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1.  Swab culture monitoring of automated endoscope reprocessors after high-level disinfection 
AIM: To conduct a bacterial culture study for monitoring decontamination of automated endoscope reprocessors (AERs) after high-level disinfection (HLD).
METHODS: From February 2006 to January 2011, authors conducted randomized consecutive sampling each month for 7 AERs. Authors collected a total of 420 swab cultures, including 300 cultures from 5 gastroscope AERs, and 120 cultures from 2 colonoscope AERs. Swab cultures were obtained from the residual water from the AERs after a full reprocessing cycle. Samples were cultured to test for aerobic bacteria, anaerobic bacteria, and mycobacterium tuberculosis.
RESULTS: The positive culture rate of the AERs was 2.0% (6/300) for gastroscope AERs and 0.8% (1/120) for colonoscope AERs. All the positive cultures, including 6 from gastroscope and 1 from colonoscope AERs, showed monofloral colonization. Of the gastroscope AER samples, 50% (3/6) were colonized by aerobic bacterial and 50% (3/6) by fungal contaminations.
CONCLUSION: A full reprocessing cycle of an AER with HLD is adequate for disinfection of the machine. Swab culture is a useful method for monitoring AER decontamination after each reprocessing cycle. Fungal contamination of AERs after reprocessing should also be kept in mind.
PMCID: PMC3325533  PMID: 22529696
Automated endoscope reprocessor; Gastrointestinal scope; High-level disinfection; Swab culture; Monitoring; Decontamination
2.  Comparative cost-efficiency of the EVOTECH endoscope cleaner and reprocessor versus manual cleaning plus automated endoscope reprocessing in a real-world Canadian hospital endoscopy setting 
BMC Gastroenterology  2011;11:105.
Reprocessing of endoscopes generally requires labour-intensive manual cleaning followed by high-level disinfection in an automated endoscope reprocessor (AER). EVOTECH Endoscope Cleaner and Reprocessor (ECR) is approved for fully automated cleaning and disinfection whereas AERs require manual cleaning prior to the high-level disinfection procedure. The purpose of this economic evaluation was to determine the cost-efficiency of the ECR versus AER methods of endoscopy reprocessing in an actual practice setting.
A time and motion study was conducted at a Canadian hospital to collect data on the personnel resources and consumable supplies costs associated with the use of EVOTECH ECR versus manual cleaning followed by AER with Medivators DSD-201. Reprocessing of all endoscopes was observed and timed for both reprocessor types over three days. Laboratory staff members were interviewed regarding the consumption and cost of all disposable supplies and equipment. Exact Wilcoxon rank sum test was used for assessing differences in total cycle reprocessing time.
Endoscope reprocessing was significantly shorter with the ECR than with manual cleaning followed by AER. The differences in median time were 12.46 minutes per colonoscope (p < 0.0001), 6.31 minutes per gastroscope (p < 0.0001), and 5.66 minutes per bronchoscope (p = 0.0040). Almost 2 hours of direct labour time was saved daily with the ECR. The total per cycle cost of consumables and labour for maintenance was slightly higher for EVOTECH ECR versus manual cleaning followed by AER ($8.91 versus $8.31, respectively). Including the cost of direct labour time consumed in reprocessing scopes, the per cycle and annual costs of using the EVOTECH ECR was less than the cost of manual cleaning followed by AER disinfection ($11.50 versus $11.88).
The EVOTECH ECR was more efficient and less costly to use for the reprocessing of endoscopes than manual cleaning followed by AER disinfection. Although the cost of consumable supplies required to reprocess endoscopes with EVOTECH ECR was slightly higher, the value of the labour time saved with EVOTECH ECR more than offset the additional consumables cost. The increased efficiency with EVOTECH ECR could lead to even further cost-savings by shifting endoscopy laboratory personnel responsibilities but further study is required.
PMCID: PMC3198958  PMID: 21967345
3.  EVOTECH® endoscope cleaner and reprocessor (ECR) simulated-use and clinical-use evaluation of cleaning efficacy 
BMC Infectious Diseases  2010;10:200.
The objective of this study was to perform simulated-use testing as well as a clinical study to assess the efficacy of the EVOTECH® Endoscope Cleaner and Reprocessor (ECR) cleaning for flexible colonoscopes, duodenoscopes, gastroscopes and bronchoscopes. The main aim was to determine if the cleaning achieved using the ECR was at least equivalent to that achieved using optimal manual cleaning.
Simulated-use testing consisted of inoculating all scope channels and two surface sites with Artificial Test Soil (ATS) containing 108 cfu/mL of Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans. Duodenoscopes, colonoscopes, and bronchoscopes (all Olympus endoscopes) were included in the simulated use testing. Each endoscope type was tested in triplicate and all channels and two surface sites were sampled for each scope. The clinical study evaluated patient-used duodenoscopes, bronchoscopes, colonoscopes, and gastroscopes (scopes used for emergency procedures were excluded) that had only a bedside flush prior to being processed in the ECR (i.e. no manual cleaning). There were 10 to 15 endoscopes evaluated post-cleaning and to ensure the entire ECR cycle was effective, 5 endoscopes were evaluated post-cleaning and post-high level disinfection. All channels and two external surface locations were sampled to evaluate the residual organic and microbial load. Effective cleaning of endoscope surfaces and channels was deemed to have been achieved if there was < 6.4 μg/cm2 of residual protein, < 1.8 μg/cm2 of residual hemoglobin and < 4 Log10 viable bacteria/cm2. Published data indicate that routine manual cleaning can achieve these endpoints so the ECR cleaning efficacy must meet or exceed these to establish that the ECR cleaning cycle could replace manual cleaning
In the clinical study 75 patient-used scopes were evaluated post cleaning and 98.8% of surfaces and 99.7% of lumens met or surpassed the cleaning endpoints set for protein, hemoglobin and bioburden residuals. In the simulated-use study 100% of the Olympus colonoscopes, duodenoscopes and bronchoscopes evaluated met or surpassed the cleaning endpoints set for protein, and bioburden residuals (hemoglobin was not evaluated).
