Battling Biofilm: Surface Science, Antimicrobials Help CombatMedical Device-Related Infections

September 1, 2002

Battling Biofilm: Surface Science, Antimicrobials Help CombatMedical Device-Related Infections

Battling Biofilm: Surface Science, Antimicrobials Help CombatMedical Device-Related Infections

By Kelly M. Pyrek

Therising number of medical device-related infections and a new emphasis onpatient-safety standards are helping fuel the explosion in a scientificdiscipline known as "surface science."1 The core of thisscience is the fact that most biological reactions occur at surface level. Howcells and proteins interact at the surface is being studied by scientists as theway to analyze and improve the function and durability of the polymers and othermaterials used to manufacture medical devices. It is also ground zero forunderstanding the mechanisms of biofilm, the adherence of bacteria and thetriggering of infection.

The mechanisms of device-related infections are still not completelyunderstood even though "the tendency of foreign bodies to predisposepatients to infection has been recognized since the 14th century," assertsone team of researchers.2 According to researchers at the Centers forDisease Control and Prevention (CDC), microbial biofilms develop whenmicroorganisms adhere to a submerged surface and produce extracellular polymersthat facilitate adhesion to a surface that may be inert, nonliving material orliving tissue.3 Biofilms can develop on the simplest of medicaldevices, such as contact lenses, or they can develop on more complex items suchas prosthetic joints, mechanical heart valves and pacemakers.

"Microbial biofilms may pose a public health problem for personsrequiring indwelling medical devices," writes Rodney M. Donlan of the CDC.4"The microorganisms in biofilms are difficult or impossible to treat withantimicrobial 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 contaminationand biofilm formation: duration of use, number and type of organisms to whichthe device is exposed, flow rate and composition of the medium in or on thedevice, device material construction and conditioning films on the device."

Biofilms can be composed of gram-positive or gram-negative bacteria, andspecies most frequently isolated from medical devices include gram-positiveEnterococcus faecalis and Staphylococcus aureus, and the gram-negativeEscherichia coli, Klebsiella pneumoniae and Pseudemonas aeruginosa. The bacteriacan originate from patients' own skin, from the hands of healthcare workers, orfrom other external sources in the environment. Biofilm is known to be tenaciousas well as highly resistant to antimicrobial treatment; however, that isn'tstopping researchers from trying to combat it with various antimicrobialcoatings.

In an effort to prevent or mitigate bacterial colonization on the surfaces ofimplants and medical devices, manufacturers are investigating surfacemodification technologies, specifically surface coatings that are engineered torelease bactericidal agents in a controlled manner.

"A variety of methods have been developed to modify the surfaces ofpolymers or other biomaterials used in the device industry," writes JonKatz in Medical Plastics and Biomaterials.5 "Examples includeconventional coating processes such as spraying or dipping; vacuum depositiontechniques; and such surface-modification technologies as diffusion, laser andplasma processes, chemical plating, grafting or bonding, hydrogel encapsulationand bombardment with high-energy particles. Traditionally, the goal was toachieve improved physical or mechanical properties in a component or device, forexample, by adding a nonstick coating to a catheter for easier insertion.Increasingly, however, surface modification also aims at inducing a specificdesired bioresponse or inhibiting a potentially adverse reaction."

According to researchers at the University of Texas at Arlington, significantresearch has been invested in the production of bacteria-inhibitory andbactericidal surfaces.6 "Generally speaking, abacteria-inhibitory surface discourages and/or prevents bacterial colonizationand profliferation, and a bactericidal surface elutes bactericides," writesT.L. Lin, et al.

One way to resolve device-related infections is to affix antimicrobial agentsdirectly onto the surface of the device, such as in the case of central venouscatheters or urinary catheters, which have been the source of life-threateningbloodstream infections. It has been estimated that central venous cathetersaccount for 90 percent of all nosocomial bloodstream infections.7Urinary tract infections (UTIs) occur in about 20 percent of patients with Foleycatheters in place for more than 10 days, and in more than 40 percent ofpatients with Foley catheters in place for more than 25 days. There areapproximately 500,000 cases of these kinds of infections in U.S. hospitalsannually, and most are associated with catheters.8 Nosocomial UTIsreportedly cost hospitals $1.8 billion annually, and urinary catheter use isassociated with up to 90 percent of these infections.9

Recent studies have shown that impregnation of catheters with antiseptic orantimicrobial agents is a viable approach to control catheter-associatedinfections. In a study conducted by Dennis Maki and colleagues,10 useof central venous catheters coated with chlorhexidine-silver sulfadiazine wasassociated with a 44 percent reduction in catheter colonization and a 79 percentreduction in the rate of catheter-related bloodstream infections. Use of thesecatheters also showed a significant reduction in the number of organismscolonizing the skin around the catheter-insertion site.

