A total of 1082 ERCPs were performed between January 2012 - December 2013 in a single referral center. All ERCPs were performed by one of five certified gastroenterologists with more than 5-years' experience in advanced endoscopy in a single dedicated room. (In only two cases (0.4%) the name of the endoscopist was not documented). Demographic and clinical characteristics including indication, complications, pre and post procedure antibiotic treatment and bacterial blood cultures were collected and documented manually from patient's records. Exclusion criteria were: (1) Age < 18 years; (2) Positive bacterial blood culture before ERCP; (3) Scheduled antibiotic treatment prior to ERCP; (4) Hospitalization longer than 14 days before ERCP; and (5) Missing critical data (mainly medical charts of documented antibiotic treatment). The study was approved by the local Institutional Review Board (IRB No: 0598-13-TLV), data was anonymous and informed consent was waivered.

Native papilla - Patients who previously underwent ERCP with papillotomy or pre-cut were considered "experienced patients" as opposed to patients with "native papilla".

Obstructive malignancy – Bile duct compression by an abdominal tumor or metastases (i.e., pancreatic origin, cholangiocarcinoma, liver metastases etc.). Malignancy without abdominal involvement was not recorded (for example breast cancer).

"Naïve obstructive malignancy" - Patients who had their first ERCP for the indication of obstructive jaundice due to compressive malignancy were labeled as "Naïve obstructive malignancy".

Antibiotic prophylaxis - antibiotic prophylaxis was defined as a single dosage of antibiotic drug given in the window period of 1 h before ERCP and up to the end of the procedure. If the procedure was ambulatory, the decision whether or not to give prophylaxis was made according to the endoscopist discretion. If the procedure was performed during hospitalization the decision was made by the treating physician in the ward.

Tandem procedures – if an endoscopic ultrasound (EUS) was preformed just prior to the ERCP (in the same room, by the same physician and under the same anesthesia).

ERCP duration - the procedure duration was calculated as the time interval between the first documented picture (papilla of Vater) and last picture (final cho-langiography). If tandem procedures were performed, only the ERCP duration was calculated.

Clinically significant PEB - bacterial blood cultures were drawn according to clinical indication (fever, systemic inflammatory response, cholangitis, etc.). PEB was defined as a positive bacterial blood culture within 7 d of ERCP date. Bacterial species and antibiotic resistance were documented.

Appropriateness of antibiotic prophylaxis - a gastroenterology specialist from the advanced endoscopy unit, who did not participate in the ERCPs included and was blinded to the outcome following the ERCPs, reviewed all the cases, and ranked the appropriateness of antibiotic prophylaxis according to the ASGE guidelines. There were 3 categories: (1) Prophylaxis was clearly indicated; (2) Prophylaxis was equivocal but was appropriate in the specific setting; and (3) Prophylaxis was not indicated.

All statistical analyses were performed using MATLAB (Mathwork Inc. version 2015b) and SPSS version 23.0 for Windows (SPSS Inc., Chicago, IL, United State). Continuous variables are presented as means ± SD, while categorical variables are presented in percentage. Univariate analyses were used for the comparison of variable's distribution between the study groups. To test differences in continuous variables between two groups the independent samples t-test (for normally distributed variables) or the Mann-Whitney U test (if non-parametric tests were required) were performed. To test the differences in categorical variables the Pearson χ²-Square test was performed, P < 0.05 was considered statistically significant for all analyses. We used stepwise Logistic Regression analysis with entry probability of 0.2 and Decision Tree algorithms with minimum leaf of 50 cases, for prediction modeling of bacteremia. The statistical methods of the study were reviewed by Leshno M, MD, from the Faculty of Management, Tel-Aviv University, Israel.

A total of 1082 consecutive ERCPs were analyzed and 456 were excluded (Figure 1). Thus, a total of 626 ERCPs performed in 434 patients were included. In 84 cases (13.4%), bacterial blood cultures were drawn based on clinical suspicion. Positive cultures were documented in 23/84 cases (27.4%), thus the rate of clinically significant PEB was 23/626 (3.7%).

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Figure 1 Study flow chart. PEB: Post endoscopic retrograde cholangiopancreatography bacteremia; ERCP: Endoscopic retrograde cholangiopancreatography.

