Abstract
Background and Aim
The appropriate duration of antimicrobial therapy for acute cholangitis (AC) arising from multiple hilar biliary obstructions as opposed to simple obstruction in the extrahepatic bile duct has not been established. This study assessed the efficacy of the duration of antimicrobial treatments in the Tokyo Guidelines 2018 for AC based on the cause and site of obstruction.
Methods
This single‐center retrospective study involved patients with AC who underwent successful biliary drainage and completed a 7‐day or shorter antimicrobial treatment. Patients were categorized into three groups: Group 1, bile duct stone or benign obstruction; Group 2, simple biliary obstruction due to malignancy; and Group 3, multiple hilar biliary obstruction due to malignancy. The primary outcome was clinical cure rate, and the secondary outcomes were 3‐month recurrence rate and length of hospital stay.
Results
A total of 373 patients were selected. Patients in Group 3 were younger or had Charlson Comorbidity Index ≥4, and had fewer positive blood cultures. In Group 3, the clinical cure rate (87.1%) and 3‐month recurrence rate (32.3%) were less favorable than those in the other groups. In Group 1, the clinical cure rate was significantly higher (98.1%, P = 0.02) with a much lower 3‐month recurrence rate of only 3.4% (P < 0.001) than that in the other groups. The median hospital stay for all groups was 7 days.
Conclusion
This study suggests that the outcomes in Group 3 may be worse than those in Groups 1 or 2, regardless of the duration of the antibiotic treatment.
Keywords: acute cholangitis, antimicrobial resistance, antimicrobial stewardship, bile duct obstruction, hilar region
This study evaluates the efficacy of antimicrobial therapy durations recommended by the Tokyo Guidelines 2018 for acute cholangitis (AC), comparing different obstruction etiologies. Results indicate that patients with multiple hilar biliary obstructions (Group 3) experience poorer outcomes compared to those with single obstructions (Groups 1 and 2), suggesting that treatment efficacy is influenced by obstruction complexity, irrespective of the antimicrobial therapy duration.
Introduction
Acute cholangitis (AC), the second or fourth most prevalent cause of community‐acquired bacteremia, 1 , 2 is one of the most common diseases requiring antimicrobial therapy. The Tokyo Guidelines 2018 (TG18), which is among the most recognized AC guidelines, advocate a 4‐ to 7‐day antibiotic treatment duration following biliary drainage. However, robust evidence specifying the duration of antibiotic treatment to effectively treat AC is lacking. 3 Recent research findings suggest that the brief use of antimicrobials, lasting only 1–3 days following biliary drainage, is comparable in efficacy to the conventional treatment duration for AC. This evidence proposes that administering antimicrobials for a short duration after biliary drainage represents a viable and reasonable approach for the treatment of AC. 4 , 5 , 6
To our knowledge, no study has investigated whether AC resulting from multiple hilar biliary obstructions requires a similar duration of antimicrobial treatment as AC resulting from simple obstruction in the extrahepatic bile duct, which the TG18 guidelines treat equally. 3 Bismuth‐IV obstruction (Figure S1, Supporting information) has been reported to have a higher clinical failure rate for bile duct drainage than other hilar obstruction. 7 In patients with hilar biliary obstruction, the number of patients who required re‐drainage of the bile duct was higher in those treated with Bismuth‐II (91.9%), Bismuth‐IIIa (65.7%), and Bismuth‐IV (92.9%) obstruction than in those treated with Bismuth‐I (22.2%) obstruction. 8 Therefore, the presence of multiple biliary obstructions may affect AC outcomes. It is unclear whether the standard treatment period recommended by the TG18 or the shorter treatment periods that have been reported to be effective for AC can be applied to cases of AC with multiple hilar biliary obstructions. Notably, performing cholangiography to determine the Bismuth classification may lead to bacteremia due to increased intrabiliary pressure. 9 Therefore, depending on the severity of AC, sufficient cholangiography cannot be performed in some cases, making it difficult to accurately determine the Bismuth classification. In this study, we considered patients with multiple hilar biliary obstructions of Bismuth‐II or higher, which was determined from computed tomography and endoscopic retrograde cholangiopancreatography (ERCP) findings, as the group susceptible to poor drainage and adverse prognosis.
This study aimed to evaluate the efficacy of antimicrobial treatment lasting 7 days or less in cases of AC, as well as to investigate whether the clinical outcomes of cholangitis are affected by the presence of multiple hilar biliary obstructions or simple biliary obstructions in the extrahepatic bile duct.
Methods
Ethical considerations
This study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. This study was reviewed and approved by the Institutional Review Board of the Future Medical Research Center Ethics Committee (approval no. TGE01849‐024). Informed consent was obtained from all participants using the opt‐out method following the latest Japanese ethical guidelines. 10 This approach was selected because the observational nature of the study relied on medical records, without involving samples derived from the human body.
