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To Improve Medtech Sterilization, Try a Little Science and Creativity

Weighing in on the rash of infections and deaths associated with Olympus’s duodenoscope, a commentator offers provocative insights into how to grapple with microbes.

Wayne Rogers

Olympus Corp.’s endoscopic retrograde cholangiopancreatography (ERCP) duodenoscope has been associated with cases of infection and death at several hospitals in the United States.

The recent infections and deaths caused by Olympus Corp.’s endoscopic retrograde cholangiopancreatography (ERCP) duodenoscopes at the Ronald Reagan UCLA Medical Center and Cedars Sinai in Los Angeles; Virginia Mason Medical Center in Seattle; Advocate Lutheran General Hospital in Park Ridge, IL; and other facilities raises significant concerns about antibiotic- and sterilization-resistant superbugs. If neither antibiotics nor sterilization can destroy antibiotic-resistant superbug organisms, we are faced with a double whammy. And if it took a recognized and important microbe to discover that sterilization processes failed, the question arises: What else is happening that isn’t being investigated or recognized, such as hospital-acquired infections?

A validated and certifiable process, sterilization is supposed to be an absolute term meaning the inactivation of all viable forms of life. Its success is expressed as the sterility assurance level (SAL)—that is, the probability that a single unit will be nonsterile after it has been subjected to sterilization. In the medical device industry, SALs are expected to be as stringent as 1 × 10–6, meaning that a device has a one in a million chance of containing a nonsterile unit.

No single sterilization method is suitable for all healthcare products. However, why do such Enterobacteriaceae as Klebsiella survive on sterilized medical devices when such bacteria can be inactivated using a simple low-steam pasteurization temperature of 63°C for 30 minutes? Klebsiella is less resistant than Mycobacterium, which can only be inactivated using high-level disinfection. Is the bioburden too hidden, too highly resistant, too protected to be reached by the sterilant?

If so, a superbug might be defined as a microorganism that can survive virtually any sterilization process, offering increased resistance in large populations because it exhibits occlusion, clumping, encrustation, heterogeneity, a nonlogarithmic response, limited accessibility, or antibiotic resistance.

Superbug Outbreaks by the Numbers

FDA and the Centers for Disease Control and Prevention (CDC) maintain that reusable devices or devices that touch mucous membranes should, at a minimum, receive high-level disinfection between patients. However, some hospitals suggest that their cleaning and sterilization processes have not been quite adequate. And because the duodenoscopes contaminated patients’ bloodstream, causing infections, it was apparent that they had not achieved a minimal sterility assurance level.

At Ronald Reagan UCLA Medical Center, carbapenem-resistant Enterobacteriaceae (CRE) was responsible for the superbug outbreak. Associated with high mortality rates, CRE-related bloodstream infections can potentially kill one in two people. For example the UCLA and Cedars-Sinai CRE clusters were the fourth and fifth reported CRE outbreaks associated with ERCP duodenoscopes.

Despite the lethality of these superbugs and the continuing use of reprocessor-delivered cleaning and sterilization procedures, hospital officials indicate that such outbreaks are only rare occurrences. Nevertheless, of the 500,000 patients that have undergone procedures involving the use of the ERCP duodenoscope, several have died. Reaching 1.8 × 10–6 SAL, this fatality rate exceeds the 1 × 10–6 SAL standard, indicating that the devices are more risky than previously indicated.

Closeup view of Olympus's ERCP duodenoscope shows areas that are hard to reach during cleaning or sterilization.

Besides Ronald Reagan UCLA Medical Center, other users have noted that the duodenoscope has remained contaminated despite reprocessing. From 2004 to 2009, it was associated with 62 reports of contamination or sterility failures, while from January 2013 to December 2014, FDA received a total of 75 reports involving 135 patients in the United States indicating possible microbial transmission from preprocessed duodenoscopes. Meanwhile, one manufacturer knows of more than 95 complaints associating the device with infections. All in all, from 2004 to 2015, the percentage of sterility failures associated with the ERCP duodenoscopes appeared to be higher than the number of contamination failures associated with large-volume parenterals in the early 1970s.

