1. “An Update: Prevention of Transmission of the ‘Superbug’ Carbapenem-Resistant Enterobacteriaceae (CRE) during Gastrointestinal (GI) Endoscopy” HEARTLAND SGNA September 26, 2015 Kansas City, MO Presentation by: Lawrence F. Muscarella, Ph.D. President, LFM Healthcare Solutions, LLC 1 (Source: The CDC) A duodenoscope (Source: FDA)

2. Webinar’s Objectives This presentation’s objectives are to: 1.Review some traits of the superbug “CRE” WWhat are they? 2.Evaluate the risk of CRE outbreaks associated with contaminated gastrointestinal (GI) endoscopes WWhat factor were likely to blame for some recent CRE outbreaks following ERCP? 3.Provide some recommendations and new information to reduce the risk of CRE outbreaks following ERCP. WWhat new advice has been published in 2015? 2

3. 1.“For review, what are ‘superbugs’?” — According to the CDC (Centers for Disease Control and Prevention): “superbugs” are certain “nightmarish bacteria” that pose a public health threat primarily because of three specific traits: 1.superbugs are resistant to many classes of antibiotics. › Some superbugs are untreatable and resistant to all antibiotics; 3 CRE (Source: US News & World Report)

4. 2.Some superbug infections are associated with high mortality rates. For example, bloodstream infections caused by some superbugs have a mortality rate of: › as high as 40 - 50%; and 3.Some superbugs can exchange their genetic material with other nearby bacteria causing previously susceptible strains to become antibiotic-resistant. … — Examples of some familiar superbugs include: a.MRSA b.multidrug-resistant Pseudomonas spp. c.“CRE” 4 Multidrug resistance High mortality rate Can swap genes Superbug traits:

5. 2.“What are ‘CRE’ exactly?” — “CRE,” or carbapenem-resistant Enterobacteriaceae (pronounced: \ˌent-ə-rō-ˌbak-ˌtir-ē-ˈā-sē-ˌē\), ■ are an important type of superbug that has recently emerged in the U.S. – with important implications to GI endoscopy. — For background, Enterobacteriaceae are a family of more than 70 genera of gram-negative bacteria. ■ Klebsiella spp, Salmonella spp. and Serratia spp. – are members of this family. 5 CRE (Source: The CDC)

6. 2.(continued) — Other traits of Enterobacteriaceae: they can be found in water and soil --- and the human GI tract; many are opportunistic, primarily affecting immuno-suppressed patients; and they are one of the most common causes of bacterial infections, both in hospital and community settings. — An important trait of CRE is their resistance to virtually every antibiotic › including --- most notably --- carbapenems, ■ which are β-lactam antibiotics – used as a “last resort” for treating serious bacterial infections. 6 (Source: FDA)

7. 3.“In what healthcare settings have CRE infections been confirmed?” — CRE are a growing health threat primarily found in: › hospitals (in the U.S. and globally) › long-term acute care facilities › nursing homes › and now in GI endoscopy units, too. ■ Reports have recently linked CRE outbreaks to contaminated duodenoscopes, – causing a national stir. o Duodenoscopes are a type of GI endoscope used to perform ERCP (or, endoscopic retrograde cholangiopancreatography). 7 A duodenoscope (Source: Olympus) A duodenoscope (Source: ABC News)

8. 4.“What are some examples of CRE?” — Examples of CRE include resistant strains of: o E. coli o Klebsiella pneumoniae — An important mechanism by which some CRE can become resistant to carbapenems is through their production of enzymes called: › carbapenemases -- which are β-lactamase enzymes that break down the carbapenem’s β-lactam ring, ■ rendering these “big gun” antibiotics ineffective for treating CRE-infected patients. 8 E. Coli (Source CDC) CRE carbapenemases carbapenems

9. 9 Source: CDC (updated: February, 2015) 5.“In how many States have CRE been confirmed?” — CRE* -- specifically, Klebsiella pneumoniae -- were first identified in a U.S. hospital (in North Carolina) in 2001. Since then, CRE have been identified throughout the U.S., but not in Idaho or Maine. * This graph includes all CRE infections, not just those associated with GI endoscopy.

10. 10 6.“What is the difference between CRE ‘infection’ and ‘colonization’?” — Patients exposed to CRE during ERCP may become either infected or colonized. Infected patients display symptoms of infection, requiring prompt treatment. Colonized patients, however, are asymptomatic:  they do not display any symptoms of infection, and may not even know they’re harboring the superbug. … — CRE colonization is a concern because it can convert to CRE infection.