Study design and patient selection
This was a single‐center, retrospective cohort study. We included patients who presented with AC at Shonan Kamakura General Hospital between January 2018 and June 2020. AC was defined according to the TG18. 11 Only patients aged ≥18 years who received a course of antibiotic treatment lasting within a 7‐day period following successful ERCP, in accordance with TG18 recommendations, were included. Technical success was defined as the placement of plastic or metallic stents above the bile duct obstruction or stones, or successful stone extraction. 7
We excluded cases complicated by acute cholecystitis and those at the terminal stage of a malignant tumor. Terminal cases were defined as those where death due to cancer was confirmed within 30 days. Patients with a severe illness before AC onset, unsuccessful biliary drainage, biliary hemorrhage, a history of intestinal reconstruction methods other than Billroth I, and those for whom the mortality status could not be ascertained after 30 days were also excluded. Moreover, cases where antimicrobial therapy duration after biliary drainage exceeded 7 days, as well as recurrent cases with a history of AC within the past 3 months, were also excluded from the study. These specific cases were excluded as they significantly impact the outcomes of AC due to factors unrelated to its characteristics.
Exposure
Patients were categorized into three groups: Group 1, bile duct stone or benign obstruction; Group 2, Bismuth‐I (simple biliary obstruction due to malignancy); and Group 3, Bismuth‐II or higher (hilar multiple biliary obstruction due to malignancy). Groups 1 and 2 were defined as the simple extrahepatic bile duct obstruction group.
In cases of Bismuth‐II or higher with hilar multiple obstructions, stent placement principally involved the insertion of two or three 7 Fr plastic stents into both lobes, depending on the extent of separation. This was performed to ensure as much drainage of the entire biliary tract as possible. However, in instances of Bismuth‐II where complete disconnection at the hilum was not evident, only a single stent was placed based on the attending physician's judgment. In cases of unsuccessful ERCP, endoscopic ultrasound‐guided drainage was performed.
The clinical success of ERCP in achieving biliary drainage is often defined as a decrease in bilirubin levels by more than 50% from the pretreatment value, measured 2 weeks after the procedure, according to the Tokyo Criteria 2014. 12 However, patients with AC are often discharged within a week, and this definition does not allow early determination of drainage effectiveness. Therefore, in this study, clinical success following ERCP or alternative biliary drainage procedures was defined as achieving a 50% decrease or normalization of total bilirubin or alanine aminotransferase levels within 1 week of the procedure.
We initially adhered to the principle of a 4–5‐day duration following the TG18 guidelines. However, toward the latter part of the study period, accumulating evidence favored shortening the duration to 1–3 days for mild to moderate cases, 4 , 5 , 6 and our hospital encouraged the shorter duration. Conversely, in severe cases or those with limited improvement in clinical symptoms and laboratory data, the duration was extended up to 7 days on a case‐by‐case basis.
Variables and outcomes
The variables measured in the study population included age, comorbidities, cause of AC, severity of AC based on the TG18, National Early Warning Score (NEWS), ERCP findings, antimicrobial therapy, and blood or bile culture findings. Blood cultures were collected before antibiotic administration and bile cultures were collected immediately after ERCP. Subsequently, we assessed the severity of AC based on the TG18, 11 factors previously reported to exacerbate outcomes in cholangitis (age, 13 Charlson Comorbidity Index [CCI], 14 , 15 primary disease as a malignant tumor, 16 , 17 and time from consultation to ERCP 18 ), antimicrobial therapy duration, 7 and NEWS within 24 h before the termination of antimicrobial administration. 7
Cholangitis is frequently associated with polymicrobial infections. Blood cultures exhibit low sensitivity and may fail to detect the causative organism, whereas bile cultures have low specificity and may detect enteric bacteria unrelated to the causative organism. This discrepancy complicates accurate identification of the causative organism of cholangitis. In this study, all identified bacteria were considered causative organisms. Interpretive standards from the Clinical and Laboratory Standards Institute for minimum inhibitory concentration or zone diameter testing were used to identify susceptible or resistant organisms. 19
We considered antimicrobial therapy duration as an important factor to investigate based on previous reports indicating that it can be shortened compared with the recommended duration in the TG18. 4 , 5 , 6
To assess the conditions of patients immediately before the discontinuation of antibiotics, we incorporated NEWS into our analysis. The United Kingdom's National Early Warning Score Development and Implementation Group developed the NEWS to assess deteriorating conditions in hospitalized patients and to predict inpatient death or intensive care unit (ICU) admission. 20 NEWS measures physiological parameters (systolic blood pressure, pulse rate, respiratory rate, temperature, and oxygen saturation), consciousness level, and oxygen supplementation, all of which are simple and easily accessible. 20 , 21 The reports placed the low‐risk group based on NEWS at ≤4 points. NEWS is utilized in several countries due to its superior capability in identifying patients at risk for the composite outcome of cardiac arrest, unexpected ICU admission, and death within 24 h compared with other early warning scores. Furthermore, the Deyo modification of the CCI was used to define the severity of the comorbid conditions. 22 A CCI score of ≥4 has been associated with poorer AC outcomes. 14 , 15 , 23
The primary outcome was clinical cure, and the secondary outcomes were the 3‐month recurrence rate and length of hospital stay. Clinical cure was defined as the absence of initial presenting symptoms by day 14 after biliary drainage, coupled with no recurrence or death by day 30. 24 , 25 Recurrence was defined as the initiation of a new antibiotic therapy for recurrent cholangitis, subsequent infection in the hepatic–pancreatic–biliary region, or any other subsequent infection possibly related to the initial episode of cholangitis. 5 , 26 , 27
Statistical analysis
The three groups were classified based on the duration of antibiotic use after ERCP, and blood culture results were compared using univariate analysis. Continuous and categorical variables were reported as medians and interquartile ranges, and numbers and percentages, respectively. Continuous and categorical variables were compared using the Mann–Whitney U and chi‐square tests, respectively. Risk differences with 95% confidence intervals were calculated for binary outcomes, and a two‐sided significance level for all tests was set at P < 0.05. All analyses were performed using the EZR software version 1.55, 28 a package for R statistical software (https://www.r-project.org/), which is a modified version of the R commander designed with statistical functions frequently used in biostatistics.
