Infectious complications in gastrointestinal endoscopy and their prevention

Accepted Manuscript Infectious complications in gastrointestinal endoscopy and their prevention Julia Kovaleva, MD, PhD, Clinical Biologist/Consultant Clinical Microbiologist

PII:

S1521-6918(16)30072-5

DOI:

10.1016/j.bpg.2016.09.008

Reference:

YBEGA 1457

To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 5 August 2016 Revised Date:

31 August 2016

Accepted Date: 6 September 2016

Please cite this article as: Kovaleva J, Infectious complications in gastrointestinal endoscopy and their prevention, Best Practice & Research Clinical Gastroenterology (2016), doi: 10.1016/j.bpg.2016.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Infectious complications in gastrointestinal endoscopy and their prevention

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Julia Kovaleva, MD, PhD (Clinical Biologist/Consultant Clinical Microbiologist)

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Centre for Medical Analysis, Herentals, Belgium

Corresponding author. Centre for Medical Analysis, Oud-Strijderslaan 199, 2200 Herentals, Belgium. Tel.: +32 14285000; fax.: +32 14225608. E-mail address: [email protected] (J. Kovaleva)

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ACCEPTED MANUSCRIPT Abstract Gastrointestinal endoscopes are medical devices that have been associated with outbreaks of health care-associated infections. Because of the severity and limited treatment options of infections caused by multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa,

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considerable attention has been paid to detection and prevention of these post-endoscopic outbreaks. Endoscope reprocessing involves cleaning, high-level disinfection/sterilization followed by rinsing and drying before storage. Failure of the decontamination process implies

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the risk of settlement of biofilm producing species in endoscope channels. This review covers the infectious complications in gastrointestinal endoscopy and their prevention and highlights

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the problem of infection risk associated with different steps of endoscope reprocessing.

Keywords: Endoscopy, Gastrointestinal endoscopes, Cross infection, Disease outbreaks,

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Disinfection, Sterilization, Biofilms

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ACCEPTED MANUSCRIPT Endoscopes are medical instruments used for diagnostic and therapeutic purposes. Because the same endoscopes are used to treat different patients, it is important that cleaning, disinfection, and sterilization take place appropriately. Flexible endoscopes are complex instruments with multiple and narrow internal channels which may become heavily

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contaminated with microorganisms during use [1]. Because of their complex structure endoscopes are difficult to clean and disinfect. The ability of microorganisms to form biofilms inside the endoscope channels can contribute to failure of endoscope reprocessing [2]. Failure

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of the decontamination process can result in microbial transmission from one patient to another and in a possible development of post-endoscopic infectious complications [3].

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Endoscope reprocessing is a multistep procedure involving cleaning, followed by disinfection or sterilization with further drying before storage. The main principle is that rigid and flexible endoscopes used in sterile body cavities should always be sterilized, while disinfection is usually enough for endoscopes that come in contact with non-sterile tissues [4].

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Heat-resistant, rigid endoscopes are generally sterilized by steam. Due to their material composition, most flexible endoscopes cannot be heat-sterilized without damage [3]. They should receive at least high-level disinfection (HLD) or be decontaminated by another

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method, for example, by means of ethylene oxide (ETO) sterilization. Preferably, cleaning and disinfection should be performed in automated endoscope reprocessors (AERs).

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Infections related to endoscopic procedures are caused by either endogenous flora (the patient’s own microorganisms) or exogenous microbes (microorganisms introduced into the patient via the endoscope and/or its accessories) [5]. Endogenous infections in gastrointestinal (GI) endoscopy are commonly caused by Escherichia coli, Klebsiella spp. or other Enterobacteriaceae, and enterococci. The exogenous microorganisms most frequently associated with transmission are Pseudomonas aeruginosa and Salmonella spp.. These microorganisms can be transmitted from previous patients or contaminated reprocessing

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ACCEPTED MANUSCRIPT equipment by contaminated endoscopes or accessories. The most common factors associated with microbial transmission during GI endoscopy involve: inadequate cleaning, disinfection and drying procedures, use of contaminated AERs, and flaws in instrument design or use of damaged endoscopes [3]. Exogenous infections are preventable with strict adherence to

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accepted reprocessing guidelines.

We review herein the infectious complications in GI endoscopy and their prevention and

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cover the problem of infection risk associated with different steps of endoscope reprocessing.

Risk of exogenous infection

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The true transmission during endoscopy may go underestimated because of low frequency, the absence of clinical symptoms, or inadequate surveillance [2]. Kimmey et al. calculated the risk of endoscopy-related infection following GI endoscopy approximately 1 in 1.8 million procedures (28 reported cases in 40 million endoscopic procedures) [6]. However,

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this method of estimating risk was found to be highly prone to reporting bias [7]. An overview of the exogenous endoscopy-related infections and cross-contaminations after GI endoscopy is presented in Tables 1-2. The 63 published reports include more than 500

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episodes of microbial transmission. The number of the reported cases per 5 years is shown in Fig. 1. The peak in 1991-1995 is probably associated with the introduction and use of

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contaminated or defective AERs which led to colonization and infections with P. aeruginosa. The second peak in 2010-2015 with more than 170 involved patients is particularly related to transmission of multidrug-resistant (MDR) Enterobacteriaceae and P. aeruginosa.