The ECR cleaning cycle provides an effective automated approach that ensures surfaces and channels of flexible endoscopes are adequately cleaned after having only a bedside flush but no manual cleaning. It is crucial to note that endoscopes used for emergency procedures or where reprocessing is delayed for more than one hour MUST still be manually cleaned prior to placing them in the ECR.
PMCID: PMC2914053  PMID: 20618935
4.  Comparison on the Efficacy of Disinfectants Used in Automated Endoscope Reprocessors: PHMB-DBAC versus Orthophthalaldehyde 
Clinical Endoscopy  2011;44(2):109-115.
Since endoscopes are reusable apparatus classified as semicritical item, thorough reprocessing to achieve high-level disinfection is of utmost importance to prevent spread of infection. To improve disinfection efficacy and safety, disinfectants and endoscope reprocessors are continuously evolving. This study aimed to compare the efficacy of the combination of polyhexamethylenebiguanide hydrochloride-alkyldimethylbenzylammonium chloride (PHMB-DBAC) and orthophthalaldehyde (OPA) used respectively in ultrasonographic cleaning incorporated automated endoscope reprocessors: COOLENDO (APEX Korea) or OER-A (Olympus Optical).
A total of 86 flexible upper endoscopes were randomly reprocessed with either COOLENDO/PHMB-DBAC or OER-A/OPA. Culture samplings were done at two sites (endoscope tip and working channel) which were later incubated on blood agar plate. Bacterial colonies were counted and identified.
The culture-positive rate at the endoscope tip and working channel was 0% and 2.33% for COOLENDO/PHMB-DBAC and 4.65% and 0% for OER-A/OPA. Staphylococcus hominis was cultured from one endoscope reprocessed with COOLENDO/PHMB-DBAC and Pseudomonas putida was isolated from two endoscopes reprocessed with OER-A/OPA.
The reprocessing efficacy of COOLENDO/PHMB-DBAC was non-inferior to that of OER-A/OPA (p=0.032; confidence interval, -0.042 to 0.042). During the study period, significant side effect of PHMB-DBAC was not observed.
PMCID: PMC3363059  PMID: 22741121
Endoscope reprocessing; Disinfectants; High-level disinfection
5.  High-level disinfection of gastrointestinal endoscope reprocessing 
High level disinfection (HLD) of the gastrointestinal (GI) endoscope is not simply a slogan, but rather is a form of experimental monitoring-based medicine. By definition, GI endoscopy is a semicritical medical device. Hence, such medical devices require major quality assurance for disinfection. And because many of these items are temperature sensitive, low-temperature chemical methods, such as liquid chemical germicide, must be used rather than steam sterilization. In summarizing guidelines for infection prevention and control for GI endoscopy, there are three important steps that must be highlighted: manual washing, HLD with automated endoscope reprocessor, and drying. Strict adherence to current guidelines is required because compared to any other medical device, the GI endoscope is associated with more outbreaks linked to inadequate cleaning or disinfecting during HLD. Both experimental evaluation on the surveillance bacterial cultures and in-use clinical results have shown that, the monitoring of the stringent processes to prevent and control infection is an essential component of the broader strategy to ensure the delivery of safe endoscopy services, because endoscope reprocessing is a multistep procedure involving numerous factors that can interfere with its efficacy. Based on our years of experience in the surveillance of culture monitoring of endoscopic reprocessing, we aim in this study to carefully describe what details require attention in the GI endoscopy disinfection and to share our experience so that patients can be provided with high quality and safe medical practices. Quality management encompasses all aspects of pre- and post-procedural care including the efficiency of the endoscopy unit and reprocessing area, as well as the endoscopic procedure itself.
PMCID: PMC4308530
Automated endoscope reprocessor; Bacterial culture; Gastrointestinal endoscopy; High-level disinfection; Liquid chemical germicide
6.  Transmission of Infection by Flexible Gastrointestinal Endoscopy and Bronchoscopy 
Clinical Microbiology Reviews  2013;26(2):231-254.
Flexible endoscopy is a widely used diagnostic and therapeutic procedure. Contaminated endoscopes are the medical devices frequently associated with outbreaks of health care-associated infections. Accurate reprocessing of flexible endoscopes involves cleaning and high-level disinfection followed by rinsing and drying before storage. Most contemporary flexible endoscopes cannot be heat sterilized and are designed with multiple channels, which are difficult to clean and disinfect. The ability of bacteria to form biofilms on the inner channel surfaces can contribute to failure of the decontamination process. Implementation of microbiological surveillance of endoscope reprocessing is appropriate to detect early colonization and biofilm formation in the endoscope and to prevent contamination and infection in patients after endoscopic procedures. This review presents an overview of the infections and cross-contaminations related to flexible gastrointestinal endoscopy and bronchoscopy and illustrates the impact of biofilm on endoscope reprocessing and postendoscopic infection.
PMCID: PMC3623380  PMID: 23554415
7.  Survey of Endoscope Reprocessing in Korea 
Clinical Endoscopy  2015;48(1):39-47.
There is a growing emphasis on quality management in endoscope reprocessing. Previous surveys conducted in 2002 and 2004 were not practitioner-oriented. Therefore, this survey is significant for being the first to target actual participants in endoscope reprocessing in Korea.