Demographics and procedure associated data is shown in Table 1. Mean age at ERCP was 66.49 ± 15.4 years with 46.5% being male. Patient's characteristics were comparable between the PEB and non-PEB groups (Table 1). The most prevalent indication for ERCP in both groups was choledocholithiasis (30.4% and 32.2% for PEB and non-PEB groups respectively, P = NS) followed by elective stent replacement (26.1% and 24.9%, respectively, P = NS). This was a first ERCP intervention (native papilla) in 60.9% of the PEB cases and 44.9% of the non-PEB cases (P = NS). ERCP duration was significantly longer among the PEB group compared to the non-PEB group (40.87 ± 42.7 vs 28.64 ± 24.3 min, respectively, P = 0.02). The prevalence of tandem procedures (EUS followed immediately by ERCP) was significantly higher among the PEB group [5 (21.7%) vs 37 (6.1%), respectively, P = 0.003). In the cases of tandem EUS/ERCP, fine needle aspiration (FNA) from a solid mass was performed in 9/37 cases of the non-PEB group and 4/5 cases of the PEB group (24.3% vs 80%, P = 0.01). Intra ductal ultrasound (IDUS) was used in 2 cases and celiac block was performed in 1 case (all 3 cases were in the non-PEB group). The utilization of sphincterotomy, pre-cut or through the scope (TTS)-dilation was equally prevalent between the groups as well as the use of pancreatic stent. The use of naso-biliary drainage is very rare in our institute and was not documented. There was no difference in the distribution of ERCPs among five operators between the PEB and non-PEB groups (respectively: #1: 26.1% vs 28.4%, #2: 39.1% vs 31.7%, #3: 17.4% vs 15.8%, #4: 13.0% vs 19.6%, 5#: 4.3% vs 4.3%, unknown: 0% vs 0.4%, P = 0.985). Blood tests performed up to 72 h before ERCP were available for a minority of cases and are elaborated in Supplementary table 1.

There were 23 cases of Bacteremia: 11 cases (1.8%) were of the Enterobacteriaceae family (E.coli and Klebsiella spp.), 8 cases (1.3%) were extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, 2 cases (0.3%) were Pseudomonas aeruginosa and the last 2 cases (0.3%) were Acinetobacter baumannii (Figure 2A). Seventy percent of the positive cultures were drawn during the three days following the ERCP procedure and 21.7% up to the fifth day, 8.9% were drawn on days 6-7 (Figure 2B).

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Figure 2 Bacterial type's dispersion among entire cohort and according to the days past endoscopic retrograde cholan-giopancreatography date. A: Bacterial type's dispersion among entire cohort; B: Bacterial type's according to the days past endoscopic retrograde cholangiopancreatography date. ERCP: Endoscopic retrograde cholangiopancreatography; ESBL: Extended spectrum beta-lactamase.

To rule out other causes for bacteremia, invasive procedures such as percutaneous trans-hepatic drainage (PTD), cholecystostomy or surgery were documented (time interval- 7 days before the procedure and up to the day of bacterial culture collection). Pre-ERCP invasive procedure was not performed in any of the PEB cases. In the non-PEB group, 8 cases (1.3%) had pre-ERCP PTD, cholecystostomy was performed in 1 case (0.2%) and surgery in 12 cases (2%). Invasive procedures post-ERCP were documented in 2 cases (8.7%) from the PEB group, both were PTD insertion, and both were diagnosed with Acinetobacter bacteremia. There were 11 cases of invasive post-ERCP procedures in the non-PEB group (1.9%), with PTD in 4 cases (0.7%), and surgery in 7 cases (1.2%).

In elective ambulatory procedures (520/626 cases, 83.1%), antibiotic prophylaxis with ceftriaxone was administrated in 14.2% of the cases. Administration was in accordance with ASGE recommendations and at the endoscopist discretion. In hospitalized patients (106/626 cases, 16.9%), antibiotic prophylaxis was administrated in 61.3% of cases (61.3% vs 14.2%, in-patients vs out-patients respectively, P < 0.001). Administration was at the treating physician discretion. Prophylaxis in hospitalized patients was administrated as a single drug in 13 cases (20.0%), two drugs in 7 cases (10.8%) and three drugs in 45 cases (69.2%).

In order to assess the appropriateness of antibiotic administration, a case by case review of the ERCP reports by an advanced endoscopist blinded to drug administration was performed. Antibiotic prophylaxis was clearly indicated in 59 cases (9.3%) and not indicated in 538 cases (85.9%). In 30 cases (4.8%) antibiotic prophylaxis was deemed appropriate in the specific setting, though not clearly indicated by ASGE guidelines (Figure 3A). In line with this classification, the antibiotic prophylaxis was indicated in only 44 cases (31.7%), appropriate in 9 cases (6.5%) and not indicated in 86 (61.9%) out of 139 cases it was given (Figure 3B).

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Figure 3 Appropriateness of antibiotic administration. A: Categorization of antibiotic prophylaxis appropriateness according to ASGE guidelines; B: Sub-categorization of prophylaxis appropriateness among cases who were actually administrated with antibiotics and those who were not.

Out of 23 cases of PEB, none (0%) were indicated for antibiotic prophylaxis. Five cases (21.7%) were found appropriate and in 18(78.3%) cases there was no indication for antibiotic prophylaxis. In 2/23 cases of PEB antibiotic prophylaxis was actually administrated (both non-indicated). One case was an ambulatory procedure where Ceftriaxone was administered and Enterobacteriaceae PEB occurred. The other was an in-patient treated prophylactically by three different antibiotics (ceftriaxone, gentamycin and metronidazole) but ended up with ESBL PEB. In both cases the procedure duration was longer than 60 min (Figure 4).

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Figure 4 Sub-categorization of prophylaxis administration in each category of prophylaxis appropriateness among cases with or without post endoscopic retrograde cholangiopancreatography bacteremia. ERCP: Endoscopic retrograde cholangiopancreatography.

