Antibiotics for cholangitis and/or cholecystitis

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the benefits and harms of antibiotic interventions for the treatment of cholangitis.

Background

Cholangitis is defined as infection of the normally sterile biliary system. It usually occurs in the presence of complete or partial obstruction of the bile ducts but may also follow surgical manipulation of the biliary tree. Bacteria can enter the bile by several routes, ascending the common bile duct from the duodenum (across an incompetent sphincter of Oddi or following instrumentation), entering directly from the small bowel after choledochoenterostomy, or by translocation from the gut into the portal vein (Hanau 2000). Biliary obstruction leads to the loss of antibacterial properties of bile (immunoglobulin A (IgA) and bile salts)(Sung 1992). In chronic obstructive jaundice, obstruction results in diminished neutrophilic function (Jiang 1997; Holman 1982), increased blood endotoxin levels (Lau 1996), and abnormal Kuppfer cell function (Clements 1996), which predispose to cholangitis.

The incidence of cholangitis varies depending on the underlying pathology, nutritional status, age, and immune function of the persons. In biliary atresia the occurrence of cholangitis may range from 46 per cent to 100 per cent of patients with a portoenterostomy (Ecoffey 1987; Rothenberg 1989). Cholangitis following liver transplantation is largely related to the development of biliary strictures which occur in five to 20 per cent of patients (Wade 1995; Hardy 1996; Stratta 1989).

Microbiology of cholangitis Cholangitis is generally caused by enteric flora. Gram negative enteric organisms such as Escherichia coli, Klebsiella species, and Enterobacter species, along with enterococcus and Pseudomonas species are the most frequent causative organisms. The majority of isolates are aerobic bacteria although anaerobic bacteria may also frequently contribute to mixed cultures. Generally anaerobic bacteria are not the sole causative organism.

Diagnosis of cholangitis The definitive diagnosis of cholangitis is based on the culture of pathogens from otherwise sterile bile fluid in the presence of symptoms based on Charcot's classic triad of jaundice, pain, and fever particularly if there is a past history of liver disease or cholangitis. This excludes patients with a biliary stent who may be colonised but otherwise asymptomatic. In searching for a cause of fever it is assumed that a thorough physical examination and common clinical tests have failed to reveal another cause of fever. Associated features supporting the diagnosis of cholangitis include leucocytosis (>10 x 109/L) and hyperbilirubinaemia (above the person's baseline level) that suggest obstruction. The level of obstruction may be indicated by ultrasonagraphy, computer tomography (CT) scan, magnetic resonance imaging (MRI), or nuclear‐labelled diisopropyliminodiacetic acid (DISIDA) scan. A number of other conditions may present with Charcot's triad. The entity most difficult to distinguish from cholangitis is acute cholecystitis and in many randomised controlled trials these have been considered together.

In those who have bile cultures taken, an organism is identified in 80 to 100 per cent of cases (Hanau 2000). More than one organism is isolated in 30 to 87 per cent of the episodes. Bacteraemia is detected in 21 to 83 per cent of patients with cholangitis.

Prevention of cholangitis A recent meta‐analysis has addressed the question of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography (ERCP) (Harris 1999). The authors found that antibiotic prophylaxis prior to ERCP may reduce the incidence of bacteraemia but did not substantially reduce the incidence of sepsis/cholangitis and thus the routine use of antibiotic prophylaxis was not recommended. The issue of prevention will not be considered in this Review.

Treatment of cholangitis The treatment of cholangitis includes antibiotic therapy and/or surgical decompression depending on the cause of the infection and the severity of illness. The choice of antibiotics and duration of treatment varies considerably between centres. If a causative organism has not been cultured, empiric antibiotic treatment is based on standard regimes for enteric pathogens. Surgical decompression is more frequently used in the adult population than in children due to differing causes of cholangitis. In adults there is an increased likelihood of stones or tumours causing cholangitis. The smaller size of children's biliary tract makes endoscopic surgical interventions more difficult than in adults.

Objectives

To evaluate the benefits and harms of antibiotic interventions for the treatment of cholangitis.

Methods

Criteria for considering studies for this review

Types of studies

All randomised clinical trials and quasi‐randomised clinical trials comparing two or more antibiotics or antibiotic versus placebo/no intervention for the treatment of cholangitis.

Types of participants

People of all ages fulfilling the microbiological diagnosis of cholangitis based on positive microbiological cultures of biliary fluid or the clinical diagnostic criteria for cholangitis (Charcot's triad ‐ fever, jaundice, and abdominal pain). Trials including additional criteria for diagnosis of cholangitis such as raised white cell count, raised direct bilirubin, and specific temperature elevations (e.g., > 39°C) for the diagnosis of cholangitis will also be included.

Types of interventions

This Review will address the following comparisons:

• Antibiotics versus placebo or no intervention.

• One type of antibiotics versus another type of antibiotics.