Results
Patient characteristics
In total, 373 patients with AC were included in this study (Fig. 1). Table 1 summarizes the patient characteristics. Compared with Group 1, Group 3 comprised a greater proportion of younger patients or those with a CCI ≥ 4. Although there was no statistically significant difference, there were fewer cases of nursing home residents in Group 3. Numbers of severe cases or cases with high NEWS before the completion of antibiotic treatment were comparable between the Groups 1 and 3.
Figure 1.
Flowchart of the inclusion and exclusion criteria. ERCP, endoscopic retrograde cholangiopancreatography; NOMI, non‐occlusive mesenteric ischemia; TG2018, Tokyo Guidelines 2018.
Table 1.
Patient characteristics
| Group 1 benign | Group 2 Bismuth‐I | Group 3 Bismuth‐II or higher | ||
|---|---|---|---|---|
| n = 267 | n = 75 | n = 31 | P‐value | |
| Age, median [IQR] | 81.00 [72.00, 87.00] | 81.00 [70.00, 85.00] | 73.00 [69.00, 83.00] | 0.039 |
| Age ≥75, n (%) | 191 (71.5%) | 50 (66.7%) | 13 (41.9%) | 0.004 |
| Male, n (%) | 130 (48.7%) | 44 (58.7%) | 13 (41.9%) | 0.198 |
| Cause of cholangitis, n (%) | ||||
| Bile duct stone | 265 (99.3%) | 0 (0.0%) | 0 (0.0%) | |
| Malignant obstruction (distal bile duct cancer) | 0 (0.0%) | 23 (30.7%) | 0 (0.0%) | |
| Malignant obstruction (pancreatic cancer) | 0 (0.0%) | 37 (49.3%) | 0 (0.0%) | |
| Malignant obstruction (gallbladder cancer) | 0 (0.0%) | 3 (4.0%) | 15 (48.4%) | |
| Malignant obstruction (hilar cholangiocarcinoma) | 0 (0.0%) | 6 (8.0%) | 12 (38.7%) | |
| Malignant obstruction (cancer of other organs) | 0 (0.0%) | 6 (8.0%) | 4 (12.9%) | |
| Benign obstruction and others | 2 (0.7%) | 0 (0.0%) | 0 (0.0%) | |
| Severity of AC, n (%) | 0.78 | |||
| Mild | 125 (46.8%) | 36 (48.0%) | 13 (41.9%) | |
| Moderate | 112 (41.9%) | 34 (45.3%) | 15 (48.4%) | |
| Severe † | 30 (11.2%) | 5 (6.7%) | 3 (9.7%) | |
| Underlying medical conditions, n (%) | ||||
| CCI (median [IQR]) | 1.00 [0.00, 1.00] | 1.00 [0.00, 2.00] | 1.00 [0.00, 4.00] | 0.296 |
| CCI ≥4 | 6 (2.2%) | 7 (9.3%) | 9 (29.0%) | <0.001 |
| AIDS.HIV, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | NA |
| Any malignancy including lymphoma and leukemia except malignant neoplasm of skin, n (%) | 12 (4.5) | 6 (8.0) | 2 (6.5) | 0.473 |
| Cerebrovascular disease, n (%) | 45 (16.9) | 6 (8.0) | 3 (9.7) | 0.114 |
| Chronic pulmonary disease, n (%) | 6 (2.2) | 2 (2.7) | 1 (3.2) | 0.933 |
| Congestive heart failure, n (%) | 12 (4.5) | 2 (2.7) | 0 (0.0) | 0.395 |
| Dementia, n (%) | 24 (9.0) | 5 (6.7) | 1 (3.2) | 0.475 |
| Diabetes with chronic complications, n (%) | 4 (1.5) | 1 (1.3) | 0 (0.0) | 0.79 |
| Diabetes without chronic complications, n (%) | 84 (31.5) | 24 (32.0) | 13 (41.9) | 0.497 |
| Hemiplegia or paraplegia, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | NA |
| Metastatic solid tumor, n (%) | 0 (0.0) | 6 (8.0) | 6 (19.4) | <0.001 |
| Mild liver disease, n (%) | 9 (3.4) | 0 (0.0) | 3 (9.7) | 0.036 |
| Moderate or severe liver disease, n (%) | 2 (0.7) | 0 (0.0) | 2 (6.5) | 0.009 |
| Myocardial infarction, n (%) | 8 (3.0) | 3 (4.0) | 0 (0.0) | 0.54 |
| Peptic ulcer disease, n (%) | 12 (4.5) | 2 (2.7) | 0 (0.0) | 0.395 |
| Peripheral vascular disease, n (%) | 8 (3.0) | 1 (1.3) | 0 (0.0) | 0.467 |
| Renal disease, n (%) | 6 (2.2) | 1 (1.3) | 0 (0.0) | 0.634 |
| Rheumatic disease, n (%) | 4 (1.5) | 0 (0.0) | 0 (0.0) | 0.448 |
| Nursing home resident | 61 (22.8%) | 11 (14.7%) | 3 (9.7%) | 0.094 |
| Immunosuppressant user | 3 (1.1%) | 2 (2.7%) | 0 (0.0%) | 0.469 |
| Duration of antimicrobial therapy after biliary drainage, median [IQR] | 4.00 [3.00, 5.00] | 4.00 [2.00, 5.00] | 3.00 [2.00, 4.50] | 0.192 |
| Duration of antimicrobial therapy 3 days or less, n (%) | 97 (36.3%) | 34 (45.3%) | 16 (51.6%) | 0.129 |
| Highest NEWS within 24 h before the termination of antimicrobial administration (median [IQR]) | 1.00 [0.00, 2.00] | 1.00 [0.00, 2.00] | 1.00 [0.00, 1.00] | 0.116 |
| Highest NEWS of ≥5 within 24 h before the termination of antimicrobial administration, n (%) | 5 (1.9%) | 1 (1.4%) | 0 (0.0%) | 0.721 |
During this trial period, there were no cases requiring intensive care unit admission among the 38 severe cases.