In order to evaluate novel risk factors for PEB, two methods were used: Multivariate logistic regression and decision tree. By univariate logistic regression, PEB (as the dependent variable) and 13 independent variables were evaluated. Four variables were found to be statistically significant: Age at ERCP (years) (OR, 1.027, 95%CI: 0.995-1.060, P = 0.096); Tandem EUS/ERCP (Yes vs No) (OR, 4.130, 95%CI: 1.494-12.084, P = 0.007); Tandem EUS/ERCP with FNA (Yes vs No) (OR, 13.984, 95%CI: 1.552-8.925, P < 0.001); ERCP duration (minutes) (OR, 1.011, 95%CI: 1.001-1.022, P = 0.034) (Table 2). Both appropriateness of prophylaxis administration and actual prophylaxis administration were not shown to increase the risk for PEB (Table 2). We elected and entered three variables (ERCP duration, age at ERCP and tandem EUS/ERCP with FNA) into a decision tree. In this preliminary model the cut points were age ≥ 75 years and ERCP duration ≥ 60 min (not shown). Therefore, we re-analyzed these variables as dichotomous variables in the univariate logistic regression (Table 2). The three mentioned variables were entered to a stepwise multivariate logistic regression along with "antibiotic prophylaxis" as a possible confounder (Table 2). All three factors were significant risk factors: Age at ERCP ≥ 75 years (OR, 3.780, 95%CI: 1.519-9.408, P = 0.004); Tandem EUS/ERCP with FNA (OR, 14.528, 95%CI: 3.571-59.095, P < 0.001); ERCP duration ≥ 60 min (OR, 5.396, 95%CI: 1.86-15.656, P = 0.002). Administration of antibiotic prophylaxis was not a significant beneficial factor.

In the second method we entered the selected 3 variables along with "antibiotic prophylaxis" as a possible confounder into a decision tree model (Figure 5). If EUS with FNA preceded ERCP, the probability for PEB was 31%. If not, but the duration of the ERCP was equal to or longer than 60 min, the probability for PEB was 10%. If the duration was less than 60 min and no FNA was preformed but the age of the patient equal or greater than 75 years, the probability for PEB was 6% without prophylaxis and 0% with prophylaxis. If the patient did not have any risk factor, the probability for PEB was 1% regardless of prophylaxis administration.

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Figure 5 Decision tree model for the outcome of post endoscopic retrograde cholangiopancreatography bacteremia. PEB: Post endoscopic retrograde cholangiopancreatography bacteremia. ERCP: Endoscopic retrograde cholangiopancreatography; EUS: Endoscopic ultrasound; FNA: Fine needle aspiration.

The area under the roc curve of the logistic regression model was 0.766 and the area under the roc curve of the decision tree model was 0.778 (Figure 6).

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Figure 6 Receiver operating characteristic curves of the logistic regression model (broken line, AUC, 0. 766) and the decision tree model (continuous line, AUC, 0.778). ROC: Receiver operating characteristic.

Endoscopic retrograde cholangiopancreatography (ERCP) is currently the method of choice for the treatment of biliary and pancreatic duct obstruction. Clinically significant post-ERCP bacteremia (PEB) occurs in up to 5% of cases, while antibiotic prophylaxis is recommended only when an ERCP is unlikely to achieve complete biliary drainage.

The current recommendations do not address specific populations or procedure-related factors that require specific management in terms of antibiotic prophylaxis. Identification of risk factors for PEB may reduce its occurrence and related complications.

The primary objective of this study was to evaluate possible risk factors for PEB. Secondary objectives were: Evaluation of PEB prevalence and to assess "real-life" practices of antibiotic administration and their competency to ASGE guidelines.

This was a retrospective study of all ERCP procedures performed in a single tertiary medical center. Data collection included: Demographic and clinical characteristics such as pre and post procedure antibiotic treatment and bacterial blood cultures and procedure related characteristics. Strict eligibility criteria were applied and 626 ERCPs were included in the final analysis. Stepwise Logistic Regression analysis and Decision Tree algorithms were used for prediction modeling of PEB.

A total of 626 ERCPs performed in 434 patients were included. PEB prevalence was 3.7%. Antibiotic prophylaxis was administrated in 22.2% cases but was indicated according to the guidelines only in 7% of cases. In all the PEB cases, prophylaxis was deemed not indicated. A stepwise logistic regression (ROC, 0.766), identified 3 variables as independent risk factors for PEB: Age at ERCP ≥ 75 years, Tandem EUS/ERCP with FNA and ERCP duration longer than 60 min. In a decision tree model (ROC, 0.778) the probability for PEB without any risk factors was 1% regardless of prophylaxis administration.

Our study demonstrated that ERCP duration longer than 60 min, tandem EUS-ERCP with FNA and age above 75 years are significant risk factors for PEB. Moreover, the prevalence of PEB in our study was similar to previous reports, despite the fact that antibiotic prophylaxis was administrated more readily than recommended. Both conclusions support a more tailor-made approach regarding antibiotic prophylaxis before ERCP. 

Future prospective studies should focus on these risk factors as indications for prophylactic antibiotic treatment before ERCP in order to reduce the prevalence of PEB.