Is antibiotic cholangitis prophylaxis proven effective? What are the risks vs benefits of cholangitis prophylaxis?

Comment by InpharmD Researcher

Evidence regarding cholangitis microbial prophylaxis has been conflicting; although one review reports benefit with prophylaxis in individuals who have recurrent acute cholangitis, several meta-analyses have reported use of prophylactic antibiotics to not have an impact on rates of cholangitis; however, this may be due to different definitions of cholangitis onsets, variable antibiotic regimens, and high risk of bias. Cholangitis prophylaxis may potentially decrease risk of bacteremia, but comes at the price of antimicrobial resistance, adverse drug reactions, and cost.

Background

Acute cholangitis, also known as ascending cholangitis, is a life-threatening condition caused by an ascending bacterial infection of the biliary tree. A 2023 article discusses management considerations for patients with acute cholangitis, highlighting both therapeutic and prophylactic measures. Regarding prophylaxis, the authors suggested that for individuals undergoing endoscopic retrograde cholangiopancreatography (ERCP), prophylactic antibiotics prior to the procedure can decrease the risk of cholangitis. Patients with recurrent acute cholangitis may also benefit from prophylactic antibiotics to reduce the incidence and severity of the disease. However, other data suggest that the prophylactic use of antibiotics in ERCP remains controversial. A 2022 meta-analysis (N=10 trials; 1,757 patients) assessed whether antibiotic prophylaxis reduces complications in patients undergoing elective ERCP. The analysis found that prophylactic antibiotic use reduces the risk of bacteremia but does not significantly impact cholangitis rates (risk difference -0.02; 95% confidence interval [CI] -0.05 to 0.01; p= 0.25). Of note, these findings are not specific to the pediatric population, and the applicability of these conclusions to younger patients remains unclear. [1], [2]

A 2016 systematic review assessed the effectiveness of prophylactic antibiotics in preventing cholangitis in biliary atresia patients after Kasai portoenterostomy. A total of four studies were included, three of which examined cholangitis incidence. Across these studies, 329 patients were assessed, with 196 receiving prophylactic antibiotics and 133 not receiving prophylactic antibiotics. In a retrospective cohort study, 89% of patients developed cholangitis within 9 months of surgery. Among those, 83% received antibiotic prophylaxis. Patients receiving antibiotics had a lower cholangitis rate (15%) compared to those who did not (57%) (p<0.03). The study noted potential confounding due to different surgical modifications. Another study followed 37 patients for 6 to 59 months. About 90% of patients developed cholangitis, with most episodes occurring before the age of two. While patients on prophylactic antibiotics had lower cholangitis rates, specific incidence data were not provided. An additional retrospective study analyzed outcomes in biliary atresia patients and found no significant reduction in cholangitis incidence with antibiotic use (62% in the antibiotic group vs. 51% in the control group). Lastly, a randomized trial evaluated the efficacy of trimethoprim-sulfamethoxazole and neomycin for preventing recurrent cholangitis (see Table 2). Although no difference was found between the two antibiotics, both showed a statistically significant reduction in cholangitis recurrence compared to historical controls. Of note, the authors highlighted limitations such as the potential for missing relevant studies in their literature search and the variability in postoperative regimens, which could impact cholangitis outcomes. Despite these limitations, the authors concluded that prophylactic antibiotic use has been inadequately studied and emphasized a lack of satisfactory evidence supporting its benefit at the time of this publication. [3]

A 2023 meta-analysis evaluated the use of prophylactic antibiotics to prevent cholangitis in children with biliary atresia after Kasai portoenterostomy. The analysis included six studies comprising 714 infants who had undergone Kasai hepatoportoenterostomy (HPE). The findings indicated that prophylactic antibiotics did not significantly reduce the risk of cholangitis compared to control groups (56.17% vs. 34.2%; odds ratio [OR] 1.15; 95% CI 0.59 to 2.25; p= 0.68; I2 = 68%). Subgroup analysis of three studies with clear antibiotic choice or duration showed no significant difference (60.5% vs. 54.7%; OR 1.25; 95% CI 0.80 to 1.96; p= 0.32; I2= 0). Overall, the results suggested that prophylactic antibiotics did not effectively reduce the risk of cholangitis compared to control groups. The authors also highlighted concerns regarding the potential increase in antimicrobial resistance associated with prophylactic antibiotic use, and emphasized the need for further well-designed randomized trials to better assess the efficacy and safety of prophylactic antibiotics in this context. [4]