AC, acute cholangitis; CCI, Charlson Comorbidity Index; CHF, chronic heart failure; CKD, chronic kidney disease; DM, diabetes mellitus; ERCP, endoscopic retrograde cholangiopancreatography; IQR, interquartile range; LC, liver cirrhosis; NEWS, National Early Warning Score.
ERCP findings
Table 2 outlines the ERCP findings. In Group 3, more patients had a longer time between the start of AC treatment and ERCP. However, when the time between the start of AC treatment and ERCP was limited to within 48 h, the proportion of patients in each group was comparable. The clinical success rates of biliary drainage and ERCP‐specific complications were also comparable between groups.
Table 2.
ERCP findings
| Group 1 benign | Group 2 Bismuth‐I | Group 3 Bismuth‐II or higher | ||
|---|---|---|---|---|
| n = 267 | n = 75 | n = 31 | P‐value | |
| Time from consultation to ERCP, n (%) | 0.053 | |||
| ≤24 | 208 (77.9%) | 53 (70.7%) | 17 (54.8%) | |
| 24–48 | 36 (13.5%) | 14 (18.7%) | 10 (32.3%) | |
| >48 | 23 (8.6%) | 8 (10.7%) | 4 (12.9%) | |
| ERCP drainage procedure, n (%) | ||||
| Stone extraction | 201 (75.3%) | 1 (1.3%) | 0 (0.0%) | |
| Plastic stent | 52 (19.5%) | 26 (34.7%) | 28 (90.3%) | |
| Self‐expandable metallic stent | 3 (1.1%) | 38 (50.7%) | 2 (6.5%) | |
| ENBD | 4 (1.5%) | 2 (2.7%) | 1 (3.2%) | |
| Others | 1 (0.4%) | 0 (0.0%) | 0 (0.0%) | |
| Stone extraction and stent placement/ENBD/others | 4 (1.5%) | 1 (1.3%) | 0 (0.0%) | |
| Technical unsuccess of ERCP † | 2 (0.7%) | 7 (9.3%) | 0 (0.0%) | |
| Clinical success of biliary drainage, n (%) | 257 (96.3%) | 72 (96.0%) | 30 (96.8%) | 0.982 |
| Complications, n (%) | ||||
| Pancreatitis | 5 (1.9%) | 1 (1.3%) | 0 (0.0%) | 0.719 |
| Bleeding | 7 (2.6%) | 1 (1.3%) | 0 (0.0%) | 0.548 |
| Perforation | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | NA |
| Others | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | NA |
| No complications | 253 (94.8%) | 70 (94.6%) | 31 (100.0%) | 0.423 |
All 9 cases of unsuccessful ERCP were transitioned to endoscopic ultrasound‐guided drainage.
ERCP, endoscopic retrograde cholangiopancreatography; IQR, interquartile range; ENBD, endoscopic nasobiliary drainage.
Microbial culture findings
The results of the microbial cultures are summarized in Table 3, which shows a lower incidence of positive blood cultures in Group 3. Blood culture results were comparable between the groups.
Table 3.
