thereby controls the elution rate of the active compound. Our coating can be applied to any medical devices that require an antimicrobial surface, as long as the product is used in a moist environment. We can accurately control the elution of the antimicrobial agent to periods from hours to weeks, to adjust for different requirements for different product.
SurModics, Inc. manufactures its PhotoLink antimicrobial coatings to deliver infection resistance properties as well as antimicrobial drug delivery or combinations of technologies. "We have two different classes of antimicrobial coatings," explains Anthony W. Dallmier, PhD, director of microbiology. "The most effective approach involves coating an antimicrobial-containing reservoir onto the medical device surface. Antimicrobials are released from this coating at a controlled rate, providing extended protection. A major feature of our photoactivatable antimicrobial reservoir is the flexibility to load a variety of antimicrobials into the coating. The device manufacturer can tailor its antimicrobial coating for optimal efficacy against the battery of microorganisms most closely associated with infecting the particular device. The second class is to coat the device with a photoactivatable hydrophilic coating that doesn't kill the invading microorganism, but prevents its attachment to the device surface. These hydrophilic coatings also help minimize microbial migration along the device surface. The hydrophilic 'smoothes' out the device surface, reducing anchoring and hiding places for microorganisms."
The origins of some companies' antimicrobial coatings lie in various medical interventions. According to Samuel P. Sawan, PhD, president of Surfacine Development Co and Intelligent Biocides, his firm became interested in antimicrobial coatings to solve a problem with patient sensitivity to antimicrobial compounds used as preservatives. "Our original interest was to create a preservative-free multi-dose dispenser that would maintain a medicament germ free without the use of a preservative. This research was the impetus to create an antimicrobial surface that did not elute or leach into contacting fluids. We then began looking for other applications for this technology. Our attention was drawn to medical devices where the incidence of nosocomial infections associated with implanted devices was high and to ife threatening complications. Our interest in permanent coatings led us to explore and develop the technology for other applications where a long-lasting antimicrobial action could be imparted to cleaning and personal care products. Our research indicated there should be a market for a technology that provided a long lasting, safe antimicrobial benefit to control surface pathogenic agents. We felt that such a technology could be very useful in reducing nosocomial rates even in cases where sanitization and disinfection processes were robustly in place. As an example, hospitals still have high rates of nosocomial problems even in the best of healthcare facilities. This research allowed us to create what we call our dispensable version of the Surfacine technology for inclusion into existing products that provides a long-lasting antimicrobial benefit. We are now in the process of beginning evaluations to demonstrate whether such technology will reduce nosocomial infections."
"The permanent coating can be thought of as a very thin paint that is bonded to the article of manufacture," Sawan says. "We have tested the permanent coating on many materials and have applied it successfully to plastics, metals and ceramics. The dispensable form of the technology was meant as an additive to many types of products for cleaning, disinfection and personal care and thus is compatible with plastics, metals, ceramics and skin. A product that contains Surfacine is used like any other product, whether it is a hand wash, a surface cleaner or a carpet deodorizer. The product leaves a microscopic thin layer of the Surfacine technology that is resistant to rubbing and water but is not permanent. That is, it can be applied to all materials including skin and provide a long lasting, wash and rub-resistant."
Antimicrobial products are not just for medical devices. EnviroCare manufactures several antimicrobial products including its EnviroCoat antimicrobial surface technology for walls and floors, EnviroShield for wood and metal surfaces, and EnviroGuard for carpets and upholstered surfaces. According to Bryan Redler, CEO, "Antimicrobials, particularly those that do not lead to antibiotic resistance, are becoming more and more important to the healthcare arena. Nosocomial infections are a big reason why the medical community is using antimicrobials to complement their normal infection control procedures. Since the mid-1990s, antimicrobial coatings have been used on a growing number of medical devices, so their acceptance has become almost second nature."
In the healthcare setting, EnviroCoat can be applied primarily to carpets, tiles, stainless steel surfaces such as bed rails or tables, and to walls. EnviroCoat's properties are water based rather than solvent based, and are designed for longevity. "The active ingredient is silver and the exact mechanism of how silver kills (bacteria) is still subject to debate," Redler says. "As for applications, one application of the coating is enough to provide efficacy and the coating will remain effective for years. Testing has shown an effectiveness rate of 99.9 percent."
According to consulting firm The Freedonia Group, the U.S. demand for disinfectants and antimicrobial chemicals is projected to approach $700 million in 2005, growing at 6.2 percent annually. In 2000, healthcare facilities accounted for 46 percent of commercial disinfectant and antimicrobial chemical demand. In addition, the large number of respiratory diseases and their associated costs dictates the need for antimicrobial technology to supplement current pharmaceuticals, therapies and remedies.
Taking stock in this need is New York-based Alistagen Corporation, a biotechnology company that has developed a nontoxic antimicrobial agent designed to destroy and prevent the growth of mold, mildew and a number of bacteria including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonae and Bacillus subtilus.
In March Alistagen received market clearance from the Environmental Protection Agency (EPA) for its Bi-Neutralizing Agent (BNA) whose active ingredient is calcium hydroxide in a multi-patented, microencapsulated formulation. When applied to surfaces, hydrated lime, also known as calcium hydroxide, has been used for thousands of years as a germ-fighting agent. The material works by increasing the alkalinity to a level that is incompatible with the life needs of microorganisms. The mode of action is as follows: The BNA system interacts with water vapor and carbon dioxide to produce a surface harmless to humans and animals. Then, bacterial, fungal, viral and algal reproductive units are unsuccessful in colonizing a BNA-treated surface. In the final stage, BNA destroys all microbes tested on contact.
