Biliary tract infection (BTI) with bacteremia represents 8–20% of community-acquired bacteremia in the elderly population and it is the second most common cause of sepsis in those subjects, leading to 10–20% of mortality [
Bacteremia in BTI is caused by a wide spectrum of pathogens. In recent years, the prevalence of antibiotic-resistant pathogens in BTIs has risen steadily [
Previously, the human appendix has been regarded as a rudimentary part of the intestine. In recent years, however, several studies have suggested its immunological importance for the development and preservation of the intestinal immune system [
The focus of the current study is to analyze whether prior appendectomy is associated with an increased risk of the development of antibiotic-resistant bacteria in bacteremic BTI.
This retrospective study was conducted at the Wakayama Rosai Hospital in Wakayama, Japan. Charts from 174 consecutive cases of bacteremia derived from BTI treated in the hospital between June 2005 and May 2016 were retrospectively reviewed. Patients with the following criteria were excluded from the study: (i) positive culture for probable skin contaminants (i.e., coagulase-negative
Medical records were reviewed and the following information was collected: age, sex, severity of infection (assessed using Pitt bacteremia score), cause of infection, underlying diseases, medication, history of appendectomy, previous antibiotic use (within 90 days), presence of indwelling biliary device, previous hospitalization (within 30 days), and history of bilioenteric anastomosis or sphincterotomy. In addition, 30-day mortality of the patients was examined.
This study was approved by the institutional review board at the Wakayama Rosai Hospital and conforms to the provisions of the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013).
Cholecystitis was diagnosed on the basis of clinical presentation of fever, right upper quadrant pain, and findings of ultrasonography or computed tomography. Cholangitis was diagnosed based on the following criteria: (a) presence of fever with upper quadrant pain; (b) radiological (sonographic or computed tomographic) or endoscopic evidence of biliary tract obstruction due to stones or stricture from benign or malignant origin; and (c) laboratory findings of hyperbilirubinemia and an elevated serum alkaline phosphatase level.
The Pitt bacteremia score was used to assess the severities of bacteremic BTIs and was calculated as follows: Oral temperature: two points for a temperature of ≤35°C or ≥40°C or one point for a temperature between 35.1 and 36.0°C or between 39.0 and 39.9°C Hypotension: two points for an acute hypotensive event with decreases in systolic (>30 mmHg) and diastolic (>20 mmHg) blood pressures, the use of intravenous vasopressor agents, or systolic blood pressure of <90 mmHg Receiving mechanical ventilation: two points Suffering cardiac arrest: four points Mental status: being alert, zero points; being disoriented, one point; being stuporous, two points; and being comatose, four points [
Antibiotic-resistant bacteria were defined as extended-spectrum
Two sets of two 8–10 mL blood samples were taken from patients who presented with ≥38°C or who showed clinical signs or symptoms associated with bacteremia. Blood samples were processed in the Oxoid Signal Blood Culture System (Kanto Kagaku, Tokyo, Japan) between June 2005 and October 2011 and processed in an automated BacT/ALERT 3D System (SYSMEX bioMérieux, Tokyo, Japan) between November 2011 and May 2016. The incubation period of blood samples was five days. Positive blood samples were subcultured onto blood agar plates or Brucella blood agar plates. Identification of aerobic and anaerobic bacteria was performed by the WalkAway System (Beckman Coulter) and RapID ANA II (AMCO Inc., Tokyo, Japan), respectively.
Differences between patients with and without antibiotic-resistant bacteria were determined using the chi-square test and Student’s
The demographic and clinical features of analyzed patients with bacteremia are summarized in Table
Characteristics of patients with bacteremia from biliary tract infection.