This survey comprised 33 self-filled questions, and was personally delivered to nurses and nursing auxiliaries in the endoscopy departments of eight hospitals belonging to the society. The anonymous responses were collected after 1 week either by post or in person by committee members.
The survey included 100 participants. In the questionnaire addressing compliance rates with the reprocessing guideline, the majority (98.9%) had a high compliance rate compared to 27% of respondents in 2002 and 50% in 2004. The lowest rate of compliance with a reprocessing procedure was reported for transporting the contaminated endoscope in a sealed container. Automated endoscope reprocessors were available in all hospitals. Regarding reprocessing time, more than half of the subjects replied that reprocessing took more than 15 minutes (63.2%).
The quality management of endoscope reprocessing has improved as since the previous survey. A national survey expanded to include primary clinics is required to determine the true current status of endoscope reprocessing.
PMCID: PMC4323430
Reprocessing; Endoscopy; Data collection
8.  Modeling microbial survival in buildup biofilm for complex medical devices 
Flexible endoscopes undergo repeated rounds of patient-use and reprocessing. Some evidence indicates that there is an accumulation or build-up of organic material that occurs over time in endoscope channels. This "buildup biofilm" (BBF) develops as a result of cyclical exposure to wet and dry phases during usage and reprocessing. This study investigated whether the BBF matrix represents a greater challenge to disinfectant efficacy and microbial eradication than traditional biofilm (TBF), which forms when a surface is constantly bathed in fluid.
Using the MBEC (Minimum Biofilm Eradication Concentration) system, a unique modelling approach was developed to evaluate microbial survival in BBF formed by repetitive cycles of drying, disinfectant exposure and re-exposure to the test organism. This model mimics the cumulative effect of the reprocessing protocol on flexible endoscopes. Glutaraldehyde (GLUT) and accelerated hydrogen peroxide (AHP) were evaluated to assess the killing of microbes in TBF and BBF.
The data showed that the combination of an organic matrix and aldehyde disinfection quickly produced a protective BBF that facilitated high levels of organism survival. In cross-linked BBF formed under high nutrient conditions the maximum colony forming units (CFU) reached ~6 Log10 CFU/peg. However, if an oxidizing agent was used for disinfection and if organic levels were kept low, organism survival did not occur. A key finding was that once established, the microbial load of BBF formed by GLUT exposure had a faster rate of accumulation than in TBF. The rate of biofilm survival post high-level disinfection (HLD) determined by the maximum Log10CFU/initial Log10CFU for E. faecalis and P. aeruginosa in BBF was 10 and 8.6 respectively; significantly different compared to a survival rate in TBF of ~2 for each organism. Data from indirect outgrowth testing demonstrated for the first time that there is organism survival in the matrix. Both TBF and BBF had surviving organisms when GLUT was used. For AHP survival was seen less frequently in BBF than in TBF.
This BBF model demonstrated for the first time that survival of a wide range of microorganisms does occur in BBF, with significantly more rapid outgrowth compared to TBF. This is most pronounced when GLUT is used compared to AHP. The data supports the need for meticulous cleaning of reprocessed endoscopes since the presence of organic material and microorganisms prevents effective disinfection when GLUT and AHP are used. However, cross-linking agents like GLUT are not as effective when there is BBF. The data from the MBEC model of BBF suggest that for flexible endoscopes that are repeatedly used and reprocessed, the assurance of effective high-level disinfection may decrease if BBF develops within the channels.
PMCID: PMC2689233  PMID: 19426471
9.  Results of gastroscope bacterial decontamination by enzymatic detergent compared to chlorhexidine 
AIM: To compare the efficacy of enzymatic detergent with chlorhexidine for gastroscope bacterial decontamination.
METHODS: A prospective randomized controlled study was undertaken to evaluate the ability of these 2 agents to achieve high level disinfection in a gastroscope. A total of 260 samples were collected from 5 different gastroscopes. Manual cleaning was done for 10 min with these 2 agents separately (n = 130 each). Then all specimens underwent 2% glutaraldehyde soaking for 20 min. After 70% alcohol was rinsed, sterile normal saline was flushed into each gastroscope channel and 40 mL of sample was collected. The sample was sent for aerobic bacterial culture after membrane was filtered. A colony count greater than 200 cfu/mL was considered significant.
RESULTS: The positive culture rate was 4.6% in the enzymatic detergent arm and 3.1% in the chlorhexidine arm. Pseudomonas species were the main organism detected from both groups (60%). Multiple organisms were found from 4 specimens (enzymatic detergent arm = 1, chlorhexidine arm = 3).
CONCLUSION: The contamination rate of both types of cleaning solution is equivalent.
PMCID: PMC4087373  PMID: 16830374
Enzymatic detergent; Gastroscope; Bacterial decontamination
10.  A microbiological evaluation of level of disinfection for flexible cystoscopes protected by disposable endosheaths 
BMC Urology  2013;13:46.
Flexible cystoscopy is used in urological outpatient departments for diagnostic cystoscopy of bladder cancer and requires a high-level disinfection between each patient. The purpose of this study was to make a microbiological post disinfection efficacy assessment of flexible cystoscopes (FC) using disposable sterile endosheaths.
One hundred endosheaths underwent a leak-test for barrier integrity after cystoscopy. Microbiological samples from these cystoscopies were obtained; after removal of the endosheath, and after cleaning the scope with a detergent cloth, rinsing with tap water followed by 70% ethanol disinfection and subsequent drying. The number of colony forming units (cfu) from the samples was counted after 72 hours and then divided in three categories, Clean FC (<5 cfu/sample), Critical FC (5–50 cfu/sample) and High-risk FC (>50 cfu/sample). The result was compared with data of 10 years continuous control sampling recorded in the Copenhagen Clean-Endoscope Quality Control Database (CCQCD) and analyzed with a Chi-square test for homogeneity.