References: [1] Virgile J, Marathi R. Cholangitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 3, 2023.
[2] Merchan MFS, de Moura DTH, de Oliveira GHP, et al. Antibiotic prophylaxis to prevent complications in endoscopic retrograde cholangiopancreatography: A systematic review and meta-analysis of randomized controlled trials. World J Gastrointest Endosc. 2022;14(11):718-730. doi:10.4253/wjge.v14.i11.718
[3] Decharun K, Leys CM, West KW, Finnell SM. Prophylactic Antibiotics for Prevention of Cholangitis in Patients With Biliary Atresia Status Post-Kasai Portoenterostomy: A Systematic Review. Clin Pediatr (Phila). 2016;55(1):66-72. doi:10.1177/0009922815594760
[4] Alatas FS, Lazarus G, Junaidi MC, Oswari H. Prophylactic Antibiotics to Prevent Cholangitis in Children with Biliary Atresia After Kasai Portoenterostomy: A Meta-Analysis. J Pediatr Gastroenterol Nutr. 2023;77(5):648-654. doi:10.1097/MPG.0000000000003935
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is antibiotic cholangitis prophylaxis proven effective? What are the risks vs benefits of cholangitis prophylaxis?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-4 for your response.

 

Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial

Design

Single-center, open-labeled, randomized control trial

N= 180

Objective

To analyze the preventive effects of short-term and long-term regimens of prophylactic intravenous (IV) antibiotics against cholangitis in post-Kasai biliary atresia (BA) patients

Study Groups

Short-term (n= 90)

Long-term (n= 90)

Inclusion Criteria

Infants diagnosed with type-III BA and underwent Kasai portoenterostomy in the Children's Hospital of Fudan University; born with gestational age >36 weeks; no allergies to the postoperative medication; did not receive other antibiotics or probiotics before the surgery

Exclusion Criteria

Had a Kasai procedure done previously at other institutions; have other liver diseases or severe comorbidities that need surgical intervention or other medications

Methods

Participants were randomized to receive either short-term (7 days) or long-term (14 days) prophylactic IV antibiotics: cefoperazone/sulbactam 50 mg/kg three times daily and ornidazole 10 mg/kg two times daily. After the IV regimens, both groups received oral antibiotics: sulfamethoxazole 25 mg/kg/day two times daily for 2 weeks, followed by cefaclor 40 mg/kg/day two times daily for 2 weeks, alternating every treatment 2 weeks until 6 months post-Kasai.

Other post-Kasai treatments were the same in the two groups, including steroids (IV methylprednisolone 4 mg/kg/day from postoperative day 8 to day 10 and 3 mg/kg/day from day 11 to day 13; IV methylprednisolone was switched to oral methylprednisolone 4 mg/kg every other day from day 14 and was tapered off at 10–12 weeks), ursodeoxycholic acid ([UDCA] oral UDCA 20 mg/kg/day from postoperative day 5), liver-protecting medication (IV Compound Glycyrrhizin 20 mg/day from postoperative day 1 to day 4 and switched to oral Compound Glycyrrhizin tablet 12.5 mg twice daily from postoperative day 5) and vitamin AD, vitamin K supplements.

Duration

Trial Duration: June 2016 to December 2016

Follow-up: 1, 3, and 6 months post-Kasai procedure

Outcome Measures

Primary: overall cholangitis incidence within 6 months post-Kasai portoenterostomy

Secondary: cholangitis incidence within 1 and 3 months post-Kasai portoenterostomy, the onset and frequency of cholangitis, jaundice clearance at 3 and 6 months post-Kasai portoenterostomy, and survival of native liver

Baseline Characteristics

  

Short-term (n= 99)†

Long-term (n= 81)†

  

Age, days

 64.4 ± 2.0 60.8 ± 1.9  

Female

48 50  

Hospital stay, days∗

 15.8 ± 0.2 16.6 ± 0.3  

Methylprednisolone use

 72 (73%) 59 (73%)  

†Results of the per-protocol analysis following initial randomization into intention-to-treat population of short-term (n= 90) and long-term (n= 90) study participants

∗P<0.05

Results

Endpoint

Short-term (n= 99)

Long-term (n= 81)

p-value

Cholangitis occurrence in time post-Kasai

1 month

3 months

6 months

 

39 (39%)

56 (57%)

68 (69%) 

 

19 (24%)

43 (53%)

51 (63%)

 

0.02

0.64

0.42

Onset of cholangitis, days

 45.2 ± 5.7 53.2 ± 5.6 0.33

Cholangitis recurrence

Early cholangitis onset 

40/68 (59%)

