The rise in healthcare associated infections (HAIs) has placed a major burden on the healthcare industry. Approximately 1.7 million cases of HAIs occur in the US each year. These account for an estimated 99,000 deaths and $45 billion in added healthcare costs annually.1, 2

In the past, the industry did not have a good grasp on the factors that contributed to these infections due to vague definitions of what constituted an HAI, discrepancies in HAI categorization, and inconsistent reporting. But in recent years, legislation pertaining to HAIs on the state and federal levels has placed increased pressure on healthcare providers to take a closer look at what is driving the HAI epidemic.

Thirty states now have laws that require healthcare facilities to report certain HAIs, and as of October 2008, Medicare reduced reimbursements for services associated with some of the most prevalent HAIs, including surgical site infections, vascular catheter-associated infections, and catheter-associated urinary tract infections.

With improvements in HAI reporting and data quality, the industry is obtaining a clearer picture of the factors that contribute to these infections. A major contributing factor that has emerged is the use of medical devices on or within the body, with at least one-half of all HAI cases being medical device related.3

To protect their devices against microbial contamination and reduce the risk of biofilm buildup, an increasing number of medical device manufacturers are designing devices that feature antimicrobial technology. This article presents background on the use of antimicrobials in medical devices and explores design considerations when selecting an antimicrobial, including manufacturing and regulatory requirements.

Understanding antimicrobials

Conventional medical devices cannot fight off microbes, so they are prone to biofilm buildup. Biofilm is an organized community of bacteria protected by a slime layer that is highly resistant to antibiotic treatment.

The objective of an antimicrobial protected device is to break this cycle of bacterial contamination by preventing microbial colonization and subsequent biofilm formation. While hand washing and other active hygiene measures are primary lines of defense against device contamination, antimicrobial technology provides a passive yet effective means by which to protect the device against microbes during its use on or within the body.

Antimicrobial protected devices on the market today include those devices most closely associated with HAIs, including urinary catheters, central venous catheters and wound care products. Certain medical devices that incorporate antimicrobial technology have gone through clinical trials and gained FDA 510(K) clearance for their capacity to reduce infections.

Choosing antimicrobial technology

There are a wide variety of antimicrobial technologies on the market today, all with their own active ingredients, modes of operation, safety profiles and application requirements. A manufacturer can narrow down the list of possible choices by evaluating only those technologies that are compatible with its manufacturing process and meet the requirements of its device’s intended use.

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Manufacturing process. Antimicrobials can be incorporated into devices in two ways: applied as a coating to the device surface or integrated into the device polymer. In choosing an antimicrobial technology, a manufacturer must ensure that its chosen technology is compatible with its manufacturing process. For example, if a manufacturer already applies a coating to its device for another reason, such as for antithrombosis or lubricity, an antimicrobial that must be integrated into the device polymer would be incompatible since the coating would cover it up and render it ineffective.

Sterilization. A manufacturer must also take into consideration its sterilization method when choosing an antimicrobial technology. It must ensure that its chosen antimicrobial has been evaluated in conjunction with its specific sterilization method and remains stable as it is subjected to the chemicals, radiation, and temperatures used in the process. If a manufacturer chooses an antimicrobial technology that is incompatible with its existing sterilization method, it must be prepared to invest the time and resources into an alternate method.

Safety and efficacy. When evaluating antimicrobial technology, a manufacturer must also take into account the safety and efficacy factors that are necessary for its intended device. These will vary considerably based on the type of device and its conditions of use. For example, an antimicrobial that is suitable for a urinary catheter that will be used on an adult patient for five days may not be appropriate for a hydroencephalitis shunt that will be used to drain fluid out of the brain of a pediatric patient for five years.

Clearing FDA

FDA review of medical devices with antimicrobial agents has been a constantly moving landscape that continues to evolve. Some manufacturers that begin the 510(k) clearance process abandon plans for their devices because what the FDA required at the beginning of the process is not what it requires towards the end, leaving the manufacturer to invest significant time and resources in additional testing.

Since most medical device manufacturers are experts in the design and function of their devices, and not in the design and function of their chosen antimicrobial, choosing an experienced antimicrobial technology with a strong track record in working through the 510(k) clearance process is important.