The fact that Ronald Reagan UCLA Medical Center and Advocate Lutheran General Hospital are now using EtO sterilization to sterilize duodenoscopes indicates that stricter and improved sterilization steps beyond FDA recommendations may help hospitals avoid more infections. However, questions remain. What constitutes stricter sterilization steps? Is double sterilization required? Are many new or liquid sterilization methods capable of sterilizing surfaces only? Are they less penetrable than traditional methods? Until the recent outbreaks, were hospitals using merely high-level disinfection instead of sterilization?

Sterile, Sterilization, and Sterilizer

Because the terms sterile, sterilization, and sterilizer were incorrectly used as synonyms for disinfection, decontamination, and commercial sterilization, the Council on Pharmacy and Chemistry of the American Medical Association issued a statement in 1936 insisting that in a bacteriological sense, these terms should be used only to connote the absence or destruction of all microorganisms. Since sterile, sterilization, and sterilizer are not relative terms, permitting their use in a relative sense is not only is incorrect, it also opens the way to abuse and misunderstanding. Is the past prologue to the future?

The more diffuse the meaning of the terms sterilization and high-level disinfection become, the more we are going to read something else into them, whereby they will lose their significance. Consequently, unless the classical definitions of sterile, sterilizer and sterilization are understood and applied, uncertainties may arise.

A variety of sterilization methods has evolved over the years. However, all sterilization methods are based on specific sterility assumptions, and all have limitations. Steam sterilization, for example, fulfills the full definition of the term sterilization in that it inactivates all microbes, including prions. Dry heat and EtO, in contrast, cannot kill prions. While new methods challenge the classical definition of the word sterilization, some of these methods cannot inactivate infrequent nonspore organisms or very small viruses. In addition, in contrast to traditional methods, new and liquid sterilization methods frequently cannot penetrate into device areas protected by biobarriers or mechanical accesses.

While cases of superbug contamination in hospitals are not uncommon, they are very rare in the dentistry field. Why? Probably because most dental equipment—whether critical or semicritical—can be heat sterilized. However, despite CDC recommendations that heat sterilization be given first priority in healthcare facilities, this method may not be compatible with many of the heat-sensitive materials and polymers that are used to manufacture medical devices. Thus, instead of heat sterilization, low-temperature steam pasteurization can be used to kill nonspore antibiotic superbugs.

Sterility

Sterilization, sterility, and statistics shouldn’t lie, but assumptions can. Unlike antibiotics, sterilization is defined as a method for killing all microbes. Thus, if sterilization fails to achieve this purpose, assuming that antibiotics can be relied upon to stop all infections in healthcare facilities can have lethal consequences.

In addition to its existing cleaning and sterilization procedures, Virginia Mason Medical Center has developed an approach to combating antibiotic-resistant superbugs that includes a test-and-hold phase. After scopes have been cleaned, they are cultured for potential pathogens and then quarantined for 48 hours until they are confirmed to be free of dangerous bacteria. To ensure that the devices are accurately and thoroughly tested for bacteria, this procedure should be performed only by skilled and knowledgeable microbiologists. CDC is investigating a similar approach. However, while this method has some merit from a liability point of view, it will remain more art than science because neither media nor sample collections can recover all microbes.

While precleaning and sterilization are supposed to reduce the likelihood of cross-contamination among patients, bacteria may remain if a device has minuscule crevices that cannot be reached using liquid or surface sterilization methods. Additionally, microbial occlusion, encrustation, or recontamination can result in microbial resistance, biofilm formation, or calcification. Beyond the presumptions of sterility tests or sterilization methods, there is always a possibility that some microorganisms will remain insoluble or inaccessible, while incubation times or sample sizes will remain insufficient.

EtO sterilization is a positive approach toward eliminating superbugs from contaminated ERCP duodenoscopes, but this method has fallen out of favor at some healthcare facilities. At Virginia Mason Medical Center, for example, it has been removed because it is seen as carcinogenic, posing a danger to the staff. For its parts, FDA has also been hesitant to recommend routine EtO sterilization because the gas can be toxic, potentially carcinogenic, explosive, mutagenic, or sensitizing to hospital workers.