Blood and bile culture results
| Group 1 benign | Group 2 Bismuth‐I | Group 3 Bismuth‐II or higher | ||
|---|---|---|---|---|
| n = 267 | n = 75 | n = 31 | P‐value | |
| Blood culture, n (%) | <0.001 | |||
| None taken | 63 (23.6%) | 44 (58.7%) | 16 (51.6%) | |
| Negative rate | 107 (40.1%) | 17 (22.7%) | 11 (35.5%) | |
| Positive rate | 97 (36.3%) | 14 (18.7%) | 4 (12.9%) | |
| Escherichia coli | 52 (19.5%) | 5 (6.7%) | 3 (9.7%) | 0.017 |
| Klebsiella sp. | 22 (8.2%) | 4 (5.3%) | 0 (0.0%) | 0.192 |
| Enterococcus sp. | 8 (3.0%) | 1 (1.3%) | 0 (0.0%) | 0.467 |
| Enterobacter sp. | 7 (2.6%) | 1 (1.3%) | 0 (0.0%) | 0.548 |
| Citrobacter sp. | 3 (1.1%) | 1 (1.3%) | 0 (0.0%) | 0.823 |
| Streptococcus sp. | 5 (1.9%) | 1 (1.3%) | 0 (0.0%) | 0.719 |
| Pseudomonas sp. | 1 (0.4%) | 0 (0.0%) | 0 (0.0%) | 0.82 |
| Anaerobes | 10 (3.7%) | 1 (1.3%) | 2 (6.5%) | 0.387 |
| Others | 8 (3.0%) | 3 (4.0%) | 1 (3.2%) | 0.91 |
| Bile culture, n (%) | <0.001 | |||
| None taken | 5 (1.9%) | 5 (6.7%) | 4 (12.9%) | |
| Negative rate | 31 (11.6%) | 26 (34.7%) | 5 (16.1%) | |
| Positive rate | 231 (86.5%) | 44 (58.7%) | 22 (71.0%) | |
| Escherichia coli | 108 (40.4%) | 18 (24.0%) | 2 (6.5%) | <0.001 |
| Klebsiella sp. | 72 (27.0%) | 18 (24.0%) | 3 (9.7%) | 0.106 |
| Enterococcus sp. | 98 (36.7%) | 12 (16.0%) | 12 (38.7%) | 0.003 |
| Enterobacter sp. | 27 (10.1%) | 8 (10.7%) | 5 (16.1%) | 0.591 |
| Citrobacter sp. | 17 (6.4%) | 4 (5.3%) | 4 (12.9%) | 0.336 |
| Streptococcus sp. | 20 (7.5%) | 8 (10.7%) | 3 (9.7%) | 0.651 |
| Pseudomonas sp. | 11 (4.1%) | 1 (1.3%) | 1 (3.2%) | 0.507 |
| Anaerobes | 20 (7.5%) | 3 (4.0%) | 4 (12.9%) | 0.262 |
| Others | 19 (7.1%) | 5 (6.7%) | 6 (19.4%) | 0.053 |
Multiple bacteria were detected in bile cultures, which were all counted. In Group 3, the prevalence of Escherichia coli was lower, whereas Enterococcus spp. were more frequently observed.
Antimicrobial therapy
Table 4 summarizes the antimicrobial therapy regimens in different groups. The most commonly used antibiotic was cefmetazole, followed by piperacillin/tazobactam and ampicillin/sulbactam. The broad‐spectrum antibiotic piperacillin/tazobactam was more commonly used in Group 3 than in the other groups. The duration of antibiotic administration after ERCP tended to be shorter in Group 3, although there were no significant differences. When considering all bacteria identified in the blood and bile cultures as causative organisms, the cases with resistance to the administered antibiotics were comparable between Groups 1 and 3. However, the bacteria identified in Group 2 showed less resistance.
Table 4.
Antimicrobial therapy.
| Group 1 benign | Group 2 Bismuth‐I | Group 3 Bismuth‐II or higher | ||
|---|---|---|---|---|
| n = 267 | n = 75 | n = 31 | P‐value | |
| Cefmetazole, n (%) | 166 (62.2%) | 56 (74.7%) | 15 (48.4%) | 0.026 |
| Piperacillin/tazobactam | 35 (13.1%) | 7 (9.3%) | 8 (25.8%) | 0.074 |
| Ampicillin/sulbactam | 43 (16.1%) | 4 (5.3%) | 2 (6.5%) | 0.026 |
| Ceftriaxone | 12 (4.5%) | 4 (5.3%) | 2 (6.5%) | 0.867 |
| Meropenem | 4 (1.5%) | 1 (1.3%) | 2 (6.5%) | 0.146 |
| Ciprofloxacin | 4 (1.5%) | 2 (2.7%) | 1 (3.2%) | 0.681 |
| Vancomycin | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | NA |
| Others | 2 (0.7%) | 1 (1.3%) | 1 (3.2%) | 0.435 |
| Antimicrobial susceptibility for blood and bile cultures, n (%) | <0.001 | |||
| Resistant bacteria | 114 (42.7%) | 18 (24.0%) | 13 (41.9%) | |
| Susceptible bacteria | 122 (45.7%) | 29 (38.7%) | 9 (29.0%) | |
| Unknown | 31 (11.6%) | 28 (37.3%) | 9 (29.0%) |
IQR, interquartile range.
Clinical outcomes
Table 5 presents the clinical outcomes of the patients. In Group 3, the clinical cure rate was 87.1%, and the 3‐month recurrence rate was 32.3%, which was less favorable than that in the other groups. In Group 2, the clinical cure rate was 92.0% and the 3‐month recurrence rate was 13.3%. In Group 1, the clinical cure rate was significantly higher at 98.1% (P = 0.002), with a much lower 3‐month recurrence rate of 3.4% (P < 0.001). The median hospital stay for all groups was 7 days.
Table 5.