39/68 (57%)

25/51 (49%)

19/51 (37%)

0.35

0.04

Cholangitis frequency, episodes

 2.3 ± 0.2

1.8 ± 0.2

 0.05

Jaundice clearance

3 months

6 months

 

37 (37%)

42 (42%)

 

26 (32%)

34 (81%)

 

0.46

0.95

Native liver survival at 6 months

 88 (89%)

64 (79%)

 0.07

Adverse Events

Serious Adverse Events: gastrointestinal (GI) hemorrhage (5 in the short-term group vs. 3 in the long-term group), GI perforation (2 in the long-term group), intestinal obstruction (1 in the long-term group)

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

Our results also showed that long-term antibiotics could be against early onset (within 1 month post-Kasai procedure) and recurrence of cholangitis in 6 months. There has been no consensus on the definition of early cholangitis so far. In conclusion, the short-term (7 days) prophylactic intravenous antibiotics treatment has similar preventive effects against cholangitis as the long-term (14 days) regimen.

InpharmD Researcher Critique

Study limitations include the following: lack of blinding for patient families and providers, short-follow periods for all outcomes, and use of empirical postoperative medication management. These all affect the overall validity of the study with potential reporting bias on symptoms of suspected cholangitis from patient families, unknown long-term outcomes of combination antibiotic prophylactic treatment, and lack of generalizability due to institutional-specific cholangitis diagnosis parameters. 



References:
[1] Chen G, Liu J, Huang Y, et al. Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial. Pediatr Surg Int. 2021;37(8):1089-1097. doi:10.1007/s00383-021-04916-z

 

Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy

Design

Prospective randomized trial

N= 37

Objective

To evaluate the efficacy of trimethoprim-sulfamethoxazole (TMP/SMZ) and neomycin as the prophylactic agents against the recurrence of cholangitis in children with biliary atresia (BA) after a Kasai portoenterostomy

Study Groups

TMP/SMZ (n= 9)

Neomycin (n= 10)

Historical Control Group (n= 18)

Inclusion Criteria

Aged 0 to 2 years, one episode of cholangitis after a Kasai portoenterostomy, biliary atresia

Exclusion Criteria

Patients older than 2 years old, without biliary atresia and cholangitis

Methods

Participants received either TMP/SMZ (TMP 4 mg/kg/d and SMZ 20 mg/kg/d in 2 divided doses) or neomycin (25 mg/kg/d, four time daily, 4 days a week) orally for prophylaxis against recurrent cholangitis until the age of three years. The historical control included patients with cholangitis but not put on long-term prophylaxis after Kasai portoenterostomy. Comparisons of the recurrence of cholangitis were made among the TMP/SMZ, neomycin, and control groups.All patients were admitted for evaluations and treatments during individual cholangitis episodes. Parenteral antibiotic treatment was used against cholangitis for 2 weeks. Ceftriaxone was used initially, which later was modified according to the culture results. Adverse reactions to TMP/SMZ or neomycin were recorded. 

Duration

Historical Control: 1991 to 1996

Prospective randomized trial: 1997 to 2000

Outcome Measures

Cholangitis reccurrence rate and survival rate

Baseline Characteristics

  

TMP/SMZ (n= 9)

Neomycin (n= 10)

 Control Group (n= 18)

Age at first cholangitis, months

 5.2 ± 2.9 6.1 ± 3.6 6.2 ± 3.2

Female

3 5 7

Episodes of recurrence∗

 1.3 ± 1.2 1.1 ± 1.8 2.8 ± 1.2

Serum level

Bilirubin, mg/dL

AST, U/L

ALT, U/L

CRP, mg/dL

 

3.6 ± 3.0

143.7 ± 84.0 

107.2 ± 71.3

3.8 ± 2.2

 

3.1 ± 1.5

124.3 ± 64.7

111.3 ± 65.6

4.0 ± 4.5

 

3.4 ± 1.7

142.3 ± 64.2

102.0 ± 36.7

3.3 ± 4.1 

∗P<0.0001

AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein.

Results

Endpoint

Relative Risk Reduction (95% Confidence Interval)

 p-value

Recurrence Rate compared to Control

TMP/SMZ

Neomycin

 

0.52 (0.28 to 0.98)

0.42 (0.22 to 0.82)

 

0.042

0.011

Survival Rate

TMP/SMZ

Neomycin

 

-

-

 

0.09

0.018

Time to first recurrence of cholangitis was longer in both the TMP/SMZ and neomycin groups (6 and 7 months respectively), compared to the control group (3 months) but only neomycin was statistically significant when compared to control (p= 0.058 vs. p=0.031). No significant differences between TMP/SMZ and neomycin on recurrence rates of cholangitis were identified (p= 0.641). 