11. 11 7.“Are any CRE infections treatable with antibiotics?” — CRE strains may be susceptible to only a few remaining antibiotics, including: colistin and tigecycline › although both can cause serious side effects in patients (e.g., nephrotoxic). — CRE strains that are resistant to all of the commonly used antibiotics are called: pan-resistant CRE, › whereas Enterobacteriaceae strains that are susceptible to all of the commonly used antibiotics are called:  pan-susceptible bacteria.

12. 12 8.“Have contaminated GI endoscopes transmitted CRE?” — Yes, particularly during the past three years.  Several publicized outbreaks of CRE have been linked to ERCP and/or duodenoscopes in the U.S. since 2012. — Five of these outbreaks occurred in: Florida, in 2008 Pittsburgh (PA) beginning in 2012 Seattle (WA) beginning in 2012 Park Ridge (IL) in 2013 Los Angeles (CA) in 2014 … — More than any others, the CRE outbreaks in Seattle, Park Ridge, and, certainly, Los Angeles caught the public’s attention,  although similar outbreaks of CRE have also occurred in North Carolina, Wisconsin and Connecticut.        

13. 8. (continued): As shown, CRE outbreaks in the U.S. following ERCP can be associated with significant patient morbidity: 13

14. 14 9.“Can you provide some updated information about CRE outbreaks linked to contaminated duodenoscopes?” — UPDATE: In response to the CRE outbreaks at the hospitals in ● Park Ridge (IL), ● Seattle (WA) and ● Los Angeles (CA), › three (3) wrongful death lawsuits were filed this year against the duodenoscope’s manufacturer. › These lawsuits claim the duodenoscope’s design is defective, infecting patients with CRE. — UPDATE: And, in August, a hospital in Pasadena (CA) confirmed that a superbug had infected › at least three patients following ERCP.

15. 15 9.(continued) Additional updates in 2015 — UPDATE: Also in August, the FDA sent warning letters to each of the three (3) duodenoscope manufacturers. › These warning letters: are in direct response to the nation’s recent spate of CRE outbreaks linked to ERCP; cite these manufacturers for several safety-related violations; and call into question the regulatory status of most duodenoscopes sold in the U.S. … — UPDATE: In 2015, the U.S. Justice Department began investigating the circumstances of these CRE outbreaks. › Last March, it reportedly sent subpoenas to all three endoscope manufacturers (and to at least one hospital.) Source: MMC News

16. 16 10.“What are some of the alerts that the FDA and CDC published in 2015 discussing the risk of CRE infections during ERCP?” — UPDATE: In 2015 the FDA published several safety alerts discussing the risk of duodenoscopes transmitting CRE, including: › “Design of Endoscopic Retrograde Cholangiopancreatography (ERCP) Duodenoscopes May Impede Effective Cleaning” (February 2015).  Highlights: To notify the public that: the complex design of duodenoscopes can hinder effective cleaning and disinfection; and duodenoscopes may infect patients with CRE even when GI staff reprocess them according to their labeling. … — Note: This alert was the 1st time that the FDA agreed that the endoscope’s design – not user error – might be causing infection. A duodenoscope Source: MMC News

17. 17 10.(continued) — UPDATE: Also in 2015, the FDA published this alert: › “Olympus Validates New Reprocessing Instructions for Model TJF-Q180V Duodenoscopes” (March 2015).  Highlights: To notify the public that: Olympus had just revised its reprocessing instructions for more enhanced manually cleaning of its TJF-Q180V duodenoscope. — UPDATE: And, in 2015, the CDC published this protocol: › “Interim Protocol for Healthcare Facilities Regarding Surveillance for Bacterial Contamination of Duodenoscopes after Reprocessing” (March 2015). …  Highlights: To provide the public with: a sampling protocol to assess the adequacy of duodenoscope reprocessing.