A study by Raad and colleagues11 found that the use of centralvenous catheters coated with minocycline and rifampin was associated withsignificant reductions in the rates of catheter colonization andcatheter-related bloodstream infections.

These studies show that none of the impregnated catheters was associated withhypersensitivity reactions, toxicity or infections caused by resistantpathogens; however, the researchers add that further study is warranted becausethe catheters were in situ for an average of six days and assessment for adverseevents required more observations. "The studies by Maki and Raad and theircolleagues suggest that impregnated catheters, although not a magic bullet, maybe an important advance in reducing the rate of central venous catheter-relatedinfections, particularly in critically ill patients with multilumen cathetersfor the short term and in settings in which rates of central venouscatheter-related bloodstream infection remain high despite full adherence toproven infection control measures," write Michele L. Pearson, MD, and EliasAbrutyn, MD, in the Annals of Internal Medicine.12

Silver Solutions

Silver has long been acknowledged as having antibacterial properties,13but its role in antimicrobial medical devices is continually debated.

"Silver compounds (silver chloride or silver oxide) are a popular choicefor infection-resistant coatings, but many commercially available silver-coatedcatheters are of marginal effectiveness because the hydrophobic polymer matrixlimits the silver ion concentration near the device surface," Jon Katzwrites.15 "A process by STS Biopolymers, Inc. has beendeveloped, however, that incorporates silver compounds in a nonreactive hydrogelpolymer system that provides greater aqueous diffusion from the coating and thusa greater concentration of silver ions at and just above the device surface. Thecoatings can be formulated for short-, intermediate-, or long-term effects;offer controllable lubricity and elution; can be applied inside lumens; anddemonstrate superior adhesion, durability and flexibility."

"Our coating is a permanent polymer coating that binds molecules of theantimicrobial agent into a hydrophilic matrix," says John Lanzafame,director of sales and marketing for STS Biopolymers, Inc. "The agents areeluted over time by diffusion into the surrounding bodily fluids, and ourtechnology allows for control of the degree of hydrophilicity of the coating,which thereby controls the elution rate of the active compound. Our coating canbe applied to any medical devices that require an antimicrobial surface, as longas the product is used in a moist environment. We can accurately control theelution of the antimicrobial agent to periods from hours to weeks, to adjust fordifferent requirements for different product.

SurModics, Inc. manufactures its PhotoLink antimicrobial coatings to deliverinfection resistance properties as well as antimicrobial drug delivery orcombinations of technologies. "We have two different classes ofantimicrobial coatings," explains Anthony W. Dallmier, PhD, director ofmicrobiology. "The most effective approach involves coating anantimicrobial-containing reservoir onto the medical device surface.Antimicrobials are released from this coating at a controlled rate, providingextended protection. A major feature of our photoactivatable antimicrobialreservoir is the flexibility to load a variety of antimicrobials into thecoating. The device manufacturer can tailor its antimicrobial coating foroptimal efficacy against the battery of microorganisms most closely associatedwith infecting the particular device. The second class is to coat the devicewith a photoactivatable hydrophilic coating that doesn't kill the invadingmicroorganism, but prevents its attachment to the device surface. Thesehydrophilic coatings also help minimize microbial migration along the devicesurface. The hydrophilic 'smoothes' out the device surface, reducing anchoringand hiding places for microorganisms."

The origins of some companies' antimicrobial coatings lie in various medicalinterventions. According to Samuel P. Sawan, PhD, president of SurfacineDevelopment Co and Intelligent Biocides, his firm became interested inantimicrobial coatings to solve a problem with patient sensitivity toantimicrobial compounds used as preservatives. "Our original interest wasto create a preservative-free multi-dose dispenser that would maintain amedicament germ free without the use of a preservative. This research was theimpetus to create an antimicrobial surface that did not elute or leach intocontacting fluids. We then began looking for other applications for thistechnology. Our attention was drawn to medical devices where the incidence ofnosocomial infections associated with implanted devices was high and to ifethreatening complications. Our interest in permanent coatings led us to exploreand develop the technology for other applications where a long-lastingantimicrobial action could be imparted to cleaning and personal care products.Our research indicated there should be a market for a technology that provided along lasting, safe antimicrobial benefit to control surface pathogenic agents.We felt that such a technology could be very useful in reducing nosocomial rateseven in cases where sanitization and disinfection processes were robustly inplace. As an example, hospitals still have high rates of nosocomial problemseven in the best of healthcare facilities. This research allowed us to createwhat we call our dispensable version of the Surfacine technology for inclusioninto existing products that provides a long-lasting antimicrobial benefit. Weare now in the process of beginning evaluations to demonstrate whether suchtechnology will reduce nosocomial infections."