Cointerventions will be allowed if used in both intervention arms.

Types of outcome measures

• Mortality (primary outcome measure).

• Blood or bile culture positive patients: eradication, relapse following treatment, or failure to eradicate infection. As antimicrobial susceptibility may vary considerably from country to country the efficacy of antibiotics will need to be evaluated according to the sensitivity of an organism to a particular antibiotic in a specific geographic location.

• Clinical variables (Charcot's triad): duration of jaundice, fever or pain also expressed as cure, improvement, relapse, requirement for clinical decompression or treatment failures.

• Harms of antibiotic interventions: side effects/adverse events related to antibiotics including liver and renal impairment.

• Quality of life.

• Health economics, e.g., duration of hospitalisation.

Due to the large number of secondary outcome measures these will be interpreted conservatively.

Search methods for identification of studies

Relevant RCTs and quasi‐randomised studies will be found by searching The Cochrane Hepato‐Biliary's Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE, and EMBASE. The search strategies are given below: The Cochrane Controlled Trials Register (CENTRAL/CCTR) in which The Cochrane Hepato‐Biliary Group Controlled Trials Register is also included: 1. BILLIARY TRACT DISEASES*: ME 2. CHOLANGITIS*:ME 3. Cholangitis 4. ANTIBIOTICS*:ME 5. Antibiotics 6. (Antibiotic therap* or Antibiotic treat*) 7. (cephalosporins or fluoroquinolone$ or tetracyclines or penicillin or metronidazole or imipenem of ceftriaxone or carbapenems or biapenem or thienamycins or cephalosporin or mezocillin or meropenem or clavulanate or sulbactam or cefotaxime or clindamycin or carbapenems or thienamycins or aminogycosides or gentamicin or tobramycin or amikacin or ciprofloxacin or isepamicin or cefpirom$ or clindamycin or ceftazidime or ticarcillin or tazobactam or cefoperazon or ampicillin or ciprofloxacin or pefloxacin or peperacillin or ofloxacin or mezlocillin) 8. #1 or #2 or #3 9. #4 or #5 or #6 or #7 10. #8 and #9 Each antibiotics individually with cholangitis will be searched in CENTRAL/CCTR.

MEDLINE: 1. randomized controlled trial$.pt,sh. 2. controlled clinical trial$.pt. 3. random allocation.sh. 4. double blind method.sh. 5. single blind method.sh. 6. clinical trial.pt. 7. exp Clinical Trials/ 8. (clin$ adj25 trial$).ti,ab. 9. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 10. placebos.sh. 11. placebo$.ti,ab. 12. random$.ti,ab. 13. research design.sh. 14. or/1‐13 15. (animal not human).sh. 16. 14 not 15 17. exp cholangitis/ 18. cholangitis.ti,ab,tw. 19. angiocholitis.ti,ab,hw,sh. 20. ((bile or biliary) adj5 (infect$ or inflam$)).ti,ab. 21. biliary tract diseases/ or bile duct diseases/ 22. Cholecystitis/ or biliary tract surgical procedures/ae, mo 23. or/17‐22 24. exp antibiotics/ 25. (antibiotics or antibiotic therap$ or antibiotic treat$).ti,ab. 26. exp Antibiotics, Aminoglycoside/ 27. aminoglycosid$.ti,ab,rw. 28. (ciprofloxacin or amikacin or gentamicin$ or cefepime or isepamicin$).ti,ab,sh,rw. 29. exp Cephalosporins/ 30. exp Anti‐Infective Agents, Fluoroquinolone/ 31. (fluoroquinolones or tetracyclines or penicillin or metronidazole or imipenem or ceftriaxone).ti,ab,sh,rw. 32. (cefpirom$ or clindamycin$ or gentamicin$ or ceftazidime or ticarcillin or clavulanic acid$ or tobramycin or amoxicillin or tazobactam or cefoperazon or ampicillin or ciprofloxacin or pefloxacin or piperacillin or ofloxacin or me#locillin).ti,ab,sh,rw. 33. exp carbapenems/ or (biapenem or thienamycins).ti,ab,sh,rw. 34. or/24‐33 35. 16 and 23 and 34