Nevertheless, the recent antibiotic-resistant CRE superbug outbreaks highlight the importance of sterilizing medical equipment and healthcare facilities, and the right sterilization reprocessing equipment provides the best approach to preventing the spread of infection while reducing resistance to antibiotics. For those facilities that no longer use EtO, perhaps a safe penetrating gaseous alternative will be developed that is compatible with the materials from which various endoscopes are made.

Developing New Sterilization Techniques

In her editorial titled “We Need Science, not Scapegoats, in Sterility Assurance Debate,” Mary Logan, president of the Association for the Advancement of Medical Instrumentation (AAMI), comments, “When it comes to contaminated medical devices, everyone wants to find a scapegoat, but this is a complex challenge that won’t be resolved by pointing fingers: It’s too easy to blame manufacturers for the design; the FDA for not forcing better designs; healthcare delivery organizations for not being disciplined enough about proper cleaning; the people who do the cleaning; etc.” True, but there is more to the universe than standard science—there is also creativity.

To get a glimpse of the larger contingencies and endeavors facing the medical device industry, start small. For example, a little creativity can go a long way toward reviewing, developing, and improving low-temperature disinfection or sporocide-based low-temperature sterilization techniques using sterile packages or filters. These methods can then be validated using a range of biological, microbiological, mathematical, and chemical- and material-compatibility studies.

Logan states that the medical device industry needs to press for more science before it settles for simple answers. There are many things that the industry doesn’t know and that require further study, including the types of bugs that exist, culturing, types of scopes, new tools, training and credentialing, extending sterilization times, asking questions during surveyor visits, standardization of reprocessing instructions, inventory standardization, and better scope designs. The concerns she raises can be addressed in the following ways.

Types of Bugs. Klebsiella should not be difficult to sterilize; it can be inactivated by performing low-steam pasteurization at 63°C for 30 minutes or less. However, this microbe can survive if it is encrusted in organic matter or calcification or if it is sterilized under low-humidity conditions using EtO. If it is hidden within mated or tight parallel surfaces, the bug can also survive sterilization using liquid sterilants. In contrast, the dental industry has shown that dry or moist heat sterilization is more effective than EtO at inactivating hidden microbes in instruments.

While precleaning, high-level disinfection, or sterilization of reprocessed devices is supposed to preclude the likelihood of cross-contamination among patients, microbes can survive for other reasons. For example, the heterogeneity of bioburden populations causes increased resistance of some microbes over others. Mathematically, heterogeneity versus homogeneity implies inherent variability and uncertainty.

In addition, in sterilization processes, microbes experience what is known as a logarithmic, or exponential, form of death. This phenomenon was discovered in 1908 by Harriette Chick, who found that logarithms of the numbers of surviving bacteria were directly related to the exposure times to disinfectants or sterilants, so that when one was plotted against the other, the points lay on a straight line. Subsequently, this phenomenon was confirmed by the disinfection of anthrax spores using phenol and mercuric chloride, although O. Rahn (1945) maintained that only 40% of the different disinfectants and sterilants demonstrated this logarithmic slope. Furthermore, there are exceptions to the rule of logarithmic death that cannot be explained simply as deviations from the norm resulting from experimental error.

Even when microbial death follows a definite logarithmic pattern, it is sometimes possible to isolate strains that resist bactericidal action. According to Rahn, when the death curve varies from the logarithmic pattern, there is strong evidence that a resistant strain may be isolated by repeatable culturing of the last survivors. This resistance may be due to mutation or adaptation.

For mathematical reasons, a logarithmic order probably results from the destruction of a single molecule in the cell. It is highly improbable that this single molecule is one of many equal enzyme molecules in the cell. It is far more probable that it is a very rare gene molecule or another important molecule of the cell division mechanism. Death caused by moist heat is quite different from death caused by dry heat. However, it would seem that any single molecule in a cascade of reproducing molecules could be responsible for the logarithmic linearity of inactivation using sterilants.