Transmission of viruses Transmission of viral pathogens via endoscopic procedures is rare because viruses are obligate intracellular microorganisms and cannot replicate outside viable human cells. Non-

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ACCEPTED MANUSCRIPT enveloped viruses (e.g., enteroviruses, rotaviruses) are more resistant to chemical disinfectants and dry conditions than enveloped viruses (e.g., human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV). Viruses from the GI tract, such as rota- and enteroviruses can persist on surfaces for approximately 2 months, while blood-

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borne viruses, such as HBV or HIV, persist for more than one week [8].

Despite the serious concern about the possibility of HIV transmission during endoscopic procedures, no cases have been reported. Three cases of HBV transmission [9-11] and 4 cases

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of patient-to-patient HCV transmission [12-15] after GI endoscopic procedures have been related to inadequate cleaning and disinfection of endoscopes and accessories [9-15] and to

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use of contaminated anesthetic vials or syringes [13,14]. It was concluded that the risk for HBV and HCV transmission by endoscopy is low when adequate endoscope reprocessing is used.

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Creutzfeldt-Jakob Disease (Prion Disease)

Creutzfeldt-Jakob disease (CJD) and other transmissible spongiform encephalopathies are transmitted by prions, which are protein particles without nucleic acid, but are capable of

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causing a transmissible disease. In classic CJD, prion protein is concentrated in the central

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nervous system and is less often found in other organs [16,17]. In variant CJD, large amounts of the prion protein are accumulated in lymphoid tissue including the GI tract. Therefore, variant CJD transmission via a GI endoscopic procedure remains theoretically possible, but no reports of such transmission are noted in the literature. Prions are highly resistant to routine methods of decontamination and sterilization (e.g., glutaraldehyde, dry heat, and ETO) [16]. Prolonged steam sterilization is effective to eliminate prion infectivity, but it can damage a flexible, heat-sensitive endoscope. Therefore, endoscopes used on patients with CJD must be single use or destroyed after use.

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Transmission of bacteria Bacteria have caused the vast majority of exogenously acquired endoscope-related infections reported in the literature. Historically, Salmonella spp. were the microorganisms

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most commonly transmitted by GI endoscopy [18-25]. Many Salmonella outbreaks were related lack of manual cleaning or to inappropriate use of disinfectants with intermediate and low potency instead of high-level disinfecting agents. There have been no reports of

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Salmonella infection since the current guidelines for HLD have been followed.

Although H. pylori is a common pathogen in patients with chronic gastritis, peptic ulcer,

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and gastric cancer, transmission of H. pylori by GI endoscopy is rare. Only 3 H. pylori outbreaks after upper GI endoscopy were related to inadequate cleaning and disinfection of endoscopes and not-sterilized biopsy forceps [26-28].

P. aeruginosa, a Gram-negative hospital environmental pathogen, is the most commonly

particularly during

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reported microorganism responsible for transmission of infection in GI endoscopy, endoscopic

retrograde

cholangiopancreaticography (ERCP)

[3].

Pseudomonas is the biofilm producing bacterium with its preference for a moist environment

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(hospital water supply, wet endoscope channels). Pseudomonas biofilms are extremely difficult to remove from plumbing, AERs, and endoscope channels [2].

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P. aeruginosa transmission during GI endoscopy has been attributed to inadequate cleaning and disinfection procedures and use of disinfectants with low potency [29-41], contaminated endoscope water bottles and the water supply to the endoscope [31,33,42-44], and rinsing the endoscope channels with tap water between procedures [45,46] (Table 1). Several post-endoscopic P. aeruginosa outbreaks have been related to contaminated or defective AERs [29,40,41] and the presence of a biofilm on the internal plumbing and detergent tank of AERs [29]. Inadequate drying of the endoscope channels prior to storage

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ACCEPTED MANUSCRIPT was responsible for the outbreaks of Pseudomonas bacteraemia/sepsis after GI endoscopy [29,41]. Endoscope channels were dried with ambient air after disinfection, but were never flushed with 70% ethanol before drying. Reported Pseudomonas infection during outbreaks after GI endoscopy included bacteraemia/sepsis [2,32-34,37,41,43,44,46], ascending

tract infection [45], pneumonia [30], and lung abscess [30].

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cholangitis [33,34,36,39,45], cholecystitis [40], liver abscess [40], pancreatitis [33], urinary

Other microorganisms responsible for infectious outbreaks are Methylobacterium

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mesophilicum [47], Elizabethkingia meningoseptica [48], and Mycobacterium chelonae [49] during ERCP, and Strongyloides stercoralis [50] and Trichosporon spp. [51,52] in upper GI

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endoscopy.