Adverse Events

No adverse reaction to TMP/SMZ or neomycin was noted.

Study Author Conclusions

Use of TMP/SMZ or neomycin is effective as a prophylactic agent against the recurrence of cholangitis after the Kasai portoenterostomy, but there is no difference in efficacy between these 2 regimens. A larger and long-term trial is warranted in the future.

InpharmD Researcher Critique

This study is limited by its older data and lack of accounting for confounding factors in the analysis of historical control. No significant differences between treatment groups on cholangitis recurrence were identified. Newer and larger studies are warranted to evaluate the use of TMP/SMZ and neomycin in this patient population. 



References:
[1] Bu LN, Chen HL, Chang CJ, et al. Prophylactic oral antibiotics in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg. 2003;38(4):590-593. doi:10.1053/jpsu.2003.50128

Analysis of Cholangitis Rates with Extended Perioperative Antibiotics and Adjuvant Corticosteroids in Biliary Atresia
Design

Retrospective single-center study

N= 54 
Objective

To analyze the effect of extended perioperative intravenous antibiotics (PI-Abx) and adjuvant corticosteroid on cholangitis and jaundice clearance rates in the 3 years post-Kasai portoenterostomy (KP) in children with biliary atresia (BA)
Study Groups

Group A (n= 25)

Group B (n= 9)

Group C (n= 20)
Inclusion Criteria Patients diagnosed with BA and underwent KP between 1999 and 2017 at KK Women's and Children's Hospital in Singapore 
Exclusion Criteria

Patients who did not undergo KP but underwent primary liver transplantation (LT)
Methods
 

Patients were divided into three groups according to their treatment with PI-Abx and corticosteroids during different time periods.

  • Group A included patients who underwent KP between 1999 and 2010 and were treated with perioperative intravenous (IV) ceftriaxone (50 mg/kg/day) or IV cefazolin (150 mg/kg/day) for 5 days.
  • Group B included patients who underwent KP between 2010 and 2012, receiving perioperative IV ceftriaxone for 5 days and low-dose oral prednisolone (2 mg/kg) starting on postoperative day (POD) 5 and weaned over one month.
  • Group C included patients treated between 2012 and 2017, who followed a revised protocol of perioperative IV piperacillin-tazobactam (100 mg/kg Q8H) for at least 14 days post-KP, along with high-dose oral prednisolone (5 mg/kg) initiated on POD 5 and weaned over one month.

Patients requiring prolonged antibiotic treatment due to acute conditions like cholangitis or other infections were analyzed according to their original groups using an intention-to-treat approach. All patients received prophylactic oral cotrimoxazole for at least one year after KP. Standard treatment for all groups included medium-chain triglyceride (MCT)-enriched formula, ursodeoxycholic acid, and fat-soluble vitamin supplementation, with additional MCT provided to breastfed infants.
Duration

Enrollment: Between 1999 and 2017

Follow-up: up to 3 years post-KP 
Outcome Measures

Primary: Number of episodes of cholangitis in the first 3 years after KP

Secondary: Clearance of jaundice at 6 months, jaundice clearance rate at 6 months, and native liver survival (NLS) at 3 years post KP
Baseline Characteristics  

Group A (n= 25)

 Group B (n= 9) Group C (n= 20)

Median age at KP, days (range)

 53 (32–109) 49 (42–119) 52 (29–97)

Male

 13 (52%) 5 (56%) 12 (60%)

Prematurity <36 weeks gestational age

 1 (4%) 0 0

Other congenital anomalies

 2 (8%) 0 0

Type 3 BA

 100% 100% 100%

INR (range)

 1.0 (0.9–1.1) 1.0 (0.9–1.1) 1.0 (0.9–1.1)

Albumin, g/L (range)

 35 (30–38) 34 (31–37) 34 (30–36)
Direct bilirubin, micromol/L (range) 86 (55–108) 111 (66–142) 100 (65–136)

Total bilirubin, micromol/L (range)

 145 (109–180) 147 (115–187) 150 (121–190)

Gamma-glutamyl transferase, U/L (range)

 491 (76–983) 848 (128–1,219) 647 (213–1,012)

Alanine transaminase, U/L (range)

 153 (17–441) 154 (67–289) 89 (50–220)

Aspartate transaminase, U/L (range)

 177 (40–302) 140 (36–391) 162 (82–391)
Results

Endpoint

 Group A (n= 25) Group B (n= 9) Group C (n= 20)

Number of episodes of cholangitis per patient, 1st year*

 1.0 1.6 1.3 

Number of episodes of cholangitis per patient, 3 years*

 1.8 2.3 1.7 

Jaundice clearance rate at 6 months*

 52% 78% 50% 

3-year NLS rate*

 76% 100% 80% 

*No statistically significant difference in values between all 3 groups. 