Caliwel will first be available as a pigmented liquid coating that can be applied to walls, floors and other hard surfaces. It is designed to be a safe, anti-infective application that kills most microbes within 5 to 15 minutes and prevents their growth for approximately six years, according to Alistagen CEO Bryan Glynson. In field effectiveness testing, at least 60 percent biocide remained active, while preserving the original pH. After 42 months of exposure, there was a 69.8 percent residual biocide, according to Alistagen's tests.
"This product represents a breakthrough in the control and spread of infectious diseases," says William Mallow, chairman of Alistagen's technical advisory board. Mallow conducted most of the research and development of the BNA technology as a scientist at the Southwest Research Institute in San Antonio, Texas. The technology was conceived for use in hospitals, nursing homes and daycare facilities that harbor microbial infestations that are particularly threatening to immunocompromised individuals.
The Clinical Acid Test
Are clinicians accepting antimicrobial coatings as good science?
"We believe antimicrobial coatings are growing in acceptance by physicians," says Lanzafame. The body of data demonstrating the effectiveness of these coatings isn't yet as large as some physicians would like to see, but that data is growing. Since infection rates are typically relatively low, large patient populations are needed to show a statistically significant improvement in the performance of the coated product. But the costs associated with treating the small percentage of complications can be very significant."
Lanzafame continues, "Antimicrobial coatings are receiving more interest now because the numbers of patients encountering infections is growing as our population ages and more people spend more time in extended hospital stays later in their lives. In addition, the growing concerns over the emergence of multi-drug resistant bacterial strains has shifted focus to antimicrobial coatings. Antimicrobial coating provide localized delivery of active agents to prevent an infection from occurring, which is better for the patient and more cost effective than treating the patient with antibiotics after an infection has developed."
According to Dallmier, "Antimicrobial coatings are part of a comprehensive plan to combat nosocomial and/or device-related infections. Nosocomial infections are the fourth leading cause of death in the United States, behind only heart disease, cancer and strokes. When a medical device is inserted, the most effective barrier to infection, the skin, is disrupted. This provides an avenue for subsequent infections in and around the wound site. The device essentially serves as a platform for biofilm formation. Another advantage of localizing antimicrobials on the device surface is less need for systemic antibiotic dosing. Resistance is a major problem with antibiotics. Also, since the antimicrobial coatings are localized at the device surface, a lower amount of the antimicrobial is needed, reducing the occurrence of detrimental side effects. Antimicrobial coatings are recognized by many clinicians as useful tools to help combat infection. However, it can be difficult to show the in situ benefits of antimicrobial coatings on some devices since they may need to be explanted to ascertain their effect. Plus, the infection process is very dynamic, and many extrinsic factors can lead to device-related infections."
M. Steven Doggett, PhD, founder of St. Paul, Minn.-based consulting firm Microbial Diagnostics, Inc., has more than 14 years of applied expertise on issues related to environmental science, microbiology and public health. He says there is little doubt that risks of nosocomial infections have played a significant role in the development and application of antimicrobial coatings. However, they are not a "silver bullet" against infections and may even convolute the situation.
"We must view antimicrobial coatings as simply one of many lines of defense," Doggett says. "Vigilant attention to hygiene, environmental monitoring and proper sterilization/disinfection protocols must also be maintained. With respect to antibiotic resistance, I find it more plausible that in the long run, antimicrobial coatings will actually hasten the resistance process. After all, most antimicrobial coatings have substantial mutagenic properties. The adherent matrix in which the biostatic or biocidal agent exists is designed simply to provide a controlled release. While effective, such a process will undoubtedly result in some genetic feedback, i.e., resistance. The degree and rate of resistance will depend on the agent, its concentration and the genetic predisposition of the exposed microbe."
While some clinicians may see antimicrobial coatings as junk science, Doggett says they will persist and flourish in the marketplace. "Whether clinicians like it or not, antimicrobial coatings are here to stay, at least until the pendulum swings in favor of a new technology," he adds. "The science of antimicrobial coatings is both theoretically and practically sound. The obvious drawbacks are the potential for too much reliance on such passive measures and the potential for resistance mechanisms in targeted microorganisms. Another significant shortcoming is the limited effectiveness at controlling fungi and other persistent microbes."
Doggett continues, "Antimicrobial coatings have withstood the test of many skeptics; however, practical applications on the clinical front lines have many confounding variables (e.g., hygiene practices, environmental conditions, sterilization/disinfectant techniques, patient condition, etc.) Antimicrobial coatings work by the controlled release of a biocidal or biostatic compound, either organic, inorganic or a combination of several chemical compounds. To be most effective, the coating should be an integral part of the surface at least to the extent possible. The number of applications necessary depends largely on the coating type, the targeted organisms and the intended purpose of the coated surface. It is important to emphasize that coatings are not designed to eliminate or control significant bioburdens. If known contamination exists, whether in environmental media or instruments with direct patient contact, antimicrobial coatings will offer little if any protection. Antimicrobial coatings are not a silver bullet, yet when used in conjunction with other sound practices, they appear to have a positive impact in controlling infection rates. Only time will tell whether any perceived or actual improvements remain significant for the long-term."
Doggett says the effectiveness of antimicrobial coatings may depend on their applications. "They likely have much greater application with medical devices, instrumentation or with environmental surfaces with minimal human contact. Coatings on surfaces such as walls, textiles, air ducts and carpets are much more variable in their overall effectiveness. The primary reason for this is the fact that so many microorganisms are actually exploiting these surfaces as nutrient sources. Add a bit of moisture and you have the conditions necessary to support a dangerous cocktail of microbial growth. For most environmental surfaces, a greater emphasis should be placed on scheduled system maintenance, general hygiene, and environmental monitoring rather than a primary reliance on antimicrobial coatings."
For the softer side of antimicrobials, visit www.infectioncontroltoday.com.