Transmission of multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa Because of the severity and limited treatment options of infections caused by multidrug-

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resistant (MDR) Enterobacteriaceae and Pseudomonas aeruginosa, considerable attention has been paid to detection and prevention of these post-endoscopic outbreaks. MDR bacteria are resistant to multiple classes of antimicrobial drugs, sometimes to all antibiotics, and can

Gram-negative

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share mobile pieces of genetic material to other susceptible Gram-negative bacteria. MDR bacteria

can

produce

extended-spectrum

β-lactamases

(ESBLs),

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carbapenemases, or plasmid-mediated AmpC enzymes. Some carbapenem-resistant Enterobacteriaceae (CRE) poses a β-lactamase (e.g., ESBL or AmpC) combined with porin mutations.

ESBLs are enzymes providing multi-resistance to all penicillins, cephalosporins (with the exception of cephamycins), and aztreonam [53]. They are commonly plasmid-encoded and typically inhibited by β-lactamase inhibitors. AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-

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ACCEPTED MANUSCRIPT β-lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid. Carbapenems are the treatment of choice for serious infections caused by ESBL-producing organisms. Carbapenemases are a diverse group of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems [53].

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Antibiotic treatment options for these MDR infections are limited and may include the administration of tigecycline, colistin, fosfomycin, and aminoglycosides [54].

Four recent outbreaks of post-endoscopic infection were caused by MDR strains of P.

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aeruginosa [2,45,55,56] (Table 2). Improper cleaning (use of inappropriate size of cleaning brushes) and inadequate drying prior storage [45,55], manufacturing endoscope defects

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[55,56], and the presence of a biofilm [2] in the undamaged endoscope channels were identified as causes of instrument contamination.

ESBL-producing Enterobacteriaceae [57-62], AmpC β-lactamase-producing E. coli [63,64], and carbapenem-resistant (KPC, NDM-1, and OXA-48-producing) K. pneumoniae

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[59-61,65-71] and E. coli [67,68,72] were responsible for outbreaks of ERCP-related nosocomial infections involving more than 200 patients in 2006-2015 (Table 2). Improper cleaning, an inadequate/insufficient drying procedure [57-61,65,66], and defects in the

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implicated duodenoscopes [63,64,69,70] were determined as the possible causes of instrument contamination. In contrast, no cause of endoscope contamination and no breaches in

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endoscope reprocessing were identified during several outbreaks: it was theorized that the complex design of the elevator mechanism makes it more difficult to clean than other parts of endoscopes [67,68]. After changing duodenoscope reprocessing from HLD to ETO sterilization, no new cases of CRE infections have been identified [67,68,71,72]. According to the American Society of Gastrointestinal Endoscopy (ASGE) [73], low temperature ETO sterilization might be employed for endoscopes used in MDR/CRE positive patients or for endoscopes thought to be contaminated with MDR/CRE.

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Risk of endogenous infection Bacteraemia results from translocation of endogenous bacteria into the blood stream via mucosal trauma. In this case, microorganisms isolated from blood cultures belong to the

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commensal microflora and are generally of low pathogenicity. The reported incidence of transient bacteraemia ranges from 0% to 8% after diagnostic upper GI endoscopy, from 0% to 54% after therapeutic upper GI endoscopy (e.g., variceal ligation, oesophageal sclerotherapy

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and dilatation), and from 0% to 25% after sigmoidoscopy and colonoscopy [3,74,75].

Other infectious complications after upper and low GI endoscopy may include

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septicaemia, endocarditis, meningitis, acute appendicitis, and peritonitis [3,74]. Most commonly isolated microorganisms are Staphylococcus epidermidis and Streptococcus spp. after upper GI endoscopy and enterococci, Enterobacteriaceae, and Bacteroides spp. after colonoscopy and sigmoidoscopy.

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ERCP is an endoscopic procedure associated with the possible development of severe infectious complications including sepsis, ascending cholangitis, liver abscess, acute cholecystitis, and necrotizing pancreatitis [3]. The rate of occurrence of bacteraemia ranges

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from 0% to 15% after ERCP of unobstructed pancreatic or bile ducts and from 0% to 27% in patients with biliary obstruction by stones or a tumor [3,74,76]. The incidence of post-ERCP

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cholangitis and sepsis, the most serious complications with a mortality rate up to 29.4%, varies from 0.25% to 5.4% in different patient populations [3]. -The most frequent organisms responsible for cholangitis/sepsis are enteric bacteria including Enterobacteriaceae, enterococci, and α-haemolytic streptococci.

Antibiotic prophylaxis in GI endoscopy

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ACCEPTED MANUSCRIPT In 2015, the ASGE updated its guideline on antibiotic prophylaxis for GI procedures [77]. Guidelines were also published by the American Heart Association in 2007 [75] and by the British Society of Gastroenterology (BSG) in 2009 [78]. The purpose of antibiotic prophylaxis during GI endoscopy is to reduce the risk of

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iatrogenic infectious complications. Prophylactic antibiotic administration is recommended for percutaneous endoscopic gastrostomy, endoscopic ultrasound/fine needle aspiration, ERCP, and for all patients with cirrhosis admitted with GI bleeding [77, 78]. Prophylactic

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administration of a first- or second-generation cephalosporin or amoxicillin-clavulanate for patients undergoing percutaneous endoscopic gastrostomy 30 min before the procedure

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provides coverage of cutaneous microorganisms and reduces the risk of peristomal wound infection [77,78]. Administration of amoxicillin-clavulanate or ciprofloxacin before endoscopic ultrasound/fine needle aspiration of cystic lesion is suggested for prevention of cyst infection. All patients with cirrhosis admitted with GI bleeding should have antibiotic

tazobactam.