"The permanent coating can be thought of as a very thin paint that isbonded to the article of manufacture," Sawan says. "We have tested thepermanent coating on many materials and have applied it successfully toplastics, metals and ceramics. The dispensable form of the technology was meantas an additive to many types of products for cleaning, disinfection and personalcare and thus is compatible with plastics, metals, ceramics and skin. A productthat contains Surfacine is used like any other product, whether it is a handwash, a surface cleaner or a carpet deodorizer. The product leaves a microscopicthin layer of the Surfacine technology that is resistant to rubbing and waterbut is not permanent. That is, it can be applied to all materials including skinand provide a long lasting, wash and rub-resistant."

Environmental Antimicrobials

Antimicrobial products are not just for medical devices. EnviroCaremanufactures several antimicrobial products including its EnviroCoatantimicrobial surface technology for walls and floors, EnviroShield for wood andmetal surfaces, and EnviroGuard for carpets and upholstered surfaces. Accordingto Bryan Redler, CEO, "Antimicrobials, particularly those that do not leadto antibiotic resistance, are becoming more and more important to the healthcarearena. Nosocomial infections are a big reason why the medical community is usingantimicrobials to complement their normal infection control procedures. Sincethe mid-1990s, antimicrobial coatings have been used on a growing number ofmedical 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 aredesigned for longevity. "The active ingredient is silver and the exactmechanism of how silver kills (bacteria) is still subject to debate,"Redler says. "As for applications, one application of the coating is enoughto provide efficacy and the coating will remain effective for years. Testing hasshown an effectiveness rate of 99.9 percent."

According to consulting firm The Freedonia Group, the U.S. demand fordisinfectants and antimicrobial chemicals is projected to approach $700 millionin 2005, growing at 6.2 percent annually. In 2000, healthcare facilitiesaccounted for 46 percent of commercial disinfectant and antimicrobial chemicaldemand. In addition, the large number of respiratory diseases and theirassociated costs dictates the need for antimicrobial technology to supplementcurrent pharmaceuticals, therapies and remedies.

Taking stock in this need is New York-based Alistagen Corporation, abiotechnology company that has developed a nontoxic antimicrobial agent designedto destroy and prevent the growth of mold, mildew and a number of bacteriaincluding Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli,Klebsiella pneumonae and Bacillus subtilus.

In March Alistagen received market clearance from the EnvironmentalProtection Agency (EPA) for its Bi-Neutralizing Agent (BNA) whose activeingredient is calcium hydroxide in a multi-patented, microencapsulatedformulation. When applied to surfaces, hydrated lime, also known as calciumhydroxide, has been used for thousands of years as a germ-fighting agent. Thematerial works by increasing the alkalinity to a level that is incompatible withthe life needs of microorganisms. The mode of action is as follows: The BNAsystem interacts with water vapor and carbon dioxide to produce a surfaceharmless to humans and animals. Then, bacterial, fungal, viral and algalreproductive units are unsuccessful in colonizing a BNA-treated surface. In thefinal stage, BNA destroys all microbes tested on contact.

Caliwel will first be available as a pigmented liquid coating that can beapplied 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 andprevents their growth for approximately six years, according to Alistagen CEOBryan Glynson. In field effectiveness testing, at least 60 percent biocideremained 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 ofinfectious diseases," says William Mallow, chairman of Alistagen'stechnical advisory board. Mallow conducted most of the research and developmentof the BNA technology as a scientist at the Southwest Research Institute in SanAntonio, Texas. The technology was conceived for use in hospitals, nursing homesand daycare facilities that harbor microbial infestations that are particularlythreatening to immunocompromised individuals.

The Clinical Acid Test

Are clinicians accepting antimicrobial coatings as good science?

"We believe antimicrobial coatings are growing in acceptance byphysicians," says Lanzafame. The body of data demonstrating theeffectiveness of these coatings isn't yet as large as some physicians would liketo see, but that data is growing. Since infection rates are typically relativelylow, large patient populations are needed to show a statistically significantimprovement in the performance of the coated product. But the costs associatedwith treating the small percentage of complications can be verysignificant."