Clinical outcomes.
| Group 1 benign | Group 2 Bismuth‐I | Group 3 Bismuth‐II or higher | ||
|---|---|---|---|---|
| n = 267 | n = 75 | n = 31 | P‐value | |
| Clinical cure, n (%) | 262 (98.1%) | 69 (92.0%) | 27 (87.1%) | 0.002 |
| 3‐month recurrence rate, n (%) | <0.001 | |||
| Recurrence | 9 (3.4%) | 10 (13.3%) | 10 (32.3%) | |
| No recurrence | 249 (93.3%) | 62 (82.7%) | 18 (58.1%) | |
| Unknown | 9 (3.4%) | 3 (4.0%) | 3 (9.7%) | |
| Length of hospital stay, median [IQR] | 7.00 [5.00, 8.00] | 7.00 [6.00, 9.00] | 7.00 [6.00, 10.00] | 0.268 |
IQR, interquartile range.
The outcome difference between Groups 1 and 3 was particularly marked. The difference in clinical cure rates between Groups 1 and 3 was 11.0%, and the difference in 3‐month recurrence rates was 28.9%. Between Groups 2 and 3, the difference in clinical cure rates was 4.9%, and the difference in 3‐month recurrence rates was 19.0%. These results were similar in an analysis limited to cases treated with a 3‐day or shorter antimicrobial therapy duration (Table S1).
A minority of cases, totaling 15 (4.0%), did not achieve clinical cure. The characteristics of these cases are presented in Table S2.
Discussion
We compared the outcomes between patients categorized into three groups. Patients in Group 3 tended to be younger and more likely to have a CCI of 4 or higher. Additionally, this group had fewer instances of positive blood cultures and fewer cases residing in nursing homes. There were no significant differences in the severity of AC, NEWS, duration of antibiotic therapy after ERCP, or technical and clinical success rates of ERCP. When all bacteria identified in the blood and bile cultures were considered causative organisms, the proportion of bacteria resistant to the administered antibiotics was comparable between Groups 1 and 3. Our findings indicated that Group 3 had significantly worse clinical outcomes than Group 1, with a lower rate of clinical cure and a higher rate of 3‐month recurrence. Additionally, compared with Group 2, Group 3 showed worse outcomes.
In cases of multiple obstructions near the hilar bile ducts, there is a higher clinical failure rate for bile duct drainage when there are more extensive obstructions. 7 , 8 Moreover, one randomized controlled trial showed that unilateral drainage is related to worse clinical success rates and an increased incidence of stent dysfunction compared with bilateral stenting in patients with hilar multiple biliary obstructions. 29 However, to the best of our knowledge, there are no reports comparing the outcomes of AC with multiple bile duct obstructions with those of AC with simple bile duct obstruction.
Our investigation suggests that the outcomes of patients with AC with multiple hilar biliary obstructions may be poor. Although it is challenging to fully align our definition of outcomes with those of previous reports, the clinical cure rate of Group 3 was 87.1%, which is inferior when compared with those of Groups 1 and 2 or previous reports. 4 , 5 , 6 Unlike the simple obstruction in the bile ducts outside the liver, in cases of multiple hilar biliary obstructions, it is sometimes difficult to achieve complete drainage of the entire bile duct. In cases of hilar multiple biliary obstructions, if drainage is achieved in more than 50% of the liver parenchyma's volume, there tends to be an improvement in blood test results, reflected in the bilirubin, alanine aminotransferase, or c‐reactive protein levels. 7 , 30 , 31 , 32 However, some bile duct branches may remain undrained. This study also achieved clinical success with bile duct drainage in most cases in all groups; however, the outcomes for Group 3 were poor. It should be noted that, even with the clinical success of biliary drainage, a complete cure for AC may not be achieved. We believe that the branches of the bile ducts that were not properly drained prevented full recovery from AC. This may also explain the high recurrence rate within 3 months. 8 , 29 Consequently, hilar multiple biliary obstructions may affect the outcomes of cholangitis. This suggests that proper treatment approaches may differ from simple obstructions of the bile ducts, particularly in the context of a standard or shorter duration of antimicrobial therapy.
Besides hilar multiple biliary obstructions, another factor that might have influenced the poorer outcomes seen in Group 3 was the CCI of ≥4. Multiple obstructions in the bile ducts can sometimes be caused by cancer metastasis from other organs. In our analysis of the CCI breakdown for Group 3, we found a notably higher prevalence of metastatic solid tumors and frequent instances of liver impairment. However, it is important to note that this observation in Group 3 may not solely stem from obstructive jaundice; substantive liver impairment induced by metastatic solid tumors could also play a significant role. Due to the inherent complexities of data extraction from the diagnosis procedure combination database, distinguishing between these causes proved challenging. While these factors may contribute to the higher number of cases with a CCI ≥4 in Group 3, future research should aim to address these confounding factors for a more accurate understanding.
These results should be interpreted with caution considering some limitations. This was a single‐center retrospective study, and the duration of antimicrobial therapy was determined by the physician in charge. Furthermore, the number of cases in Group 3 and the number of events without a clinical cure were small. Additionally, as this study was descriptive in nature, it did not adjust for confounding factors. Therefore, validation through prospective studies is necessary.