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therapy instituted at admission with a third-generation cephalosporin or piperacillin-

ERCP with drainage and antibiotics are required for patients with cholangitis as part of

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their treatment, so additional single-dose ERCP prophylaxis is not recommended. Prophylactic antibiotics are recommended for patients with biliary obstruction (e.g., primary

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sclerosing cholangitis and/or hilar cholangiocarcinoma) when complete biliary drainage is unlikely to be achieved, and in patients with communicating pancreatic cysts or pseudocysts for prevention of cyst infection that is unlikely to be drained [77,78]. Antibiotic prophylaxis is not required in the absence of cholangitis, if biliary drainage is likely to be successful. Prophylactic antibiotics should cover biliary flora such as Enterobacteriaceae, Bacteroides spp., P. aeruginosa, and enterococci. Antibiotic prophylaxis should be started orally or

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ACCEPTED MANUSCRIPT intravenously at least one to two hours before the procedure. Oral ciprofloxacin, intravenous piperacillin-tazobactam or gentamicin is recommended [77,78]. The administration of prophylactic antibiotics to prevent infective endocarditis is not recommended for patients who undergo GI tract procedures [75,78]. For patients with the

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highest-risk cardiac conditions (e.g., prosthetic cardiac valves, congenital heart disease, or history of previous infective endocarditis) who have established infections of the GI tract (such as cholangitis) and for those who undergo an endoscopic procedure that may increase

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the risk of bacteraemia (such as ERCP), it is recommended that the antibiotic regimen include

or vancomycin [75,77].

Overview of endoscope reprocessing

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an antimicrobial agent active against enterococci, such as penicillin, amoxicillin, piperacillin,

Cleaning and high-level disinfection methods

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In 1968 Spaulding proposed classifying medical devices into three categories based on the risk of infection related to their use [79]. Critical devices that enter the vascular system and normally sterile tissues (e.g., biopsy forceps) and that carry a high degree of infection risk

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if contaminated during use should be sterilized. Noncritical devices contact intact skin and require low-level disinfection or simple cleaning with detergent and water. Upper and lower

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GI endoscopes are defined as semi-critical devices which come into contact with the mucous membranes during use and require HLD to destroy all microorganisms except some bacterial spores. Most organizations, including the Centers for Disease Control and Prevention (CDC), the ASGE, the European Society of Gastrointestinal Endoscopy (ESGE), and the World Gastroenterology Organization recommend HLD as appropriate for these instruments [4,8082].

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ACCEPTED MANUSCRIPT ERCP endoscopes and reusable accessories, such as biopsy forceps, are used in sterile body cavities and should be classified as critical devices. They require sterilization to destroy all forms of microbiological life including bacterial spores. Most flexible endoscopes cannot be steam sterilized due to their material composition, but can tolerate ETO and hydrogen

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peroxide plasma sterilization [3,83]. However, both sterilizers may damage the endoscopes and are not available in many hospitals. ETO is toxic and carcinogenic, and a lengthy aeration time is required for equipment post-exposure in order to allow desorption of all residual toxic

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gas from the endoscope to occur. ETO and hydrogen peroxide plasma sterilization may fail in the presence of organic debris inside narrow lumina after inadequate cleaning and when a

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biofilm has been settled in internal endoscope channels [2,84]. Some sterilization technologies that should be evaluated for endoscope reprocessing include ozone plus hydrogen peroxide vapor, nitrogen dioxide, supercritical CO2, peracetic acid vapor, and gaseous chlorine dioxide [83].

drying, and storage.

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Endoscope reprocessing can be divided into five separate steps: cleaning, HLD, rinsing,

Cleaning procedure includes pre-cleaning, a leak test, and manual cleaning. Cleaning is a

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critical step that must precede HLD or sterilization [85]. It reduces the number of microorganisms and organic debris by 4 logs, or 99.99%. Manual cleaning procedure of GI

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endoscopes includes brushing of external surface and removable parts (e.g., suction valves), immersion in an enzymatic detergent solution followed by irrigation of internal channels with a detergent [4,81]. A fresh detergent solution should be used for each endoscope to prevent cross-contamination. For duodenoscopes, it is important that the elevator mechanism located at the distal tip of the duodenoscope is thoroughly cleaned. The visible inspection should be done using of a magnifying glass to improve detection of residual debris around the elevator mechanism [73].