All 100 endosheaths passed the leak-test. All samples showed a Clean FC and low means of cfu. A query to the CCQCD, showed that 99.8% (1264/1267) of all FC with a built-in work-channel reprocessed in a WD were clean before use.
The reprocessing of FC using endosheaths, as preformed in this study, provides a patient-ready procedure. The results display a reprocessing procedure with low risk of pathogen transmission, high patient safety and a valid alternative to the recommended high-level disinfection procedure of FC. However, the general impression was that sheaths slightly reduced vision and resulted in some patient discomfort.
PMCID: PMC3852551  PMID: 24099332
Flexible cystoscopy; Endosheaths; Microbiological assessment; Disinfection; Bladder cancer
11.  Risk of transmission of carbapenem-resistant Enterobacteriaceae and related “superbugs” during gastrointestinal endoscopy 
To evaluate the risk of transmission of carbapenem-resistant Enterobacteriaceae (CRE) and their related superbugs during gastrointestinal (GI) endoscopy. Reports of outbreaks linked to GI endoscopes contaminated with different types of infectious agents, including CRE and their related superbugs, were reviewed. Published during the past 30 years, both prior to and since CRE’s emergence, these reports were obtained by searching the peer-reviewed medical literature (via the United States National Library of Medicine’s “MEDLINE” database); the Food and Drug Administration’s Manufacturer and User Facility Device Experience database, or “MAUDE”; and the Internet (via Google’s search engine). This review focused on an outbreak of CRE in 2013 following the GI endoscopic procedure known as endoscopic retrograde cholangiopancreatography, or ERCP, performed at “Hospital X” located in the suburbs of Chicago (IL; United States). Part of the largest outbreak of CRE in United States history, the infection and colonization of 10 and 28 of this hospital’s patients, respectively, received considerable media attention and was also investigated by the Centers for Disease Control and Prevention (CDC), which published a report about this outbreak in Morbidity and Mortality Weekly Report (MMWR), in 2014. This report, along with the results of an independent inspection of Hospital X’s infection control practices following this CRE outbreak, were also reviewed. While this article focuses primarily on the prevention of transmissions of CRE and their related superbugs in the GI endoscopic setting, some of its discussion and recommendations may also apply to other healthcare settings, to other types of flexible endoscopes, and to other types of transmissible infectious agents. This review found that GI endoscopy is an important risk factor for the transmission of CRE and their related superbugs, having been recently associated with patient morbidity and mortality following ERCP. The CDC reported in MMWR that the type of GI endoscope, known as an ERCP endoscope, that Hospital X used to perform ERCP in 2013 on the 38 patients who became infected or colonized with CRE might be particularly challenging to clean and disinfect, because of the complexity of its physical design. If performed in strict accordance with the endoscope manufacturer’s labeling, supplemented as needed with professional organizations’ published guidelines, however, current practices for reprocessing GI endoscopes, which include high-level disinfection, are reportedly adequate for the prevention of transmission of CRE and their related superbugs. Several recommendations are provided to prevent CRE transmissions in the healthcare setting. CRE transmissions are not limited to contaminated GI endoscopes and also have been linked to other reusable flexible endoscopic instrumentation, including bronchoscopes and cystoscopes. In conclusion, contaminated GI endoscopes, particularly those used during ERCP, have been causally linked to outbreaks of CRE and their related superbugs, with associated patient morbidity and mortality. Thorough reprocessing of these complex reusable instruments is necessary to prevent disease transmission and ensure patient safety during GI endoscopy. Enhanced training and monitoring of reprocessing staffers to verify the proper cleaning and brushing of GI endoscopes, especially the area around, behind and near the forceps elevator located at the distal end of the ERCP endoscope, are recommended. If the ERCP endoscope features a narrow and exposed channel that houses a wire connecting the GI endoscope’s control head to this forceps elevator, then this channel’s complete reprocessing, including its flushing with a detergent using a procedure validated for effectiveness, is also emphasized.
PMCID: PMC4198391  PMID: 25324917
Endoscopy; Gastrointestinal; Carbapenem-resistant Enterobacteriaceae; Cross infection; Disease outbreaks; Healthcare-associated infections; Risk assessment; Disinfection; Sterilization; Anti-bacterial agents; Bacterial infections; Carbapenems; Beta-lactams
12.  Elimination of high titre HIV from fibreoptic endoscopes. 
Gut  1990;31(6):657-659.
Concern about contamination of fibreoptic endoscopes with human immunodeficiency virus (HIV) has generated a variety of disruptive and possibly unnecessary infection control practices in endoscopy units. Current recommendations on the cleaning and disinfection of endoscopes have been formulated without applied experimental evidence of the effective removal of HIV from endoscopes. To study the kinetics of elimination of HIV from endoscope surfaces, we artificially contaminated the suction-biopsy channels of five Olympus GIF XQ20 endoscopes with high titre HIV in serum. The air and water channels of two instruments were similarly contaminated. Contamination was measured by irrigating channels with viral culture medium and collecting 3 ml at the distal end for antigen immunoassay. Endoscopes were then cleaned manually in neutral detergent according to the manufacturer's recommendations and disinfected in 2% alkaline glutaraldehyde (Cidex, Surgikos) for two, four, and ten minutes. Contamination with HIV antigens was measured before and after cleaning and after each period of disinfection. Initial contamination comprised 4.8 x 10(4) to 3.5 x 10(6) pg HIV antigen/ml. Cleaning in detergent achieved a reduction to 165 pg/ml (99.93%) on one endoscope and to undetectable levels (100%) on four. After two minutes in alkaline glutaraldehyde all samples were negative and remained negative after the longer disinfection times. Air and water channels, where contaminated, were tested after 10 minutes' disinfection and were negative. These findings underline the importance of cleaning in removing HIV from endoscope and indicate that the use of dedicated equipment and long disinfection times are unnecessary.