In conclusion, this study suggests that, in cases of AC with hilar multiple biliary obstructions, even when drainage is technically or clinically successful, the outcomes may be worse than those of simple extrahepatic bile duct obstructions with standard or shorter antibiotic treatment durations. Therefore, we suggest that proper treatment approaches for cases of AC with multiple hilar biliary obstructions differ from those of AC with simple obstructions in the extrahepatic bile duct.
Supporting information
Figure S1. Bismuth classification. (A) Tumor is located at the common hepatic duct, but below the confluence of the right and left hepatic ducts. (B) Tumor involves the confluence of the right and left hepatic ducts but does not extend into secondary biliary radicals. (C) Tumor extends into the right (Type IIIa) or left (Type IIIb) hepatic duct. (D) Tumor involves both right and left hepatic ducts and/or has multifocal spread affecting secondary biliary radicals on both sides.
Table S1. Analysis limited to cases treated with shortened duration of antimicrobial therapy.
Table S2. Characteristics of patients who did not show clinical improvement.
Acknowledgments
We thank Ayumu Sugitani for their help with statistical analysis.
Declaration of conflict of interest: The authors declare no competing interests.
Author contribution: Conceptualization was done by Sakue Masuda and Yoshinori Imamura. Methodology was developed by Sakue Masuda. Sakue Masuda also contributed to the software, formal analysis, investigation, resources, writing—original draft preparation, writing—review and editing, visualization, and project administration. Yoshinori Imamura and Chikamasa Ichita were involved in validation. Data curation was carried out by Sakue Masuda and Chikamasa Ichita. Supervision was provided by Sakue Masuda and Yoshinori Imamura. Ryuhei Jinushi, Chikamasa Ichita, Ryo Sato, Jun Kubota, Haruki Uojima, Chikamasa Ichita, and Kazuya Koizumi contributed to project administration and provided input for writing the paper. All authors, including Sakue Masuda, Yoshinori Imamura, Chikamasa Ichita, Kazuya Koizumi, Makomo Makazu, Haruki Uojima, Jun Kubota, Karen Kimura, Ryuhei Jinushi, Masahiro Kobayashi, and Makoto Kako, have read and agreed to the final version of the manuscript.
Data availability statement
The datasets generated and analyzed in the current study are available from the corresponding author upon reasonable request.
References
- 1. Melzer M, Toner R, Lacey S, Bettany E, Rait G. Biliary tract infection and bacteraemia: presentation, structural abnormalities, causative organisms and clinical outcomes. Postgrad. Med. J. 2007; 83: 773–776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Esposito AL, Gleckman RA, Cram S, Crowley M, McCabe F, Drapkin MS. Community‐acquired bacteremia in the elderly: analysis of one hundred consecutive episodes. J. Am. Geriatr. Soc. 1980; 28: 315–319. [DOI] [PubMed] [Google Scholar]
- 3. Gomi H, Solomkin JS, Schlossberg D et al. Tokyo guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis. J. Hepatobiliary Pancreat. Sci. 2018; 25: 3–16. [DOI] [PubMed] [Google Scholar]
- 4. Haal S, Wielenga MCB, Fockens P et al. Antibiotic therapy of 3 days may be sufficient after biliary drainage for acute cholangitis: a systematic review. Dig. Dis. Sci. 2021; 66: 4128–4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Satake M, Yamaguchi Y. Three‐day antibiotic treatment for acute cholangitis due to choledocholithiasis with successful biliary duct drainage: a single‐center retrospective cohort study. Int. J. Infect. Dis. 2020; 96: 343–347. [DOI] [PubMed] [Google Scholar]
- 6. Masuda S, Koizumi K, Makazu M et al. Antibiotic administration within two days after successful endoscopic retrograde cholangiopancreatography is sufficient for mild and moderate acute cholangitis. J. Clin. Med. Res. 2022; 11: 2697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Martins BC, Perez CA, Ruas JN et al. Results of endoscopic biliary drainage in patients with malignant hilar stricture. Clinics. 2023; 78: 100153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Miura S, Kanno A, Masamune A et al. Bismuth classification is associated with the requirement for multiple biliary drainage in preoperative patients with malignant perihilar biliary stricture. Surg. Endosc. 2015; 29: 1862–1870. [DOI] [PubMed] [Google Scholar]
- 9. Lygidakis NJ, Brummelkamp WH. The significance of intrabiliary pressure in acute cholangitis. Surg. Gynecol. Obstet. 1985; 161: 465–469. [PubMed] [Google Scholar]
- 10. Eba J, Nakamura K. Overview of the ethical guidelines for medical and biological research involving human subjects in Japan. Jpn. J. Clin. Oncol. 2022; 52: 539–544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kiriyama S, Kozaka K, Takada T et al. Tokyo guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J. Hepatobiliary Pancreat. Sci. 2018; 25: 17–30. [DOI] [PubMed] [Google Scholar]
- 12. Isayama H, Hamada T, Yasuda I et al. TOKYO criteria 2014 for transpapillary biliary stenting. Dig. Endosc. 2015; 27: 259–264. [DOI] [PubMed] [Google Scholar]
- 13. Pang YY, Chun YAW. Predictors for emergency biliary decompression in acute cholangitis. Eur. J. Gastroenterol. Hepatol. 2006; 18: 727–731. [DOI] [PubMed] [Google Scholar]