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ACCEPTED MANUSCRIPT AERs are strongly recommended for reprocessing of flexible endoscopes to document all steps and to minimize contamination and contact with chemicals and contaminated instruments [4,81]. All reprocessing steps can be performed in an AER including cleaning, rinsing, disinfection, final rinsing, and drying (optional). However, contaminated and

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defective AERs can result in inadequate reprocessing and contamination of endoscopes and have been associated with outbreaks of endoscopy-related infections [29,40,41].

Disinfectants used for endoscope reprocessing must be completely effective against a

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broad range of microorganisms including bacteria, fungi, mycobacteria, viruses, and bacterial spores [80,81]. Concentration and exposure time of a disinfecting agent are crucial;

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inappropriate dilution and insufficient exposure can result in failure of effective reprocessing. High-level disinfectants recommended for endoscope disinfection include glutaraldehyde, ortho-phthalaldehyde, peracetic acid, chlorine dioxide, and electrolytically generated disinfectants (e.g., electrolyzed acid water) [81]. Other disinfectants such as alcohols,

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phenols, and ammonium compounds should not be used for endoscope disinfection because they do not have sporicidal activity.

Glutaraldehyde (2 to 4%) is one of the most commonly used disinfectants in endoscopy

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units. It is relatively inexpensive, noncorrosive to metal, and does not damage endoscopes and reprocessing equipment [3,81]. However, glutaraldehyde has irritant properties for the

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respiratory tract, eyes, and skin and can cause allergic reactions, contact dermatitis, and asthma [86]. It has slow action against bacterial spores and mycobacteria at 25°C within standard contact times of 20 min [81]. Microorganisms possessing resistance to glutaraldehyde include atypical mycobacteria (M. chelonae and Mycobacterium avium complex), P. aeruginosa, M. mesophilicum, Trichosporon spp., and Cryptosporidium parvum [3,80,81].

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ACCEPTED MANUSCRIPT Ortho-phthalaldehyde (0.55%) is a high-level disinfectant with a higher mycobactericidal efficacy than glutaraldehyde, but it is less effective against bacterial spores [80,81]. Disadvantages of this disinfectant include irritation of the respiratory tract and eyes, staining of the skin, instruments, and surfaces, and coagulation and fixation of proteins [3,81].

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Peracetic acid is a high-level disinfectant usually used for HLD of flexible endoscopes in AERs. It is characterized by rapid action against all microorganisms, has the ability to remove hardened material from surfaces, and no development of microorganism resistance to

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peracetic acid has been reported [3,80,81]. It can be used at low temperatures, but is less stable than glutaraldehyde and has corrosive action depending on the pH value and

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concentration. Peracetic acid has the ability to fixate biofilms and can show limited efficacy in biofilm removal from the surfaces [87-89].

Chlorine dioxide rapidly destroys resistant organisms and spores, but it can damage endoscopes [81]. Electrolytically generated disinfectants are produced by the electrolysis of

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sodium chloride solutions. They are effective against spores and mycobacteria, are inexpensive, nontoxic to biological tissues rarely shows adverse effects on the human skin and mucosa.

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Immediately after HLD, the endoscope is rinsed with sterile or filtered water [4,81]. The rinse water must be discarded after each cycle, and water bottles used for irrigation during the

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procedure should be high-level disinfected or sterilized at least daily.

Drying and storage procedures Accurate endoscope drying is crucial, whereas a humid environment facilitates replication of Gram-negative bacteria (e.g., P. aeruginosa and E. coli) [89]. A short drying cycle between endoscopic procedures and an intensive final drying cycle at the end of the day should be performed in AERs or manually [81,89]. According to the different guidelines, the

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ACCEPTED MANUSCRIPT length of time between endoscope disinfection and endoscope reuse (without drying in a drying cabinet) should be not longer than 3 [90], 4 [91], or 12 hours [92]. The ASGE and CDC recommend forced air-drying, preceded by flushing of the internal channels with 70% to

used in all countries because of their fixative properties.

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90% ethanol or isopropanol at the end of a clinic day [4,80]. Ethanol and isopropanol are not

During reprocessing, endoscopes are dried at least 30 min and then stored in a vertical position in a dust-free storage cabinet or in a drying cabinet with continuous flow of dry

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compressed air to prevent the accumulation of moisture and to avoid their recontamination [81,89,93]. However, because of the lack of scientific evidence, the length of time endoscopes

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may be stored in a drying cabinet prior to use without reprocessing and before they pose a contamination risk, is not clear. This time varies from 12 to 72 h to 10-14 days according to the Australian guideline [94] and the ASGE [4]. The Dutch guideline [91] determines one month as a storage period for a clean and dry endoscope. The CDC [80] makes no

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recommendations and the ESGE [81] refers to local policies about the length of time endoscopes can be safely stored before reuse. Five studies demonstrated that flexible endoscopes may be stored within 5 to 21 days after standard reprocessing with a low risk of

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pathogenic microbial colonization [95-99]. The outcome, endoscope contamination, was measured by flushing endoscope channels with sterile water at various time periods and by

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culturing.

