Place of Antibiotics in the Postoperative Acute Lithiasic Cholecystitis

Official Title: “Antibiotic Treatment Versus no Antibiotics in the Postoperative Acute Cholecystitis Low and Moderately Severe”

Assess whether postoperative antibiotics after cholecystectomy for acute lithiasic cholecystitis little or moderately severe, is effective and therefore justified.

The main objective is to compare the occurrence of postoperative infectious complications including surgical site infections (SSI) and remote infections after early cholecystectomy (performed within 5 days after onset of symptoms) for acute lithiasic cholecystitis (ALC) little or moderately serious (without organ dysfunction) with and without postoperative antibiotics.

The secondary objectives are: - Rates of infectious complications according to duration of preoperative antibiotic - Influence of surgical drainage after surgery for occurrence of postoperative infectious complications - Analysis of the nature of infectious complications (surgical site infections, remote surgical site infections) - Comparison of germs found in the bile during the postoperative infectious complications - Duration of hospitalization - Readmission rate for surgical site infections - Rate of reoperation for surgical site infection - Overall mortality rate at 30 days - Mortality rates specific to 30 days

This is a multicentre national, comparative, randomized, uncontrolled, non-inferiority, unblinded (open). Two groups of patients are compared (postoperative antibiotics versus no antibiotics postoperatively) in a ratio (1:1), intention to treat.

The international consensus conference held in Tokyo, has defined precisely the ALC(acute lithiasic cholecystis)and distinguished several stages of severity. For this study, this definition of degrees of severity will be used.

ALC is defined by the association of local signs: - Murphy's sign - mass - pain - defense of the right upper quadrant - systemic signs (fever, leukocytosis, elevated C-reactive protein).

When the diagnosis of ALC is clinically suspected, an imaging procedure (ultrasound, a CT or MRI) is needed to confirm the diagnosis.

The morphological evidence for the diagnosis of ALC are: - thickened gallbladder wall (> 4 mm) - gallbladder distention (> 8cm by 4cm long axis and minor axis) - presence of stones or debris bile (sludge) - infiltration of fat perivesicular - presence of an effusion perivesicular.

In this work, early ALC was defined by a disease duration of symptoms less than 5 days. This period is defined by the early onset of abdominal pain and / or fever. These criteria will be collected in case report forms.

Because the events of the ALC may range from a mild disease and confined to the gallbladder disease, to a fulminant life-threatening, a new classification of the severity of ALC has been established.

This classification has 3 levels: - ALC mild, - ALC moderately severe - ALC severe. - ALC mild (Grade I) ALC mild (Grade I) corresponds to a ALC in a patient in good general condition, without organ dysfunction, with mild inflammatory signs. At this stage there are no criteria higher stages (Grade II and III). - ALC moderately severe (Grade II)

ALC moderately severe comprises at least one of the following criteria: - Leukocytosis greater than 18,000 leucocytes/mm3 - Tense palpable mass on clinical examination at the right hypochondrium - Duration of symptoms exceeding 72 hours - Presence of local signs of inflammation (biliary peritonitis, perivesicular abscess, liver abscess, gangrenous cholecystitis, emphysematous cholecystitis) - ALC severe (Grade III) (non-inclusion criteria of the study ABCAL)

ALC(Grade III) is accompanied by dysfunction of one of the following: - Dysfunction Cardiovascular: hypotension requiring treatment with dopamine ≥ 5μg/kg per minute or whatever dobutamine dose. - Neurological dysfunction: alteration of consciousness - Respiratory dysfunction: report PaO2/FiO2 <300 - Renal dysfunction: oliguria, creatinine> 176μmol / l - Hepatocellular dysfunction: INR> 1.5 - Hematologic dysfunction: platelet count <100 000/mm3

Patients will be included age and suffering from: - acute lithiasic cholecystitis confirmed by morphological examination - low and moderately severe (confined to the gallbladder) - requiring early cholecystectomy (progression of symptoms <5 days) - signed consent for participation

The patient will be informed of the existence of the protocol during the consultation asking the indication of cholecystectomy for acute cholecystitis.

