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

September 1, 2002

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 Solutions

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."

Environmental Antimicrobials

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.