Biofilm formation and endoscope reprocessing Many bacteria, including P. aeruginosa and atypical mycobacteria, are capable of existing in a planktonic state and can produce biofilms. A biofilm can be defined as a microbial derived sessile community characterized by cells that are attached to a substratum, interface to each other, and are embedded in a matrix of extracellular polymeric substance [100]. The

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ACCEPTED MANUSCRIPT structure and physiological attributes of biofilms makes microorganisms in biofilms, in contrast to a normal planktonic state, very resistant to antimicrobial agents and allows pathogens to survive under conditions of drying and chemical exposure. The ability of bacteria to form biofilms is an important factor in their potential to cause

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endoscopy-related infections [3]. In time, residual levels of organic material and microorganisms in the incomplete cleaned endoscope channels and moisture remaining after inadequate drying can contribute to development of a biofilm by the residual bacteria. The

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presence of a biofilm was detected in 55% of the suction and biopsy channels and in 77% of the water and air channels of the 79 tested endoscopes by using scanning electron microscopy

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[101]. The biofilm formation in endoscope channels has been related to reuse of detergent, incomplete manual cleaning and drying procedures. A recent study [102] confirmed a high efficiency of the drying procedure after the disinfection step against the bacteria and yeasts in biofilms. Microbial regrowth in biofilms occurred if the drying step after disinfection was

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skipped.

The presence of biofilms on the inner surface of endoscope channels [2] and in the contaminated AERs [29,103,104] has been reported as a cause of infectious outbreaks in

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literature. Cross-contaminations of M. chelonae and M. mesophilicum resulted in colonization of patients after endoscopy with no infectious complications [103]. Reported post-ERCP

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infections included P. aeruginosa bacteraemia/sepsis and cholangitis [2,29,104]. Biofilms can be removed from artificial surfaces by physical and chemical methods [105]. Physical methods such as ultrasound and manual cleaning are generally effective but difficult to control in practice. Chemical methods can be unsuccessful because of the resistance of biofilms to disinfectants and due to poor penetration of the cleaning and disinfecting products in biofilms. In three studies enzymatic and non-enzymatic detergents, ortho-phthalaldehyde, glutaraldehyde, peracetic acid, and hydrogen peroxide were tested to determine if biofilms

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ACCEPTED MANUSCRIPT could be either removed or the bacteria within the biofilms killed [106-108]. None of the detergents alone could remove the biofilm or reduce the bacterial level in a biofilm as determined by viable count and scanning electron microscopy [106]. The combination of detergents and disinfectants [106] and disinfectants alone [107] provided a significant

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microbial growth inhibition in biofilms occurred after disinfection. Nevertheless, viable microorganisms within the biofilm were still detected by confocal microscopy, more so with glutaraldehyde than with peracetic acid or ortho-phataladehyde [107]. Peracetic acid

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demonstrated a limited blood cleaning effect and a substantial blood fixation potential [108]. It was concluded that disinfection using peracetic acid may be insufficient if the preceding

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cleaning step is not performed adequately and that peracetic acid-based formulations should not be used for cleaning flexible endoscopes [108].

The most efficient methods in biofilm removal were autoclaving and treatment with a concentrated bleach solution [105]. High-temperature treatments (80-90˚C) were not effective

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for biofilm removal. The use of anti-biofilm oxidising agents with an antimicrobial coating inside washer disinfectors could reduce biofilm build-up inside endoscopes and AERs and

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decrease the risk of transmitting infections [105].

Microbiological surveillance of endoscope reprocessing

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Routine microbiological testing for endoscopes and AERs remains a controversial issue in many guidelines. The Australian [94], French [109], and ESGE [110] guidelines recommend routine culturing of flexible endoscopes and AERs for specific pathogens. Although routine culturing of endoscopes is not part of current U.S. guidelines, recent CRE outbreaks associated with duodenoscopes have led to consideration for regular monitoring of duodenoscope reprocessing [111]. Microbiological surveillance of flexible endoscopes is appropriate to trace contaminations of endoscopes and to prevent contaminations and

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ACCEPTED MANUSCRIPT infections in patients after endoscopic procedures [2,112]. Microbiological surveillance systems have several important limitations. If there is a clinical demand for reuse of an endoscope, surveillance culture results will not be obtained until after the endoscope is used on the next patient because culture results take a minimum of 24 to 48 hours to be produced

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[110].

Some techniques are recommended for microbiological sampling of flexible endoscopes [113]. A swab-rinse technique should be used for sampling the exterior surfaces and the distal

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opening of the suction-biopsy channel port. For adequate sampling the interior surface of endoscope channels a "flush/brush/flush" technique should be performed with rinsing through

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the channel with a sterile fluid and using a sterile cleaning brush to obtain samples from the biopsy port. A simple flush-through technique may be considered when brushing of the channel lumens is impossible, but it is less efficient [113]. Endoscopes can be sampled in an anterograde and retrograde manner [112]. Endoscope culturing with a retrograde technique

anterograde sampling.

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was found to be effective in monitoring endoscope reprocessing and more sensitive than the

There are no standards about the frequency of testing intervals of surveillance cultures.

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The Australian guideline recommends microbiologic monitoring of duodenoscopes, bronchoscopes, and AERs every 4 weeks and all other GI endoscopes every 4 months [94].