The medical examination and imaging procedure prior to the study correspond to a routine practice (no additional cost):

A clinical examination with collection of demographic data (gender, age, weight, size) will be noted. All co-morbidities as well as situations of potential risk of infection (diabetes type 2 steroids ongoing chronic renal failure, body mass index above 30, age over 65 years, recent surgery, serum albumin less than 35 , chronic obstructive bronchitis, tobacco weaned or unweaned? coronary insufficiency) will be noted (CRF).

A review of imaging vesicular confirming the diagnosis of acute cholecystitis, which may be based on habits and ultrasound or CT and / or MRI.

All patients then selecting checking the inclusion criteria and non-inclusion will be offered to participate in the study. They will be orally informed of the progress of the study and the various examinations, an information form will be issued.

The day of surgery, after a period of reflection varies with the date and result of surgery, the inclusion visit will be conducted and include: - The verification of inclusion criteria and non-inclusion - A clinical examination - The organization's planning examinations specific to the study. When the inclusion of a patient, the investigator will inform the proponent of a fax that inclusion by submitting the Form of Inclusion form (see report forms).

Patient monitoring - Preoperative support Preoperative prescription of antibiotics will be systematic when the patient will be included in the study. The preoperative antibiotic association include: amoxicillin-clavulanate (Augmentin ® 2gx3/jour or generic with dosage equivalent). In case of allergy to beta-lactam antibiotics, the patient will be excluded from the study. Patients will be included in the study, either before hospitalization (through the use of emergency shelter), either when the patient will be hospitalized in a department (gastroenterology, geriatrics, internal medicine, etc..).

A proportion of patients will have already started antibiotics (prescribed by the physician, or by the department where the patient is hospitalized). The history of antibiotics received by patients will be collected in case report forms and analyzed.

For these patients, after inclusion in the study and prior cholecystectomy, antibiotic being arrested and will be replaced by amoxicillin - clavulanic acid at a dose of 2gx3/jour, in the absence of beta-lactam antibiotics allergies . The total duration of preoperative antibiotic will depend on the time of surgery and should last, in all cases, less than 5 days (inclusion criteria). The total duration of antibiotic therapy by amoxicillin - clavulanate is analyzed. - Postoperative support The intraoperative antibiotics will be identical to the antibiotic started in preoperative(amoxicillin and clavulanic acid).

A skin preparation before surgery (antiseptic shower) and surgical (debridement and antisepsis of the operative field) will be performed. The intervention will begin with a thorough exploration of the entire peritoneal cavity and gallbladder to confirm the macroscopic diagnosis of CAL. The treatment consists of cholecystectomy with complete choice of surgical approach is left to the discretion of the operator. The laparoscopic route is preferred. The realization of a systematic sampling biliary be to compare the germs found in the gallbladder and any germs found in postoperative complications. The achievement of intraoperative cholangiography will be left to the discretion of the surgical team. The need for surgical drainage (aspiration or not) will be left to local conditions and customs of the service. The operating time will be recorded and analyzed. These variables will be collected for statistical analysis (CRF).

In the waning of the intervention, patients with bile peritonitis and those with stones in the bile duct discovered on intraoperative cholangiography can not be included in the study. - Randomization

Randomization will be performed in the operating theater immediately after surgery. The randomization will be done by drawing lots at the patient's statement via the Internet. It will be stratified by center and to ensure a better balance, blocks of equal size with as many patients randomized to either treatment, will be used at each center. - Postoperative management - Monitoring Visits - Choice of postoperative antibiotic Prescription or not postoperative antibiotic, will be determined by randomization. Before administration of the antibiotic, the patients included will be questioned on the existence of a possible allergy to beta-lactam antibiotics (CRF). The postoperative antibiotic therapy will be identical to the preoperative antibiotic therapy and include the following antibiotics: amoxicillin - clavulanate (Augmentin ® 2gx3/jour). Antibiotic treatment will be issued by pharmacies centers investigators.