18. 11.“What do these several CRE outbreaks share in common? — These CRE outbreaks share in common: 1)the infectious agent?  CRE (or a related superbug); 2)the mode of transmission?  often confirmed to be the duodenoscope (or what may be called an “ERCP endoscope”); 3)the lapse?  inadequate removal of CRE from the duodenoscope  despite the endoscope being manually cleaned per the manufacturers’ instructions; 4)the outcome?  Each outbreak was associated with patient morbidity and, in some cases, patient mortality. 18

19. 12.“What’s primarily to blame for duodenoscopes retaining CRE despite being cleaned as instructed?” — The FDA has attributed CRE remaining on the duodenoscope after` reprocessing to the design of: › the endoscope’s complex forceps elevator mechanism and surrounding recessed areas,  which hinder cleaning. — One specific duodenoscope model – the Olympus TJF-Q180V – is particularly difficult to clean. › This model has been associated with the majority of the nation’s CRE outbreaks following ERCP. – However, duodenoscopes from the other two manufacturers also have been linked to CRE outbreaks. 19 Olympus 180 series duodenoscope featuring a “sealed” elevator channel. (Source: FDA)

20. 20 13.“How many different types of duodenoscopes are there?” — There are two types of duodenoscopes:  older models featuring an “exposed” elevator wire channel that requires reprocessing -- e.g., Olympus TJF-160V; and  newer models featuring a “sealed” elevator wire channel that is not reprocessed -- e.g., Olympus TJF-Q180V. › Most CRE outbreaks have been linked to these newer models. — Some reports suggest that this channel’s “seal” might wear, however, allowing bacteria inside the endoscope,  where it can grow but not be removed during cleaning. › This factor may be a cause of some CRE outbreaks.

21. 21 13.(continued) The TJF-Q180V duodenoscope’s dismantled forceps elevator mechanism: An o-ring may become worn facilitating contamination of the “sealed” elevator wire channel with inaccessible CRE. The newer duodenoscope model: The Olympus TJF-Q180V whose elevator wire channel is sealed. An older duodenoscope model: The Olympus TJF-160V whose elevator wire channel is exposed. The “sealing” o-ring of a dismantled 180-series duodenoscope. (Source: FDA) The exposed elevator wire. The forceps elevator mechanism. The images of these two duodenoscopes are from Olympus.

22. 14.“What is the calculated risk of CRE infection following ERCP?” — Unknown. This risk of CRE infection following ERCP  can only be estimated – it cannot be accurately calculated. — Why? Because of under-reporting.  In fact, CRE infections disclosed to the FDA may represent only a fraction of the actual number of infections. › The actual risk could be significantly higher than reported. — UPDATE: According to the FDA, however, the risk of a CRE infection following ERCP is “low.”  As a result, the FDA has not ordered that duodenoscopes be removed form the market. › The FDA has concluded that the benefits of ERCP outweigh its infection risk (for most patients). 22

23. 15.“What other types of endoscopes might transmit CRE?” — UPDATE: Duodenoscopes are not the only type of flexible endoscope that’s been linked to CRE infections. — Other types of endoscopic instruments that have been linked to CRE infections include: › urological equipment › bronchoscopes, and › linear “EUS” ultrasound endoscopes. — UPDATE: Underscoring this point, two weeks ago the FDA issued another safety communication about CRE: › “Infections Associated with Reprocessed Flexible Bronchoscopes” (September 2015). — Attention to the proper reprocessing of these instruments, too, is necessary to prevent CRE transmissions. 23 Source: Olympus

24. 24 Source: FDA 16.“What supplemental measures did the FDA recently recommend to reduce the risk of CRE outbreaks following ERCP?” — UPDATE: Last month, the FDA published another safety alert entitled: › “Supplemental Measures to Enhance Duodenoscope Reprocessing” (August 2015).  Highlights: To provide the public with: four additional reprocessing measures that may further reduce the risk of duodenoscopes transmitting CRE.  These four measures are: — 1. -- FDA: Microbiologically culturing the “reprocessed” duodenoscope.  Sample the duodenoscope using the CDC’s interim sampling protocol (published in March 2015).

25. 25 16.(continued) — 2. -- FDA: Using ethylene oxide (EtO) gas to sterilize the duodenoscope following cleaning and high-level disinfection.  This process may not be feasible for many hospitals. — 3. -- FDA: Using a liquid chemical sterilant (LCS) processing system following cleaning and high-level disinfection.  Remember to clean the endoscope meticulously before any terminal process. — 4. -- FDA: Repeating the high-level disinfection cycle, whether it was performed manually or using an automated endoscope reprocessor, or AER.  Again, meticulous manual cleaning prior to high-level disinfection is required. CRE (Source: CDC)