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According to the ESGE guideline, intervals of routine microbiological endoscope testing should be no longer than 3 months [110]. The use of routine environmental microbiologic testing of therapeutic endoscopes once a month and diagnostic endoscopes once every 3 months has been reported [3,112].

Practice points

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ACCEPTED MANUSCRIPT • GI endoscopes are medical devices that have been associated with outbreaks of health care-associated infections • Contaminated GI endoscopes have been linked to cross-transmission and infectious outbreaks caused by multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa

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• Flexible GI endoscopes require high-level disinfection or should be sterilized after use • Accurate endoscope drying is crucial, whereas a humid environment facilitates replication of Gram-negative bacteria

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contribute to failure of endoscope reprocessing

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• The ability of microorganisms to form biofilms inside the endoscope channels can

Research agenda

• Ways to improve the disinfection and drying process need to be searched • More studies are necessary to reduce the risk of biofilm formation in endoscopes

Conflict of interests

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• Evidence of microbiological surveillance of endoscope reprocessing needs to be clarified

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EP

No conflicts of interests have been declared by the author.

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ACCEPTED MANUSCRIPT

Table 1 Microorganisms associated with infection transmission during gastrointestinal endoscopy (multidrug-resistant bacteria not included). Contaminated

Infected

procedure

patients, n

patients, n

Upper GI endoscopy [9-11]

3

3

Hepatitis C virus

1) Upper GI endoscopy [12]

3) Colonoscopy [14;15]

9

1

1) Upper GI endoscopy [18-22]

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3

29

HCV infection

1

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Salmonella spp

(cetrimide); lack of disinfection procedure

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2) ERCP [13]

Inappropriate cleaning and disinfection

9

(HCV)

Problem identified

HBV infection

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(HBV)

Infection(s)

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Hepatitis B virus

Endoscopic

SC

Microorganism

3

1) Inappropriate cleaning and disinfection; contaminated syringe/anesthetic vial 2) Inadequate disinfection (insufficient exposure); failure to perfuse elevator channel 3) Inappropriate cleaning and disinfection; contaminated syringe/anesthetic vial; biopsy forceps not sterilized

26

Bacteraemia/sepsis,

1) Lack of manual cleaning;

Gastroenteritis,

inappropriate cleaning and disinfection

urinary tract

(cetrimide); insufficient disinfectant exposure

infection

ACCEPTED MANUSCRIPT

3

3) Colonoscopy [18;24;25]

2

11

3

Sepsis,

2) Inappropriate cleaning and disinfection

gastroenteritis

(povidone-iodine/ethanol)

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2) ERCP [23]

Gastroenteritis

3) Inappropriate cleaning and disinfection

Upper GI endoscopy [26-28]

4

4

114

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Helicobacter pylori Pseudomonas

1) Upper GI endoscopy [29-32]

13

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aeruginosa

131

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2) ERCP [29;33-46]

SC

(phenolic solution, ionophor solution); lack of

93

Bacteraemia

manual cleaning; biopsy forceps not sterilized

Inappropriate disinfection between patients; biopsy forceps not sterilized

Sepsis,

1) Inappropriate cleaning and disinfection

cholangitis,

(cetrimide); contaminated water bottle;

pneumonia,

contaminated AER (a flaw in design, presence

lung abscess

of a biofilm); drying with no ethanol flushing

Bacteraemia/sepsis, 2) Inappropriate cleaning and disinfection cholangitis,

(ethanol, cetrimide); rinsing with non-sterile tap

cholecystitis,

water; contaminated water bottles; contaminated

lever abscess,

AER (design defect, presence of a biofilm);

pancreatitis,

drying with no ethanol flushing

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urinary tract

Methylobacterium ERCP [47]

RI PT

infection 1

1

Gastritis

Contaminated endoscope channels

20

5

Sepsis,

Not identified

Elizabethkingia

ERCP [48]

Mycobacterium

cholangitis ERCP [49]

M AN U

meningoseptica 14

0

chelonae Upper GI endoscopy [50]

4

Upper GI endoscopy [51;52]

10

stercoralis

AC C

EP

Trichosporon spp

4

TE D

Strongyloides

SC

mesophilicum

1

No

Contaminated AER; inappropriate disinfection; rinsing with tap water; lack of drying procedure

Esophagitis

Not identified

Esophagitis

Inappropriate cleaning and disinfection (cetrimide); biopsy forceps not sterilized

GI – gastrointestinal; ERCP – endoscopic retrograde cholangiopancreaticography; AER – automated endoscope reprocessor.