Patients | |
Total | 174 |
Age (mean) | 70.2 ± 13.9 |
Male | 106 (61%) |
Pitt bacteremia score (mean) | 1.22 ± 1.21 |
Site of biliary tract infection | |
Cholangitis | 149 (86%) |
Cholecystitis | 25 (14%) |
Cause of biliary tract infection | |
No malignancy | 116 (67%) |
Malignancy | 58 (33%) |
Comorbidity | |
Chronic kidney disease | 47 (27%) |
Diabetes mellitus | 42 (24%) |
Liver cirrhosis | 21 (12%) |
Medication | |
Proton pump inhibitor | 43 (25%) |
Corticosteroids | 22 (13%) |
Prior appendectomy | 32 (18.4%) |
Antibiotic use within the preceding 3 months | 57 (33%) |
Indwelling biliary device | 56 (32%) |
Hospitalization within the preceding 30 days | 51 (29%) |
Bilioenteric anastomosis or sphincterotomy | 42 (24%) |
30-Day mortality | 14 (8%) |
The bacteria strains isolated from the blood cultures are listed in Table
Spectrum of bacteria isolated from blood culture in patients with biliary tract infection.
Bacteria | Total ( |
---|---|
Gram-negative organisms | |
|
83 (38%) |
|
72 (33%) |
|
10 (5%) |
|
8 (4%) |
|
3 (1%) |
|
3 (1%) |
|
1 (1%) |
|
1 (1%) |
Gram-positive organisms | |
|
18 (8%) |
|
17 (8%) |
|
2 (1%) |
Anaerobes | |
|
3 (1%) |
Forty-two antibiotic-resistant bacteria strains were identified in 34 patients (Table
Identified antibiotic-resistant bacteria.
Antibiotic-resistant bacteria | Total ( |
---|---|
SPACE |
|
|
10 (24%) |
|
8 (19%) |
|
3 (7%) |
|
1 (2%) |
|
1 (2%) |
Ampicillin-resistant |
|
|
7 (17%) |
|
1 (2%) |
ESBL-producing |
6 (14%) |
ESBL-producing |
5 (12%) |
SPACE consists of
Differences between patients with and without antibiotic-resistant bacteria are shown in Table
Differences between patients with and without antibiotic-resistant bacteria.
Antibiotic-resistant bacteria | |||
---|---|---|---|
(+) ( |
(−) ( |
|
|
Age (mean) | 71 | 69 | 0.67 |
Male | 19 (56%) | 87 (62%) | 0.50 |
Pitt bacteremia score (mean) | 1.65 | 1.11 | 0.021 |
Site of biliary tract infection | |||
Cholangitis | 29 (85%) | 120 (86%) | 0.95 |
Cholecystitis | 5 (15%) | 20 (14%) | 0.95 |
Cause of biliary tract infection | 0.058 | ||
No malignancy | 18 (53%) | 98 (70%) | |
Malignancy | 16 (47%) | 42 (30%) | |
Comorbidity | |||
Chronic kidney disease | 10 (29%) | 37 (26%) | 0.73 |
Diabetes mellitus | 8 (24%) | 34 (24%) | 0.92 |
Liver cirrhosis | 2 (6%) | 19 (14%) | 0.21 |
Medication | |||
Proton pump inhibitor | 9 (26%) | 34 (24%) | 0.80 |
Corticosteroids | 5 (15%) | 17 (12%) | 0.69 |
Prior appendectomy | 12 (35%) | 20 (14%) | 0.0046 |
Antibiotic use within the preceding 3 months | 19 (56%) | 38 (27%) | 0.0014 |
Indwelling biliary device | 15 (44%) | 41 (29%) | 0.090 |
Hospitalization within the preceding 30 days | 15 (44%) | 36 (26%) | 0.035 |
Bilioenteric anastomosis or sphincterotomy | 14 (41%) | 28 (20%) | 0.0096 |
30-Day mortality | 4 (12%) | 10 (7%) | 0.79 |
Multivariate analysis revealed that prior appendectomy (OR, 3.02; CI, 1.15–7.88;
Risk factors for antibiotic-resistant bacteria (multivariate analysis).