PMCID: PMC1378490  PMID: 2379868
13.  Controlled comparison of bioMérieux VITAL and BACTEC NR-660 systems for detection of bacteremia and fungemia in pediatric patients. 
Journal of Clinical Microbiology  1997;35(8):2007-2012.
The bioMérieux VITAL automated blood culture system measures a decrease in fluorescence to detect the presence of microorganisms in blood. To assess the performance of VITAL with AER aerobic medium versus that of the nonradiometric BACTEC NR-660 PEDS PLUS medium for the detection of sepsis in children, a total of 12,146 blood specimens were collected at three university medical centers and inoculated into AER and PEDS PLUS bottles that were weighed before and after filling. The sample volumes were considered adequate in 6,276 bottle pairs. The total yield of isolates was 629, of which 489 (78%) were judged to be the cause of true infections. Staphylococci (P < 0.001) and yeasts (P < 0.05) were detected more often in PEDS PLUS bottles, as were all microorganisms combined (P < 0.001). The improved detection in the PEDS PLUS medium was most marked for patients on antimicrobial therapy (P < 0.001), but remained statistically significant even for patients not on therapy (P < 0.025). There were 431 episodes of sepsis, including 407 considered adequate for analysis. Of the 363 unimicrobial episodes, 278 were detected by both bottles, 64 were detected by PEDS PLUS bottles only, and 21 were detected by AER bottles only (P < 0.01). No false-negative cultures were detected by terminal subculture of the PEDS PLUS bottles when the companion AER bottle was positive. However, there were 14 false-negative cultures (7 yeasts, 5 staphylococci, 1 Enterococcus faecalis, and 1 Enterobacter sp.) on terminal subculture of the AER bottles when the companion PEDS PLUS bottle was positive. When both systems were positive, the VITAL system detected bacteria earlier than did the BACTEC system by a mean of 1.6 h. Also, false-positive signals were less common with the VITAL system. We conclude that the VITAL system with AER medium must be modified to improve the detection of clinically important staphylococci and yeasts if it is to perform comparably to the BACTEC NR-660 nonradiometric system with PEDS PLUS medium for a pediatric population.
PMCID: PMC229892  PMID: 9230371
14.  Discovery of early-stage biomarkers for diabetic kidney disease using ms-based metabolomics (FinnDiane study) 
Metabolomics  2011;8(1):109-119.
Diabetic kidney disease (DKD) is a devastating complication that affects an estimated third of patients with type 1 diabetes mellitus (DM). There is no cure once the disease is diagnosed, but early treatment at a sub-clinical stage can prevent or at least halt the progression. DKD is clinically diagnosed as abnormally high urinary albumin excretion rate (AER). We hypothesize that subtle changes in the urine metabolome precede the clinically significant rise in AER. To test this, 52 type 1 diabetic patients were recruited by the FinnDiane study that had normal AER (normoalbuminuric). After an average of 5.5 years of follow-up half of the subjects (26) progressed from normal AER to microalbuminuria or DKD (macroalbuminuria), the other half remained normoalbuminuric. The objective of this study is to discover urinary biomarkers that differentiate the progressive form of albuminuria from non-progressive form of albuminuria in humans. Metabolite profiles of baseline 24 h urine samples were obtained by gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS) to detect potential early indicators of pathological changes. Multivariate logistic regression modeling of the metabolomics data resulted in a profile of metabolites that separated those patients that progressed from normoalbuminuric AER to microalbuminuric AER from those patients that maintained normoalbuminuric AER with an accuracy of 75% and a precision of 73%. As this data and samples are from an actual patient population and as such, gathered within a less controlled environment it is striking to see that within this profile a number of metabolites (identified as early indicators) have been associated with DKD already in literature, but also that new candidate biomarkers were found. The discriminating metabolites included acyl-carnitines, acyl-glycines and metabolites related to tryptophan metabolism. We found candidate biomarkers that were univariately significant different. This study demonstrates the potential of multivariate data analysis and metabolomics in the field of diabetic complications, and suggests several metabolic pathways relevant for further biological studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-011-0291-6) contains supplementary material, which is available to authorized users.
PMCID: PMC3258399  PMID: 22279428
Diabetic kidney disease; Nephropathy; Metabolite profile; Metabolomics; Urine; GC–MS; LC–MS; Multivariate data analysis
15.  Microalbuminuria among Type 1 and Type 2 diabetic patients of African origin in Dar Es Salaam, Tanzania 
BMC Nephrology  2007;8:2.
The prevalences and risk factors of microalbuminuria are not full described among black African diabetic patients. This study aimed at determining the prevalence of microalbuminuria among African diabetes patients in Dar es Salaam, Tanzania, and relate to socio-demographic features as well as clinical parameters.
Cross sectional study on 91 Type 1 and 153 Type 2 diabetic patients. Two overnight urine samples per patient were analysed. Albumin concentration was measured by an automated immunoturbidity assay. Average albumin excretion rate (AER) was used and were categorised as normalbuminuria (AER < 20 ug/min), microalbuminuria (AER 20–200 ug/min), and macroalbuminuria (AER > 200 ug/min). Information obtained also included age, diabetes duration, sex, body mass index, blood pressure, serum total cholesterol, high-density and low-density lipoprotein cholesterol, triglycerides, serum creatinine, and glycated hemoglobin A1c.