EMBASE: 1. exp controlled study/ or controlled study.ti,ab,hw,tn,mf. 2. exp statistical analysis/ or clinical study.ti,ab,hw,tn,mf. 3. exp major clinical study/ or major clinical study.ti,ab,hw,tn,mf. 4. exp randomized controlled trial/ or randomi#ed controlled study.ti,ab,hw,tn,mf. 5. random$.ti,ab,hw,tn,mf. 6. exp double blind procedure/ or double blind procedure.ti,ab,hw,tn,mf. 7. exp single blind procedure/ or single blind procedure.ti,ab,hw,tn,mf. 8. exp multicenter study/ or multicenter study.ti,ab,hw,tn,mf. 9. exp placebo/ or placebo$.ti,ab,hw,tn,mf. 10. or/1‐9 11. (human not animal).sh,de,hw. 12. 10 and 11 13. (aminogycosides or gentamicin or tobramycin or amikacin or ciprofloxacin or isepamicin or cefpirom$ or clindamycin or ceftazidime or ticarcillin or clavulanic acid$ or tazobactam or cefoperazon or ampicillin or ciprofloxacin or pefloxacin or peperacillin or ofloxacin or me#locillin).ti,ab,hw,tn. 14. (cephalosporins or fluoroquinolone$ or tetracyclines or penicillin or metronidazole or imipenem of ceftriaxone or carbapenems or biapenem or thienamycins or cephalosporin or mezocillin or meropenem or clavulanate or sulbactam or cefotaxime or clindamycin or carbapenems or thienamycins).ti,ab,hw,tn. 15. exp Antibiotic Agent/ or exp Antibiotic Therapy/ 16. or/13‐15 17. (cholangitis or choecystitis).ti,ab,hw. 18. exp cholangitis/ or exp biliary tract infection/ or exp biliary tract inflammation/ or bile duct infection/ 19. angiocholitis.ti,ab,hw. 20. ((bile or biliary) adj5 (infect$ or inflam$)).ti,ab. 21. or/17‐20 22. bacterial infection/ or sepsis/ 23. biliary tract surgery/ or common bile duct/ or bile duct obstruction/ or common bile duct obstruction/ 24. 22 and 23 25. 21 or 24 26. 12 and 16 and 25

Other sources to be searched include reference lists of textbooks, reviews (Cochrane Database of Systematic Reviews and others), previous trials, and conference proceedings. Authors of identified trials will be contacted to see if they know of unpublished trials. Studies in languages apart from English will be included and duplicate publications of the same trial will be identified through reading the articles in question and contacting the authors if required.

Data collection and analysis

At least two independent reviewers will screen the title of abstracts resulting from the literature searches. Study eligibility for inclusion in the Review will be assessed against defined criteria. Methodological quality of trials including patient randomisation (generation of allocation sequence and allocation concealment); blinding of participants, investigators, and outcome assessors; intention‐to‐treat analysis; and completeness of follow‐up will be assessed separately and not combined to give a quality score. Authors of primary studies will be contacted when necessary to clarify data and to provide missing information. The characteristics and outcomes of included studies and details of excluded studies will be entered into RevMan. An additional reviewer will resolve disagreements between primary reviewers. The presence of publication bias will be determined using a funnel plot or other method if sufficient studies are available.

Statistical analysis For dichotomous outcomes results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Data will be pooled using the random effects model. Where continuous scales of measurement are used to assess the effects of treatment the weighted mean difference (WMD) between groups with 95% CI will be used. The standardised mean difference (SMD) with 95% CI will be used to compare different measurement scales. Statistical heterogeneity will be analysed. Applicability of the results to the individual patients will be determined by calculating absolute risk reductions with therapy in relation to the baseline risk of the outcome occurring with no intervention or with a different intervention.

Subgroup analysis will only be considered if strongly indicated by the preliminary analyses. However, we will perform subgroup analyses stratifying the RCTs into those with adequate generation of allocation sequence, adequate allocation concealment, and adequate blinding of patients and investigators versus those RCTs with one or more inadequate components versus quasi‐randomised studies.

What's new

Date	Event	Description
22 November 2018	Amended	This protocol is withdrawn as it has not been developed in a review within the expected time frame. A new protocol "Antibiotics for people with acute cholangitis or acute cholecystitis or both" by Markotic F, Grgic S, Fox A, et al is beng prepared and expected to be published in the beginning of 2019.

Contributions of authors

Renata Kukuruzovic: Conceived the idea for the Review, designed and will coordinate the Review Screening search results, retrieval of papers and screening retrieval papers against inclusion criteria Abstracting data from papers Appraising quality of papers Writing to authors for additional information Methodological perspective Obtaining and screening data on unpublished studies Data entry into RevMan Analysis of data Clinical perspective Policy and consumer perspective Writing of the Review

Elizabeth Elliott: Screening search results, retrieval of papers and screening retrieval papers against inclusion criteria Abstracting data from papers Appraising quality of papers Methodological perspective Obtaining and screening data on unpublished studies Analysis of data Policy and consumer perspective Writing of the Review

Stuart Dorney: Clinical perspective

Sunita Chauhan: Developing and performed search strategy Policy and consumer perspective

General advice on the Review will be provided by Norelle Willis (Cochrane Renal Group)

Declarations of interest

None known.

Notes

This protocol is withdrawn as it has not been developed in a review within the expected time frame. A new protocol "Antibiotics for people with acute cholangitis or acute cholecystitis or both" by Markotic F, Grgic S, Fox A, et al is beng prepared and expected to be published in the beginning of 2019.

Withdrawn from publication for reasons stated in the review