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Table 2 Infections associated with multidrug-resistant Enterobacteriaceae and Pseudmonas aeruginosa

Fraser 2004 [39]

Microorganism

P. aeruginosa

Endoscopic

Contaminated

Infected

procedure

patients, n

patients, n

ERCP

5

3

P. aeruginosa

ERCP

3

(carbapenem-

Bajolet 2013 [55]

P. aeruginosa ESBL

Gastroscopy

P. aeruginosa CP (VIM-2)

AC C

CTX-M)

Verfaillie 2015 [56]

4

3

3

Sepsis

ERCP

30

Cause(s) of contamination

Not determined; endoscope reprocessing not described

Presence of a biofilm in intact endoscope channels; no lapses in endoscope reprocessing identified

Psoas haematoma,

Improper cleaning (use of inappropriate

pneumonia

size of cleaning brushes, suction

EP

(TEM, SHV-2a,

TE D

resistant)

M AN U

resistant) Kovaleva 2009 [2]

Sepsis, cholangitis

SC

(carbapenem-

Infection(s)

RI PT

Reference

cylinders not sterilized), insufficient drying procedure, a defect in the sheath of the contaminated gastroscope 7 (4

Positive clinical

Multiple manufacturing defects of the

infections

cultures (blood,

novel-design duodenoscope

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abscess,

1 year)

endotracheal

RI PT

within

aspirate, pleural

fluid, drain fluid)

Klebsiella

ERCP

13

13

Aumeran 2010 [58]

K. pneumoniae

ERCP

16

and Naas 2010 [60]

(KPC-2/MLST 258)

and Kassis-

and K. pneumoniae

Chikhani [61]

ESBL (SHV-12)

Sanderson 2010 [65]

K. pneumoniae (carbapenemresistant)

ERCP

ERCP

no endoscope service maintenance

Bacteraemia/sepsis,

Insufficient manual cleaning and drying

cholangitis

procedure; insufficient compliance with reprocessing procedures

13 [59]

4 [59]

Bacteraemia/sepsis,

Improper cleaning; insufficient drying

15 [60]

3 [60]

biliary tract

procedure

4 [61]

4 [61]

infection,

EP

K. pneumoniae CP

AC C

Carbonne 2010 [59]

12

Improper cleaning; inadequate drying;

TE D

ESBL (CTX-M-15)

M AN U

pneumoniae ESBL

Bacteraemia

SC

Cooke 2006 [57]

13

pulmonary infection 8

Not reported

Improper cleaning of elevator

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E. coli ESBL

ERCP

1

1

Endocarditis

Not determined

Alrabaa 2013 [66]

K. pneumoniae CP

ERCP

10

7

Bacteraemia/sepsis,

Improper cleaning of the endoscope

RI PT

Lupse 2012 [62]

urinary tract

elevator

infection,

E. coli CP (NDM-1)

Epstein 2014 [68]

(patients and

ERCP

44 [67] 39 [68]

endoscopes);

(KPC) (endoscopes)

and Kola 2015 [70]

(OXA-48)

Marsh 2015 [71]

K. pneumoniae CP (KPC-2/MLST 258,

ERCP

ERCP

10 [68]

Positive clinical

Not found, no breaches in endoscope

cultures (blood,

reprocessing identified, no additional

abscess, sputum,

cases after gas sterilization of

urine, wound)

endoscopes with ethylene oxide

15 [69]

10 [69]

Bacteraemia/sepsis,

Defects in the implicated duodenoscope

12 [70]

9 [70]

pulmonary infection,

resulted in imperfect disinfection

EP

K. pneumoniae CP

AC C

Gastmeier 2014 [69]

TE D

K. pneumoniae CP

8 [67]

M AN U

CDC 2014 [67] and

SC

biliary tract infection

37

surgical site infection 37

Positive clinical

Not found, no breaches in endoscope

cultures (blood, bile,

reprocessing identified

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wound, urine,

K. pneumoniae ESBL

sputum,

RI PT

MLST 307) and

bronchoalveolar lavage)

Wendorf 2015 [64]

AmpC β-lactamase

ERCP

32

32

ERCP

TE D

E. coli CP (NDM-1)

5

AC C

EP

Smith 2015 [72]

3

Positive clinical

Defects of the implicated

cultures (blood, bile,

duodenoscopes, leak in an instrument

abdominal fluid,

channel; no breaches in endoscope

urine, sputum,

reprocessing identified

SC

E. coli

M AN U

Ross 2015 [63] and

wound) Bacteraemia/sepsis,

Not found, no breaches in endoscope

cholangitis,

reprocessing identified; no additional

urinary sepsis

cases after gas sterilization with ethylene oxide

ERCP – endoscopic retrograde cholangiopancreaticography; ESBL – extended-spectrum β-lactamase; CP – carbapenemase-producing; KPC – Klebsiella pneumoniae carbapenemase; MLST – multilocus sequence typing.

RI PT

200

160

AC C

Microbial transmission in GI endoscopy not associated with MDR bacteria Microbial transmission in GI endoscopy due to MDR bacteria

Fig. 1. Episodes of microbial transmission in GI endoscopy reported in the medical publications. GI – gastrointestinal; MDR – multidrug-resistant.

2010 - 2015

2006 - 2009

2001 -2005

1986 -1990

1981 - 1985

1976 -1980

1970 - 1975

0

TE D

40

1996 - 2000

80

1991 - 1995

M AN U

SC

120

EP

Number of cases of microbial transmission

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