Overall prevalence of microalbuminuria was 10.7% and macroalbuminuria 4.9%. In Type 1 patients microalbuminuria was 12% and macroalbuminuria 1%. Among Type 2 patients, 9.8% had microalbuminuria, and 7.2% had macroalbuminuria. Type 2 patients with abnormal albumin excretion rate had significantly longer diabetes duration 7.5 (0.2–24 yrs) than those with normal albumin excretion rate 3 (0–25 yrs), p < 0.001. Systolic and diastolic blood pressure among Type 2 patients with abnormal albumin excretion rate were significantly higher than in those with normal albumin excretion rate, (p < 0.001).
No significant differences in body mass index, glycaemic control, and cholesterol levels was found among patients with normal compared with those with elevated albumin excretion rate either in Type 1 or Type 2 patients.
A stepwise multiple linear regression analysis among Type 2 patients, revealed AER (natural log AER) as the dependent variable to be predicted by [odds ratio (95% confidence interval)] diabetes duration 0.090 (0.049, 0.131), p < 0.0001, systolic blood pressure 0.012 (0.003–0.021), p < 0.010 and serum creatinine 0.021 (0.012, 0.030).
The prevalence of micro and macroalbuminuria is higher among African Type 1 patients with relatively short diabetes duration compared with prevalences among Caucasians. In Type 2 patients, the prevalence is in accordance with findings in Caucasians. The present study detects, however, a much lower prevalence than previously demonstrated in studies from sub-Saharan Africa. Abnormal AER was significantly related to diabetes duration and systolic blood pressure.
PMCID: PMC1781433  PMID: 17224056
16.  Standardizing adverse drug event reporting data 
The Adverse Event Reporting System (AERS) is an FDA database providing rich information on voluntary reports of adverse drug events (ADEs). Normalizing data in the AERS would improve the mining capacity of the AERS for drug safety signal detection and promote semantic interoperability between the AERS and other data sources. In this study, we normalize the AERS and build a publicly available normalized ADE data source. The drug information in the AERS is normalized to RxNorm, a standard terminology source for medication, using a natural language processing medication extraction tool, MedEx. Drug class information is then obtained from the National Drug File-Reference Terminology (NDF-RT) using a greedy algorithm. Adverse events are aggregated through mapping with the Preferred Term (PT) and System Organ Class (SOC) codes of Medical Dictionary for Regulatory Activities (MedDRA). The performance of MedEx-based annotation was evaluated and case studies were performed to demonstrate the usefulness of our approaches.
Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). In total, the AERS-DM contains 37,029,228 Drug-ADE records. Seventy-one percent (10,221/14,490) of normalized drug concepts in the AERS were classified to 9 classes in NDF-RT. The number of unique pairs is 4,639,613 between RxNorm concepts and MedDRA Preferred Term (PT) codes and 205,725 between RxNorm concepts and SOC codes after ADE aggregation.
We have built an open-source Drug-ADE knowledge resource with data being normalized and aggregated using standard biomedical ontologies. The data resource has the potential to assist the mining of ADE from AERS for the data mining research community.
PMCID: PMC4142531  PMID: 25157320
17.  Early Urinary Markers of Diabetic Kidney Disease: A Nested Case-Control Study From the Diabetes Control and Complications Trial (DCCT) 
Urinary markers were tested as predictors of macroalbuminuria or microalbuminuria in type 1 diabetes.
Study Design
Nested case:control of participants in the Diabetes Control and Complications Trial (DCCT)
Setting & Participants
Eighty-seven cases of microalbuminuria were matched to 174 controls in a 1:2 ratio, while 4 cases were matched to 4 controls in a 1:1 ratio, resulting in 91 cases and 178 controls for microalbuminuria. Fifty-five cases of macroalbuminuria were matched to 110 controls in a 1:2 ratio. Controls were free of micro/macroalbuminuria when their matching case first developed micro/macroalbuminuria.
Urinary N-acetyl-β-D-glucosaminidase, pentosidine, AGE fluorescence, albumin excretion rate (AER)
Incident microalbuminuria (two consecutive annual AER > 40 but <= 300 mg/day), or macroalbuminuria (AER > 300 mg/day)
Stored urine samples from DCCT entry, and 1–9 years later when macroalbuminuria or microalbuminuria occurred, were measured for the lysosomal enzyme, N-acetyl-β-D-glucosaminidase, and the advanced glycosylation end-products (AGEs) pentosidine and AGE-fluorescence. AER and adjustor variables were obtained from the DCCT.
Sub-microalbuminuric levels of AER at baseline independently predicted microalbuminuria (adjusted OR 1.83; p<.001) and macroalbuminuria (adjusted OR 1.82; p<.001). Baseline N-acetyl-β-D-glucosaminidase independently predicted macroalbuminuria (adjusted OR 2.26; p<.001), and microalbuminuria (adjusted OR 1.86; p<.001).
Baseline pentosidine predicted macroalbuminuria (adjusted OR 6.89; p=.002). Baseline AGE fluorescence predicted microalbuminuria (adjusted OR 1.68; p=.02). However, adjusted for N-acetyl-β-D-glucosaminidase, pentosidine and AGE-fluorescence lost predictive association with macroalbuminuria and microalbuminuria, respectively.
Use of angiotensin converting-enzyme inhibitors was not directly ascertained, although their use was proscribed during the DCCT.
Early in type 1 diabetes, repeated measurements of AER and urinary NAG may identify individuals susceptible to future diabetic nephropathy. Combining the two markers may yield a better predictive model than either one alone. Renal tubule stress may be more severe, reflecting abnormal renal tubule processing of AGE-modified proteins, among individuals susceptible to diabetic nephropathy.