Culturing. We know that bioburden and laboratory identification media can recover microbes better that general sterility media can. However, while we have learned to advance analytical physical, chemical, and computerized measuring equipment and instrumentation, sterility media have not advanced in the last 50 years. Beyond simple sterility tests or culturing, it is probable that the product tested may not be sterile. For example, there is a statistical relationship between sample size/sample area and the probability of accepting an unsterile product at different contamination levels.

Types of Scopes. Logan remarks: “This problem is broader than a single type of scope, so we need to be careful not to focus too narrowly on a single point of failure with one type of scope.” In addition, we must bear in mind that scopes are not the only instruments that require sterilization. Meanwhile, while many surface sterilants have appeared on the market, at least one could only achieve disinfection rather than sterility, despite original claims to the contrary.

New Tools. Some new solutions can potentially create new problems by complicating the initial process. For example, dry heat can cause some microbes to desiccate under the right microenvironmental conditions, increasing their longevity. Thus, some manufacturers of sterile devices have shown that humidity levels ranging from 20 to 40% RH have a greater impact on reducing bioburden than drier conditions or higher humidities can under ambient conditions.

Will the creation of EtO sterilization residuals or the potential harm to hospital staff posed by performing EtO sterilization pose a greater risk than the survival of superbugs? Will EtO sterilization overcome natural bioburden barriers that other methods will not overcome? Besides new tools, we should look back historically and see what other solutions may exist. The use of synergistic equipment and processes could improve both EtO residuals and the EtO sterilization process itself.

Proper Training and Credentialing. Because the demands of the reprocessing industry have evolved, we need personnel with higher skills. Too often, people are thought to be skilled when they are not (e.g., the nurse at the Dallas hospital where the Ebola tragedy occurred wasn’t trained properly). While many technicians have been credentialed, they need to be upgraded and recredentialed.

Extending Sterilization Times. Logan remarks, “Reprocessing professionals advocate slowing down the process and maintaining a sufficient inventory of reusable medical devices, so that each step in sterility assurance is followed in a disciplined way, using AAMI standards, and in recognition of the full cycle.” Slowing down the process may create other, unforeseen problems. Applying just-in-time problem solving may offer a better solution.

Asking Questions during Surveyor Visits. If surveyors find that one institution is doing things right, they might be willing to train and help other institutions that aren’t there yet. For starters, they can disseminate information on what they learned during surveyor visits.

Standardization of Reprocessing Instructions. Because reprocessing instructions are voluminous and highly variable, the medical device industry should seek other alternatives to the paradigms of standardization—for example, creativity. Possibly, more than one technician should be involved to reduce variability and mistakes. In addition, better sterilization techniques must be applied to overcome reprocessing failures.

Inventory Standardization. “Healthcare delivery organizations need to standardize their scope inventory,” Logan says. While maintaining a standardized inventory could be helpful, prioritizing is also crucial. Manufacturers should know what equipment to use, what to do first, or how to develop a strategic plan or alternative approach if a different brand, model, or type of product must be used. Manufacturers should also consider partnering with companies that provide contract reprocessing or contract sterilization services.

Better Scope Designs. We need better scope designs that ensure easier cleaning and sterilization, but we also need better sterilizers and sterilization processes that can be effective under normal or worst-case conditions. Simply inoculating a device with a known biological indicator or challenge and then running a routine sterilization process is not enough. It is also necessary to determine whether microbes can be sterilized under natural conditions.

Under natural conditions, most microbes may not be inactivated logarithmically, presenting a barrier challenge to the sterilization process. Sterilization experts should therefore ask themselves how the sterilization process can be changed or modified to overcome this inherent natural logarithmic deviation problem without having to perform a cleaning step. But to get there, the use of standardized equipment or standardized methods is not enough. We need to be creative, which means that we need to review and develop techniques that may already exist or do not exist yet.

Wayne Rogers is a consultant and a member of the editorial advisory board of Medical Device and Diagnostic Industry (MDDI). Reach him at [email protected].

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