- 14. Parikh MP, Garg R, Chittajallu V et al. Trends and risk factors for 30‐day readmissions in patients with acute cholangitis: analysis from the national readmission database. Surg. Endosc. 2021; 35: 223–231. [DOI] [PubMed] [Google Scholar]
- 15. Tagashira Y, Sakamoto N, Isogai T et al. Impact of inadequate initial antimicrobial therapy on mortality in patients with bacteraemic cholangitis: a retrospective cohort study. Clin. Microbiol. Infect. 2017; 23: 740–747. [DOI] [PubMed] [Google Scholar]
- 16. Thompson J, Bennion RS, Pitt HA. An analysis of infectious failures in acute cholangitis. HPB Surg. 1994; 8: 139–144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Lee CC, Chang IJ, Lai YC, Chen SY, Chen SC. Epidemiology and prognostic determinants of patients with bacteremic cholecystitis or cholangitis. Am. J. Gastroenterol. 2007; 102: 563–569. [DOI] [PubMed] [Google Scholar]
- 18. Kiriyama S, Takada T, Hwang TL et al. Clinical application and verification of the TG13 diagnostic and severity grading criteria for acute cholangitis: an international multicenter observational study. J. Hepatobiliary Pancreat. Sci. 2017; 24: 329–337. [DOI] [PubMed] [Google Scholar]
- 19. Humphries R, Bobenchik AM, Hindler JA, Schuetz AN. Overview of changes to the clinical and laboratory standards institute performance standards for antimicrobial susceptibility testing, M100, 31st edition. J. Clin. Microbiol. 2021; 59: e0021321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 2013; 84: 465–470. [DOI] [PubMed] [Google Scholar]
- 21. Bilben B, Grandal L, Søvik S. National Early Warning Score (NEWS) as an emergency department predictor of disease severity and 90‐day survival in the acutely dyspneic patient – a prospective observational study. Scand. J. Trauma Resusc. Emerg. Med. 2016; 24: 80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Quan H, Sundararajan V, Halfon P et al. Coding algorithms for defining comorbidities in ICD‐9‐CM and ICD‐10 administrative data. Med. Care. 2005; 43: 1130–1139. [DOI] [PubMed] [Google Scholar]
- 23. Shi H, Wan J, Xu SP, Liao L. A retrospective analysis of clinical characteristics and mortality risks in elderly patients with acute cholecystitis and cholangitis. Zhonghua Nei Ke Za Zhi. 2019; 58: 415–418. [DOI] [PubMed] [Google Scholar]
- 24. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) . Complicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry . FDA 2018. Available from URL: https://www.fda.gov/files/drugs/published/Complicated-Urinary-Tract-Infections---Developing-Drugs-for-Treatment.pdf.
- 25. Srinu D, Shah J, Jena A et al. Conventional vs short duration of antibiotics in patients with moderate or severe cholangitis: non‐inferiority randomized trial. Am. J. Gastroenterol. 2023; 119: 176–182. [DOI] [PubMed] [Google Scholar]
- 26. Simeonova M, Daneman N, Lam PW, Elligsen M. Addition of anaerobic coverage for treatment of biliary tract infections: a propensity score‐matched cohort study. JAC Antimicrob. Resist. 2023; 5: dlac141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Haal S, Ten Böhmer B, Balkema S et al. Antimicrobial therapy of 3 days or less is sufficient after successful ERCP for acute cholangitis. United Eur. Gastroenterol. J. 2020; 8: 481–488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Kanda Y. Investigation of the freely available easy‐to‐use software “EZR” for medical statistics. Bone Marrow Transplant. 2013; 48: 452–458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Chen ZK, Zhang W, Xu YS, Li Y. Unilateral versus side‐by‐side metal stenting for malignant hilar biliary obstruction: a meta‐analysis. J. Laparoendosc. Adv. Surg. Tech. A. 2021; 31: 203–209. [DOI] [PubMed] [Google Scholar]
- 30. Takahashi K, Tsuyuguchi T, Saiga A et al. Risk factors of ineffective drainage in uncovered self‐expandable metal stenting for unresectable malignant hilar biliary strictures. Oncotarget. 2018; 9: 28185–28194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Vienne A, Hobeika E, Gouya H et al. Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment. Gastrointest. Endosc. 2010; 72: 728–735. [DOI] [PubMed] [Google Scholar]
- 32. Tringali A, Boškoski I, Costamagna G. Endoscopic stenting in hilar cholangiocarcinoma: when, how, and how much to drain? Gastroenterol. Res. Pract. 2019; 4: 5161350. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Bismuth classification. (A) Tumor is located at the common hepatic duct, but below the confluence of the right and left hepatic ducts. (B) Tumor involves the confluence of the right and left hepatic ducts but does not extend into secondary biliary radicals. (C) Tumor extends into the right (Type IIIa) or left (Type IIIb) hepatic duct. (D) Tumor involves both right and left hepatic ducts and/or has multifocal spread affecting secondary biliary radicals on both sides.
Table S1. Analysis limited to cases treated with shortened duration of antimicrobial therapy.
Table S2. Characteristics of patients who did not show clinical improvement.
Data Availability Statement
The datasets generated and analyzed in the current study are available from the corresponding author upon reasonable request.