PMCID: PMC2864367  PMID: 20138413
Diabetic nephropathy; Advanced glycosylation end-products; N-acetyl beta glucosaminidase; Albuminuria
18.  Development and Progression of Renal Insufficiency With and Without Albuminuria in Adults With Type 1 Diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2010;33(7):1536-1543.
This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).
Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.
A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.
Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.
PMCID: PMC2890355  PMID: 20413518
19.  Bactericidal, virucidal, and mycobactericidal activities of reused alkaline glutaraldehyde in an endoscopy unit. 
Journal of Clinical Microbiology  1993;31(11):2988-2995.
Baths with 2% alkaline glutaraldehyde are often reused for 14 days to decontaminate flexible fiberoptic endoscopes (FFEs) between patients, but the effect of such reuse on the disinfectant's activity has not been known. Many busy endoscopy units also disinfect FFEs with contact times shorter than those recommended by the disinfectant manufacturer. We therefore collected samples of the disinfectant over the 14-day reuse period from two manual and one automatic bath used for bronchoscopes and gastroscopes at a local hospital. Control samples were also collected from a manual bath of 2% alkaline glutaraldehyde which did not receive any endoscopes. The germicidal activities of the samples were assessed in a carrier test against a mixture of hepatitis A virus, poliovirus 1 (Sabin), and Pseudomonas aeruginosa; the mixture also contained either Mycobacterium bovis or Mycobacterium gordonae. Bovine serum (5%) was the organic load. The criterion of efficacy was a minimum of a 3-log10-unit reduction in the infectivity titers of the organisms tested. The initial disinfectant concentration in all the baths was nearly 2.25%; it became about 1.8% in the control bath and fell to approximately 1% in the three test baths after 14 days. No protein was detected in the control bath, while its concentration rose gradually in the test baths to a maximum of 1,267 micrograms/ml after 14 days. With a contact time of 10 min at 20 +/- 2 degrees C, all the samples from the control bath were effective against all the test organisms and all the samples from all the test baths were also effective against P. aeruginosa. With a contact time of 10 or 20 min at 20+/-2 degrees C, the virucidal and mycobactericidal activities of the samples from the test baths showed broad-spectrum germicidal activity when the contact time was increased to 45 min and the temperature was raised to 25 degrees C. These findings emphasize the care needed in the disinfection of FFEs, especially in view of the increasing threat of AIDS and the resurgence of tuberculosis.
PMCID: PMC266182  PMID: 8263184
20.  Assessment on Experimental Bacterial Biofilms and in Clinical Practice of the Efficacy of Sampling Solutions for Microbiological Testing of Endoscopes 
Journal of Clinical Microbiology  2012;50(3):938-942.
Opinions differ on the value of microbiological testing of endoscopes, which varies according to the technique used. We compared the efficacy on bacterial biofilms of sampling solutions used for the surveillance of the contamination of endoscope channels. To compare efficacy, we used an experimental model of a 48-h Pseudomonas biofilm grown on endoscope internal tubing. Sampling of this experimental biofilm was performed with a Tween 80-lecithin-based solution, saline, and sterile water. We also performed a randomized prospective study during routine clinical practice in our hospital sampling randomly with two different solutions the endoscopes after reprocessing. Biofilm recovery expressed as a logarithmic ratio of bacteria recovered on bacteria initially present in biofilm was significantly more effective with the Tween 80-lecithin-based solution than with saline solution (P = 0.002) and sterile water (P = 0.002). There was no significant difference between saline and sterile water. In the randomized clinical study, the rates of endoscopes that were contaminated with the Tween 80-lecithin-based sampling solution and the saline were 8/25 and 1/25, respectively (P = 0.02), and the mean numbers of bacteria recovered were 281 and 19 CFU/100 ml (P = 0.001), respectively. In conclusion, the efficiency and therefore the value of the monitoring of endoscope reprocessing by microbiological cultures is dependent on the sampling solutions used. A sampling solution with a tensioactive action is more efficient than saline in detecting biofilm contamination of endoscopes.
PMCID: PMC3295158  PMID: 22170930
21.  Recent Update of Gastrointestinal Endoscope Reprocessing 
Clinical Endoscopy  2013;46(3):267-273.
As infection-related issues have become one of the most important concerns in endoscopy centers, proper reprocessing of endoscopes has attracted great interest. Compliance with established guidelines for reprocessing is critical to prevent pathogen transmission. However, hospital compliance with guidelines has not been satisfactory. To increase compliance, efforts have focused on developing new and more innovative disinfectants and an automated endoscope reprocessor. Reprocessing must be performed by appropriately trained personnel and regular monitoring of reprocessing is essential for quality assurance to improve compliance.
PMCID: PMC3678065  PMID: 23767038
Endoscopy, gastrointestinal; Reprocessing, compliance
22.  Hygienic safety of reusable tap water filters (Germlyser®) with an operating time of 4 or 8 weeks in a haematological oncology transplantation unit 
Microbial safe tap water is crucial for the safety of immunosuppressed patients.
To evaluate the suitability of new, reusable point-of-use filters (Germlyser®, Aquafree GmbH, Hamburg, Germany), three variations of a reusable filter with the same filter principle but with different outlets (with and without silver) and inner surface coating of the filter encasements (with and without nano-crystalline silver) were tested. The filter efficacy was monitored over 1, 4 and 8 weeks operating time in a haematological oncology transplantation unit equipped with 18 water outlets (12 taps, 6 showers).
The filtered water fulfilled the requirements of absence of pathogens over time. From 348 samples, 8 samples (2.3%) exceeded 100 cfu/ml (no sample ≥ 500 cfu/ml). As no reprocessed filter exhibited 100% filter efficacy in the final quality control after each reprocessing, these contaminations could be explained by retrograde contamination during use.