The combination of a nitro-imidazole is not allowed in this study. The route of administration (intravenous or oral) and the date of the relay orally depend on the clinical and biological postoperative patient are collected in case report forms. The introduction of the antibiotic will be performed in hospitals with surveillance of tolerance to the drug.

The duration of postoperative antibiotic treatment will be 5 days. - Support during postoperative hospitalization Patients will be clinically monitored daily by the surgical team. All patients have a blood test with a blood count the day after the operation (CRF). Other blood tests may be performed according to clinical and biological patient evolution. Patients may leave the service when the surgeon deems necessary, from the 2nd postoperative day. The antibiotic treatment Augmentin ® is issued by the pharmacy at each center investigator. Antibiotics will be stored and dispensed by pharmacies in each center. Antibiotics will be issued to the patient (1 gram packets) at its output for the entire duration of 5 days.

Intervention(s) in this Clinical Trial

• Drug: amoxicillin clavulanic acid
  • Postoperative administration of 2g, 3 times daily, since 5 days, of amoxicillin clavulanic acid (Augmentin or generic) oral form or parenteral form according to clinical patient and by the choice of medical teams
• Drug: No medication
  • no postoperative antibiotics

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Amoxicillin claculanic acid
  • Postoperative administration of 2g of Augmentin, 3 times daily for 5 days.
• No Intervention: No medication
  • no postoperative antibiotics

Primary Measures

• All complications occurring during hospitalization or within 30 days postoperative. There are 2 main types of postoperative infectious complications: - Surgical site infections (SSI) - Systemic infections - Remote surgical site infections.
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes

Secondary Measures

• Rates of infectious complications according to duration of preoperative antibiotic
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Influence of surgical drainage after surgery for occurrence of postoperative infectious complications
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Nature of infectious complications analysis (surgical site infections, infections distance)
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Comparison of germs found in bile, the germs found in postoperative infectious complications
  • Time Frame: since the infectious complication persist
    Safety Issue?: Yes
• Duration of hospitalization
  • Time Frame: until the release of hospitalization, otherwise at 30 days postoperative
    Safety Issue?: Yes
• Readmission rate for surgical site infections (SSI)
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Rate of reoperation for SSI
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Overall mortality rate
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes
• Specific mortality rates
  • Time Frame: 30 days postoperative
    Safety Issue?: Yes

Inclusion Criteria:

• Acute lithiasic cholecystitis low or moderately severe (confined to the gall bladder)
• Requiring early cholecystectomy (progression of symptoms <5 days
• In an adult patient (>18 years)
• For each patient included the consent form must have been read, understood and signed.

Exclusion Criteria:

• Severe acute cholecystitis (with organ dysfunction)
• Acalculous cholecystitis
• Biliary peritonitis
• Abscess perivesicular
• Cholangitis
• Acute Pancreatitis
• Septic shock
• Stone of bile duct
• Physical or mental state does not allow participation in the study
• Contraindication to surgery
• Classification ASA (American Society of Anesthesiologists) IV-V or life expectancy
• <48 hours
• Suspected pre-or intraoperative cancer of the gallbladder
• Pregnancy or breastfeeding
• Treatment course with methotrexate, imidazole
• Known history of allergy to Augmentin ®

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Centre Hospitalier Universitaire, Amiens Other

Overall Clinical Trial Officials and Contacts

Jean-marc REGIMBEAU, Pr Study Director Centre Hospitalier Universitaire, Amiens  

Overall Contact: Jean-Marc REGIMBEAU, Pr +33 3 22 66 83 01 Regimbeau.jean-marc@chu-amiens.fr

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01015417

Study ID Number: Amiens ABCAL

ClinicalTrials.gov Identifier: NCT01015417

Health Authority: France: Afssaps - French Health Products Safety Agency