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October 24, 2013
5 Min Read
By Bob Michaels, Senior Technical Editor
"By definition, all antimicrobial-coated devices are combination products," explains Marc Mittelman, senior managing scientist, occupational and environmental health, Exponent (Menlo Park, CA). "Thus, if a catheter is coated with silver--probably the most common type of coating today, particularly for urinary catheters--that's considered to be a combination product. It combines an antimicrobial and an underlying device."
For the most part, device-antimicrobial combinations are used to prevent infections that are associated with the underlying use of the device. The idea behind a device-antimicrobial combination, according to Mittelman, is to either inhibit microorganisms from attaching to the device or to inactivate or kill microbes if they came into contact with the device.
Examples of medical device-related bacteria that can cause infections include Pseudomonas aeruginosa on a silver peritoneal dialysis catheter (left), Proteus vulgaris biofilm on a ureteral stent (middle), and Staphylococcus aureus on a silicone catheter (right).
The key to preventing device-related infections is to prevent bacterial attachment and subsequent biofilm formation. Biofilms are composed of a discrete association between a manmade device and bacteria or, less frequently, fungi. Once the organisms attach, they elaborate an extracellular polymeric substance, which stabilizes their attachment, and then they divide. Known as colonization, this process results in the formation of a biofilm, which often has an intrinsic resistance to all antimicrobials. Biofilm-mediated infections are difficult to treat, Mittelman says, and in some cases, the only way to eradicate them is to remove the medical device until the infection is resolved.
"The purpose of antimicrobial combination devices is to prevent microbial adhesion, or biofilm formation," Mittelman comments. "They are interesting because they offer delivery at the attachment site--the host-device interface. In contrast, the use of systemic antimicrobials involves dosing the whole body with a drug in the hope of getting a sufficient concentration right at the device-host tissue interface."
Originally, most of the effort to develop combination products was directed toward developing coatings for different types of devices. These coatings, in turn, often contained antibiotics. Probably the earliest example of such a device was bone cement, which has been mixed with gentamicin and other antibiotics since the early 1960s. The standard approach involved coating devices with various kinds of antibiotics and hoping that they would provide enough activity for a long enough period of time to prevent infections.
With the evolution of materials science in the intervening years, manufacturers have learned how to fabricate antibiotic-laden combination products with longer lives. Other materials breakthroughs have resulted in the creation of polymers that incorporate antimicrobials into the backbone of the material and then release the agent under controlled conditions as the polymer degrades. Meanwhile, efforts have been made to eliminate antimicrobials altogether from medical devices and design microbe-resistant surfaces. "Such antifouling technology," Mittelman says, "usually means using steric hindrance at the molecular level to prevent microorganisms from attaching to the surface of the device or using materials with functional groups on the surface that inhibit the growth of microorganisms."
Advances have also been made in the development of antithrombogenic surfaces that reduce blood-clot formation--a method, Mittelman notes, that is also known to inhibit microbial adhesion. Because several types of bacteria require blood components to be able to attach to surfaces and form biofilms, reducing thrombus formation on medical devices that make contact with the blood can minimize microbial adhesion and the incidence of infections.
Two distinct types of challenges confront the manufacture of combination devices: regulatory and a scientific. On the regulatory side, FDA in the past few years has been requiring human clinical trials to support any infection-reduction claims. This requirement, however, retards the development of new antimicrobial combination devices because small companies have difficulty recruiting the large numbers of patients required to conduct trials. Moreover, the incidence of many kinds of device-related infections is very low--less than 1% for many kinds of orthopedic devices, for example.
Moreover, because of concerns that low-level release of antimicrobials over time could select for antimicrobial-resistant bacterial populations, FDA has been asking manufacturers to demonstrate that their antimicrobial combination devices will not result in the generation of resistant isolates. Finally, manufacturers should also demonstrate that their antimicrobial combination devices will not significantly affect host-normal flora--a suggestion that is difficult to meet from a clinical-trial standpoint, Mittelman says.
From a science standpoint, the main challenge is ensuring that a sufficient concentration of an antimicrobial agent will be available at the device surface for an extended period of time--for example, 30 days. For long-term implantable devices, extended antimicrobial protection may provide the host tissue with sufficient time to integrate with the device, reducing the risk of infection.
"How do you achieve good antimicrobial activity for 30 days?" Mittelman asks. One of the most promising technologies is a polymer-antimicrobial combination in which the polymer is part of the actual delivery system. In such designs, the antimicrobial becomes part of the device, and you achieve drug residence as long as the device remains intact. Other developments include engineered surfaces that both greatly limit the amount of thrombus formation and also seem to retard microbial adhesion to surfaces. "But at the molecular level," Mittelman adds, "it's ultimately material structures that will sterically inhibit the development of bacteria on device surfaces. This also includes fungi, which are also associated with device-related infections."
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