As a consequence of the study, the manufacturer recommends changing filters after 4 weeks in high risk areas and after 8 weeks in moderate infectious risk areas, together with routine weekly alcohol-based surface disinfection and additionally in case of visible contamination. The filter efficacy of the 3 filters types did not differ significantly regarding total bacterial counts. Manual reprocessing proved to be insufficient. Using a validated reprocessing in a washer/disinfector with alkaline, acid treatment and thermic disinfection, the filters were effectively reprocessable and now provide tap water meeting the German drinking water regulations as well as the WHO guidelines, including absence of pathogens.
PMCID: PMC1892024  PMID: 17521416
23.  Molecular Detection, Quantification, and Toxigenicity Profiling of Aeromonas spp. in Source- and Drinking-Water 
Aeromonas is ubiquitous in aquatic environments and has been associated with a number of extra-gastrointestinal and gastrointestinal illnesses. This warrants monitoring of raw and processed water sources for pathogenic and toxigenic species of this human pathogen. In this study, a total of 17 different water samples [9 raw and 8 treated samples including 4 basin water (partial sand filtration) and 4 finished water samples] were screened for Aeromonas using selective culturing and a genus-specific real-time quantitative PCR assay. The selective culturing yielded Aeromonas counts ranging 0 – 2 x 103CFU/ml and 15 Aeromonas isolates from both raw and treated water samples. The qPCR analysis indicated presence of a considerable nonculturable population (3.4 x 101 – 2.4 x 104 cells/ml) of Aeromonas in drinking water samples. Virulence potential of the Aeromonas isolates was assessed by multiplex/singleplex PCR-based profiling of the hemolysin and enterotoxin genes viz cytotoxic heat-labile enterotoxin (act), heat-labile cytotonic enterotoxin (alt), heat-stable cytotonic enterotoxin (ast), and aerolysin (aerA) genes. The water isolates yielded five distinct toxigenicity profiles, viz. act, alt, act+alt, aerA+alt, and aerA+alt+act. The alt gene showed the highest frequency of occurrence (40%), followed by the aerA (20%), act (13%), and ast (0%) genes. Taken together, the study demonstrated the occurrence of a considerable population of nonculturable Aeromonads in water and prevalence of toxigenic Aeromonas spp. potentially pathogenic to humans. This emphasizes the importance of routine monitoring of both source and drinking water for this human pathogen and role of the developed molecular approaches in improving the Aeromonas monitoring scheme for water.
PMCID: PMC4062929  PMID: 24949108
Aeromonas; drinking water; real-time qPCR; singleplex and multiplex PCR; virulence genes.
24.  Evaluation of the efficacy of akacid plus® fogging in eradicating causative microorganism in nosocomial infections 
Objective: The novel polymeric guanidine Akacid Plus® is a member of the cationic family of disinfectants. The aim of the present study was to evaluate the activity of Akacid Plus® against bacteria which cause nosocomial infections and remain viable after contaminating the environment and determine the effects of organic materials to the activity. Methods: Closed room and control room were created for experimental disinfection. Bacterial suspensions of 0.5 McFarland were prepared from methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and vancomycine-resistant Enterococcus faecium (VRE) strains. A 0.1 mL of each suspension was applied on the chipboard (25 cm2) and tile (25 cm2) test surfaces without albumin and with 2% albumin to simulate organic dirt, and the test surfaces were placed in the test and control rooms after drying. Before testing, cotton swab premoistened with serum physiologic was used to obtain samples from various surfaces in the environment and the samples were transferred onto 5% sheep blood agar for incubation at 37°C. Akacid Plus® solution at a concentration of 0.5% was nebulized with an aerosol applicator (Prowi-06, Germany) for 45 minutes. After a 2-hour waiting period, 1 mL neutralizing broth (Dey-Engley Neutralizing Broth, Fluka) was transferred on the test surfaces, and samples were collected with a swab from the test surfaces and various surfaces in the testing room and inoculated on 5% sheep blood agar for incubation at 37oC for 24 hours. At the end of the incubation period, number of colonies were evaluated on the control and test plates. Results: Although coagulase-negative staphylococci, Bacillus spp., and fungi were grown in cultured samples obtained from the environment of experimental laboratory, no growth was observed in the test plates after room disinfection with Akacid Plus®. After room disinfection, MRSA and A. baumannii were not detectable in the cultured media prepared from the test surfaces with or without albumin. The bacterial count for vancomyine-resistant E. faecium was reduced from 107 to 5×102 on surfaces without albumin and from 107 to 2.5×103 on surfaces with albumin. All test plates prepared from the surfaces in the control room showed abundant growth of the microorganism. Conclusion: The nebulization of Akacid plus® solution at a concentration of 0.5% proved to be an efficient means of disinfection for the removal of pathogenic microorganisms that cause hospital outbreaks and use of isolation measures.
PMCID: PMC4307569  PMID: 25664122
Akacid plus®; MRSA; A. baumanni; VRE
25.  Aldehyde-Resistant Mycobacteria Associated with the Use of Endoscope Reprocessing Systems 
Bacteria can develop resistance to antibiotics, but less is known about their ability to increase resistance to chemical disinfectants. This study randomly sampled three AERs in the USA using aldehydes for endoscope disinfection. Bacterial contamination was found post-disinfection in all AERs and some mycobacteria isolated demonstrated significant resistance to glutaraldehyde and OPA disinfectants. Bacteria can survive aldehyde-based disinfection and may pose a cross-contamination risk to patients.
PMCID: PMC3523318  PMID: 22325730

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