26. 17.“What other recommendations can you provide to reduce the risk of a contaminated GI endoscope transmitting CRE?” — Practice the following steps recommended by the CDC, FDA, both SGNA and ASGE, and the endoscope’s manufacturer: a)Manually clean and flush the duodenoscope’s elevator wire channel (if it’s open and exposed); and Rigorously flush and brush the forceps elevator mechanism and surrounding areas. b)Manually clean and flush the exposed elevator wire channel of (linear) “EUS” endoscopes, too. c)Manually clean duodenoscopes and EUS endoscopes, even if the AER is labeled to eliminate manual cleaning. 26 From: Medscape

27. 17.(continued) d)Always “leak test“ the duodenoscope  and consider servicing it more often (per manufacturer’s instructions). e)You may consider using a duodenoscope model with an exposed elevator wire channel, if feasible, to reduce risk. f)Whether manufacturers will redesign the duodenoscope in the future is unclear,  but a redesign may be cheaper for hospitals than sterilizing duodenoscopes to reduce risk. – Such a redesign might include a detachable distal tip for enhanced cleaning of the duodenoscope. … g)Consider actively tracking patients following ERCP (and EUS) for CRE infections or colonizations. 27 Source: FujiFilm

28. THE END  Attention: — Download for free an article I wrote in the “World Journal of Gastrointestinal Endoscopy” (October, 2014): › “Risk of transmission of carbapenem-resistant Enterobacteriaceae and related ‘superbugs’ during gastrointestinal endoscopy.” — Visit: http://goo.gl/N6YxHB (this article is free to download). › This peer-reviewed article provides additional recommendations to prevent CRE transmissions during GI endoscopy. 28

29. Thank you for your time. Contact me if you have any questions: Larry@LFM-HCS.com Twitter: @MuskiePhD 29 Copyright © 2015. LFM Healthcare Solutions, LLC

30. BONUS QUESTIONS 30 Copyright © 2015. LFM Healthcare Solutions, LLC

31. QUIZ 1.Q: “What are the three characteristics of a ‘superbug’?” — Answer: According to the CDC, “superbugs”: 1.are multidrug-resistant; 2.can be associated with high mortality rates (e.g., 50%); and 3.can share their genes of resistance with nearby bacteria. 31

32. 2.Q: “What are ‘CRE’?” — Answer: CRE are an important type of superbug that has recently emerged in the U.S. and globally – with important implications to GI endoscopy.  Examples include: › E. coli › Klebsiella pneumoniae 32

33. 3.Q: “What are four important traits of ‘CRE’?” — Answer: CRE: – are members of the Enterobacteriaceae family; – are resistant to virtually every antibiotic including carbapenems; – may colonize or infect a patient’s GI tract; and – can be transmitted by GI endoscopes. 33

34. 4.Q: “Which three CRE outbreaks caught the public’s attention and caused a national discussion about duodenoscopes?” — Answer: More than any others in the U.S., the CRE outbreaks in: – Park Ridge (IL) – Seattle (WA); and – Los Angeles (CA) › caught the FDA’s and public’s attention, causing a national discussion about the design and regulation of duodenoscopes. 34

35. 5.Q: “What were two conclusions of the FDA’s first safety communication, issued in February 2015, discussing the risk of the newer models of duodenoscopes transmitting CRE?” — Answer: › In February, 2015, the FDA issued its first safety alert entitled, “Design of … Duodenoscopes May Impede Effective Cleaning.”  This alert notified the public that: the complex design of duodenoscopes with sealed elevator wire channels can hinder effective cleaning and disinfection; and these newer models of duodenoscopes may infect patients with CRE even when GI staff reprocess them according to their labeling. 35

36. 36 6.Q: “Have CRE outbreaks been linked only to ‘sealed’ duodenoscopes models?” — Answer: › No. Whereas most CRE outbreaks have been linked to newer duodenoscope models with a sealed elevator wire channel, bronchoscopes, urological instrumentation, “EUS” (linear ultrasound) endoscopes, and duodenoscopes with an “exposed” elevator wire channel  have also all been linked to CRE outbreaks.

37. 7.Q: “What were the four ‘supplemental measures’ that the FDA’s August 2015 safety communication recommended hospitals consider to prevent CRE outbreaks following ERCP?” — Answer: › In August 2015, the FDA published another safety alert entitled, “Supplemental Measures to Enhance Duodenoscope Reprocessing.”  This alert recommends that hospitals consider one or more of the following four measures to prevent CRE infections: microbiological culturing of the duodenoscope, EtO gas sterilization of the duodenoscope, use of a liquid chemical sterilant processing system, and repeating the high-level disinfection cycle. 37