The FDA’s current requirements for antimicrobial protected devices focus on the device’s purpose, safety, efficacy and conditions under which the devices are tested. Below are some of the key factors that a manufacturer must consider when embarking on the 510(k) clearance process.4

Market need. A manufacturer must clearly state why it is treating its device with an antimicrobial agent, including the infection challenges that it is trying to address and the potential benefits to the patient. If the device category has not been linked to infections, the manufacturer will have little chance for securing FDA clearance.

Antimicrobial technology. The FDA requires details on the active ingredient, how much is incorporated into the device, and its mechanism of action.

Efficacy. During efficacy testing, the manufacturer must test the antimicrobial protected device against the specific organisms that cause the infections associated with the device.

Conditions of use. The manufacturer must test its device under conditions that accurately model the conditions in which it will be used in clinical practice, including the relevant aspects of the intended biological system. For example, a central venous catheter must be tested in conditions that appropriately model blood flow, while a urinary catheter must be tested in a relevant urine model.

Kinetics of release. To prove efficacy, a manufacturer must clearly demonstrate the kinetics of the antimicrobial’s release from the device into the body. For example, if the device is a urinary catheter that is intended for use within the body for seven days, the kinetics of release must clearly show that the antimicrobial is released at an appropriate rate to remain effective through that sevenday period.

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Avoiding pitfalls

There are a number of pitfalls that can be avoided by thinking ahead and anticipating additional information that the FDA may require during 510(k) clearance process. In most cases, it is better to have collected too much data than not enough. Below are some common pitfall scenarios and solutions.

Shelf-life scenario: A manufacturer comes to the end of its testing protocols on its final device formulation and realizes that it needs to demonstrate to the FDA that the antimicrobial within its device is still effective six months after the device was manufactured. Since the manufacturer didn’t set aside device samples in appropriate storage conditions, it must wait an additional six months before performing these shelf-life tests because the FDA does not accept accelerated aging on antimicrobial protected devices.

Solution: If a manufacturer desires an extended shelf life for its device, it must be sure to store device samples under appropriately modeled conditions at the beginning of its testing process. It’s also important to note that the FDA requires that the manufacturer store samples of the device in its completed form rather than components of the device material.

Data collection scenario: A manufacturer performs tests, measuring the concentration of the antimicrobial used in its device, runs the device through use conditions for a month, measures the antimicrobial concentration and its performance tests successfully. Once this primary challenge has been met, the manufacturer begins performing additional tests to answer the variety of other questions posed by the FDA.

Solution: By conducting experiments in parallel or designing them to produce answers to several questions, a manufacturer can collect additional data to satisfy the FDA’s requirements and avoid serial experiments, which can lengthen a device’s development time.

Device variants scenario: A manufacturer has two versions of its device – a catheter intended for use over the course of a week and another version intended for use over the course of a month. It performs its efficacy testing on the weeklong device only and submits its data to the FDA, which in turn, requests efficacy data for the month-long device. As a result, the manufacturer must repeat its testing on the more complex device.

Solution: A manufacturer must keep in mind that if it has two variants of its device, such as different sizes or different usages within the body, it is likely that the FDA will request data on the more complex of the variants, so it is in the manufacturer’s best interest to invest the time and resources into performing its tests on that version of the device rather than the less challenging of the two.

Right direction

It has become clear to the healthcare industry that there is no silver bullet for the HAI epidemic because it is a complex problem that requires a myriad of solutions. Thanks to better data quality and reporting, there is greater awareness among healthcare providers and medical device manufacturers on the role that devices play in HAIs – and an understanding of how certain antimicrobial-treated devices can help break the cycle of infection and promote cleaner healthcare environments.

While HAI awareness is high among device manufacturers, securing regulatory clearance for antimicrobial-treated devices remains a challenge due to the FDA’s ever-changing requirements. Not until the FDA stabilizes its device requirements will more manufacturers adopt antimicrobial protection. Fortunately, it appears that the FDA is moving in this direction as it provides manufacturers with more concrete guidance to aid them in developing these advanced – and in many cases urgently needed – devices.

FOOTNOTES:
1. Centers for Disease Control and Prevention
2. Scott II, R. Douglas, The Direct Medical Costs of Healthcare Associated Infections in U.S. Hospitals and the Benefits of Prevention, March 2009
3. Multidisciplinary Alliance Against Device-Related Infections (MADRI)