Persistence of jaundice at 6 months was significantly associated with decompensated cirrhosis/death at 3 years (p<0.001).
Adverse Events

No reported short-or long-term adverse effects from the use of postoperative corticosteroids
Study Author Conclusions

The extended duration of PI-Abx and adjuvant corticosteroids was not associated with improved rates of cholangitis, jaundice clearance, or NLS in patients with BA.
Critique

While the findings suggested that an extended duration of PI-Abx and adjuvant corticosteroids was not associated with improved rates of cholangitis, the study's retrospective single-center design carries inherent limitations. The authors also noted that dividing the study population into three groups due to protocol changes may have affected the quality of the statistical analysis. Additionally, the study could not assess the impact of extending PI-Abx administration beyond 14 days, although it was suggested that such an extension might have a limited effect on overall outcomes.
References:
[1] Goh L, Phua KB, Low Y, Chiang LW, Yong C, Chiou FK. Analysis of Cholangitis Rates with Extended Perioperative Antibiotics and Adjuvant Corticosteroids in Biliary Atresia. Pediatr Gastroenterol Hepatol Nutr. 2021;24(4):366-376. doi:10.5223/pghn.2021.24.4.366

 

Ten-Year Experience in the Prevention of Post-Kasai Cholangitis
Design

Retrospective cohort study

N= 218   
Objective

To evaluate the effectiveness of an advanced prophylactic protocol in preventing early-onset cholangitis after the Kasai procedure in children with biliary atresia
Study Groups

Group A (n= 76)

Group B (n= 142)   
Inclusion Criteria

Children with biliary atresia who underwent the Kasai procedure between January 2002 and March 2013 and were followed up for at least six months
Exclusion Criteria Children lost to follow-up (20 participants excluded)   
Methods

Patients in Group A received intravenous third-generation cephalosporin and metronidazole for two weeks, intravenous immunoglobulin (IVIG) for five days, followed by oral third-generation cephalosporin for six months. Patients in Group B were treated with intravenous imipenem-cilastatin for two weeks, IVIG for five days, and then transitioned to oral third-generation cephalosporin for six months.
Duration

Trial: January 2002 and March 2013

Follow-up: 6 months   
Outcome Measures

Incidence of cholangitis, jaundice clearance rate, and long-term survival rate   
Baseline Characteristics   Group A (n= 76) Group B (n= 142)
Operative age, days 81.20 ± 12.30

76.18 ± 23.13
Female 35

65
Body weight, kg

4.93 ± 0.67

 4.75 ± 0.76
Results

Endpoint

 Group A (n= 76) Group B (n= 142)

Incidence of cholangitis*

Cholangitis

No cholangitis

 

45

31

 

14

128

*There was a significant difference in the incidence of post-operative cholangitis between groups A and B (59.2% vs. 9.9%; p = 0.000). 

No significant difference in bile drainage before the development of cholangitis between Group A (61.7%) and Group B (63.1%) (p >0.05). 
Five-year native liver survival rate was 23.7% in Group A and 60.6% in Group B (p= 0.000).
Adverse Events

Not disclosed 
Study Author Conclusions

Cholangitis in the early period after a Kasai procedure can be effectively prevented with an advanced prophylactic protocol involving imipenem-cilastatin and human immunoglobulin.   
Critique
The study's strengths include a large sample size, a long follow-up period, and a clear differentiation between two treatment protocols. However, its limitations involve the retrospective design which carries inherent biases and a lack of detailed reporting on adverse events. Additionally, factors such as the use of a standardized Kasai procedure and variations in follow-up care may have influenced the outcomes.
 
References:
[1] Pang WB, Zhang TC, Chen YJ, et al. Ten-Year Experience in the Prevention of Post-Kasai Cholangitis. Surg Infect (Larchmt). 2019;20(3):231-235. doi:10.1089/sur.2018.047