Lanzafame continues, "Antimicrobial coatings are receiving more interestnow because the numbers of patients encountering infections is growing as ourpopulation ages and more people spend more time in extended hospital stays laterin their lives. In addition, the growing concerns over the emergence ofmulti-drug resistant bacterial strains has shifted focus to antimicrobialcoatings. Antimicrobial coating provide localized delivery of active agents toprevent an infection from occurring, which is better for the patient and morecost effective than treating the patient with antibiotics after an infection hasdeveloped."

According to Dallmier, "Antimicrobial coatings are part of acomprehensive plan to combat nosocomial and/or device-related infections.Nosocomial infections are the fourth leading cause of death in the UnitedStates, behind only heart disease, cancer and strokes. When a medical device isinserted, the most effective barrier to infection, the skin, is disrupted. Thisprovides an avenue for subsequent infections in and around the wound site. Thedevice essentially serves as a platform for biofilm formation. Another advantageof localizing antimicrobials on the device surface is less need for systemicantibiotic dosing. Resistance is a major problem with antibiotics. Also, sincethe antimicrobial coatings are localized at the device surface, a lower amountof the antimicrobial is needed, reducing the occurrence of detrimental sideeffects. Antimicrobial coatings are recognized by many clinicians as usefultools to help combat infection. However, it can be difficult to show the in situbenefits of antimicrobial coatings on some devices since they may need to beexplanted to ascertain their effect. Plus, the infection process is verydynamic, and many extrinsic factors can lead to device-related infections."

M. Steven Doggett, PhD, founder of St. Paul, Minn.-based consulting firmMicrobial Diagnostics, Inc., has more than 14 years of applied expertise onissues related to environmental science, microbiology and public health. He saysthere is little doubt that risks of nosocomial infections have played asignificant role in the development and application of antimicrobial coatings.However, they are not a "silver bullet" against infections and mayeven convolute the situation.

"We must view antimicrobial coatings as simply one of many lines ofdefense," Doggett says. "Vigilant attention to hygiene, environmentalmonitoring and proper sterilization/disinfection protocols must also bemaintained. With respect to antibiotic resistance, I find it more plausible thatin the long run, antimicrobial coatings will actually hasten the resistanceprocess. After all, most antimicrobial coatings have substantial mutagenicproperties. The adherent matrix in which the biostatic or biocidal agent existsis designed simply to provide a controlled release. While effective, such aprocess will undoubtedly result in some genetic feedback, i.e., resistance. Thedegree and rate of resistance will depend on the agent, its concentration andthe genetic predisposition of the exposed microbe."

While some clinicians may see antimicrobial coatings as junk science, Doggettsays they will persist and flourish in the marketplace. "Whether clinicianslike it or not, antimicrobial coatings are here to stay, at least until thependulum swings in favor of a new technology," he adds. "The scienceof antimicrobial coatings is both theoretically and practically sound. Theobvious drawbacks are the potential for too much reliance on such passivemeasures and the potential for resistance mechanisms in targeted microorganisms.Another significant shortcoming is the limited effectiveness at controllingfungi and other persistent microbes."

Doggett continues, "Antimicrobial coatings have withstood the test ofmany skeptics; however, practical applications on the clinical front lines havemany confounding variables (e.g., hygiene practices, environmental conditions,sterilization/disinfectant techniques, patient condition, etc.) Antimicrobialcoatings work by the controlled release of a biocidal or biostatic compound,either organic, inorganic or a combination of several chemical compounds. To bemost effective, the coating should be an integral part of the surface at leastto the extent possible. The number of applications necessary depends largely onthe coating type, the targeted organisms and the intended purpose of the coatedsurface. It is important to emphasize that coatings are not designed toeliminate 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. Antimicrobialcoatings are not a silver bullet, yet when used in conjunction with other soundpractices, they appear to have a positive impact in controlling infection rates.Only time will tell whether any perceived or actual improvements remainsignificant for the long-term."

Doggett says the effectiveness of antimicrobial coatings may depend on theirapplications. "They likely have much greater application with medicaldevices, instrumentation or with environmental surfaces with minimal humancontact. Coatings on surfaces such as walls, textiles, air ducts and carpets aremuch more variable in their overall effectiveness. The primary reason for thisis the fact that so many microorganisms are actually exploiting these surfacesas nutrient sources. Add a bit of moisture and you have the conditions necessaryto support a dangerous cocktail of microbial growth. For most environmentalsurfaces, a greater emphasis should be placed on scheduled system maintenance,general hygiene, and environmental monitoring rather than a primary reliance onantimicrobial coatings."

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