Odds ratio |
| |
---|---|---|
(95% confidence interval) | ||
Appendectomy | 3.02 (1.15–7.87) |
|
Pitt bacteremia score (per 1) | 1.31 (0.54–1.48) | 0.13 |
Malignancy | 1.47 (0.60–3.56) | 0.40 |
Antibiotic use within the preceding 3 months | 3.06 (1.26–7.64) |
|
Indwelling biliary device | 1.34 (0.55–3.19) | 0.51 |
Hospitalization within the preceding 30 days | 2.45 (0.99–6.09) | 0.051 |
Bilioenteric anastomosis or sphincterotomy | 3.77 (1.51–9.66) |
|
The present study demonstrates that history of appendectomy is a significant risk factor for development of antibiotic-resistant pathogens in bacteremia patients resulting from BTIs. Of the 174 patients examined, 34 developed bacteremia with antibiotic-resistant pathogens, 12 (35%) of which had a history of appendectomy, whereas only 20 (14%) of the remaining 140 subjects had the history. Because the lifetime risk of appendectomy has been reported to be 17.6% in the national hospital discharge survey [
The immunological functions of the appendix may work for prevention of prevalence of antibiotic-resistant bacteria. The human appendix is associated with the highest concentration of gut-associated lymphoid tissue (GALT) in the gut [
Other functions of the appendix associated with intestinal flora may also be correlated with the results of the current study. The human appendix contains a wealth of microbes, including members of 15 phyla, which constitute more than 98% of the normal colonic microbiome [
The present study indicates that appendectomy contributes to the development of antibiotic-resistant bacteria in relatively younger subjects with BTIs. Older subjects generally have more comorbid diseases and are relatively immunocompromised. Therefore, appendectomy may no longer affect their immunological defense. Alternatively, the functions of the appendix may attenuate in older subjects because the number of lymphoid follicles and length and diameter of the appendix are known to degenerate with age [
Considering these facts, the appendix should no longer be regarded as a rudimentary organ and we should carefully decide whether appendectomy should always be indicated for appendicitis. Efficacy of conservative treatment with antibiotics on appendicitis is still controversial. A meta-analysis of randomized controlled trials showed that antibiotics were both effective and safe as primary treatment for patients with uncomplicated acute appendicitis [
Based on the results of the current study, the recommended first choice of antibiotics for patients with bacteremia from BTI could be based on the presence or absence of identified risk factors including a history of appendectomy. In the Tokyo Guidelines [
We demonstrated that history of appendectomy is a risk of development of antibiotic-resistant bacteria in patients with bacteremia from BTI. The majority of BTI patients, however, showed negative results in blood culture. The causative pathogens in these blood culture-negative BTI patients may also be different according to the risk factors including history of appendectomy. Although it may be difficult to verify the hypothesis due to difficulty in bacteria detection, bile culture could be an alternative, particularly in cases of cholangitis. Moreover, it is potentially useful to investigate whether causative microorganisms in a variety of infectious diseases other than BTI differ between patients with and without a history of appendectomy. Further studies are expected for these clinically relevant issues.
There are limitations to this study. First, the number of the examined patients was relatively small and all subjects were Japanese. Reproducibility should be confirmed with larger cohorts including other ethnic populations. Another drawback, due to the study being retrospective, is the possibility of missing relevant clinical parameters and inclusion of bias caused by missed blood culture at appropriate timing.
In conclusion, prior appendectomy was identified as an independent risk factor for antibiotic-resistant bacteria in BTIs. Before the choice of antibiotics, interviews regarding history of appendectomy are mandatory as well as other risk factors, including antibiotic use within the preceding three months and bilioenteric anastomosis or sphincterotomy.
Biliary tract infection
Extended-spectrum
Gut-associated lymphoid tissue
The authors have no conflicts of interest to declare in relation to this study.
All authors contributed significantly towards the completion of this study. Koki Kawanishi and Jun Kato contributed to study design and execution, data analysis, and manuscript writing; Jun Kinoshita, Hiroko Abe, Tetsuhiro Kakimoto, Yuko Yasuda, and Takeshi Hara contributed to study execution and data analysis.