Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA)

Study Overview
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Brief Summary
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This study is an internal pilot for a multicenter, blinded randomized controlled trial. The purpose of the multicenter trial is to determine whether post-operative piperacillin/tazobactam is more effective than ceftriaxone and metronidazole for children treated with laparoscopic appendectomy for perforated appendicitis. We plan to conduct an internal pilot study to determine whether a blinded multicenter randomized controlled trial is feasible.

Detailed Description
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Acute appendicitis is the most common indication for emergency surgery in children. The management of this condition is typically an urgent laparoscopic appendectomy under general anesthesia. If the appendix is found to be perforated at the time of surgery, then patients need to stay in hospital for intravenous antibiotics. Patients who do not respond to antibiotic therapy experience prolonged length of stay, need for additional procedures (such as percutaneous drain insertion), or other complications. This represents significant morbidity for patients and their families. Children with perforated appendicitis were previously treated with post-operative ampicillin, gentamicin, and metronidazole (also known as triple therapy). In 2008, a randomized controlled trial showed that triple therapy is non-inferior to ceftriaxone and metronidazole (CM) in terms of intra-abdominal abscess formation and wound infection. CM is also less expensive and has a simplified dosing regimen. As such, post-operative CM became the standard of care for perforated appendicitis at most children's hospitals. In 2021, an open-label RCT suggested that piperacillin/tazobactam (PT) is more effective than CM for children with perforated appendicitis. Patients randomized to PT had a reduced rate of intra-abdominal abscess formation compared to those treated with CM (odds ratio (OR) 4.80, p=0.002). This trial was not blinded and there was no allocation concealment. In contrast, a multicenter, observational study reported no difference in the rate of intra-abdominal abscess formation among patients treated with PT compared to CM. The conflicting results of these two studies add further uncertainty regarding the choice of antibiotics for these patients. Another factor that should be considered regarding the use of PT versus CM in children with perforated appendicitis is antibiotic stewardship. PT is a broad-spectrum antibiotic with increased effectiveness against Pseudomonas aeruginosa and resistant Escherichia coli. As a result, this medication is often reserved for patients with confirmed Pseudomonas infection, oncology patients with febrile neutropenia, or those who are critically ill and admitted to the intensive care unit. The current study is an internal pilot for a multicenter, blinded randomized controlled trial. The purpose of the multicenter trial is to determine whether post-operative piperacillin/tazobactam is more effective than ceftriaxone and metronidazole for children treated with laparoscopic appendectomy for perforated appendicitis. We plan to conduct an internal pilot study to determine whether a blinded multicenter randomized controlled trial is feasible.

Official Title
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Assessing the Longitudinal Outcomes of Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA): a Randomized Controlled Trial

Conditions
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Appendicitis Perforated

Intervention / Treatment
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* Drug: Piperacillin/tazobactam
* Drug: Normal saline
* Drug: CefTRIAXone Injection
* Drug: Metronidazole Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Laparoscopic appendectomy Perforated appendicitis confirmed intra-operatively (i.e., visible hole in appendix, fecalith found in peritoneal cavity, intra-abdominal abscess, and/or purulent fluid in peritoneal cavity) Exclusion Criteria: Non-operative treatment (e.g., due to abscess) Interval laparoscopic appendectomy Conversion to open procedure Non-perforated appendicitis Confirmed or suspected allergy to penicillins or cephalosporins Renal impairment

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Internal pilot study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Piperacillin/tazobactam<br> | Drug: Piperacillin/tazobactam<br>* Post-operative piperacillin/tazobactam 100 mg/kg IV q8h (to a maximum of 4.5 g IV q8h)<br>Drug: Normal saline<br>* Post-operative normal saline 50 mL once daily<br>|
| Active Comparator: Ceftriaxone and metronidazole<br> | Drug: CefTRIAXone Injection<br>* Post-operative ceftriaxone 50 mg/kg IV once daily (to a maximum of 2 g IV once daily)<br>Drug: Metronidazole Injection<br>* Post-operative metronidazole 10 mg/kg IV q8h (to a maximum of 500 mg IV q8h)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of stay | Length of stay in hospital during index admission | Index admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percutaneous drain insertion | Percutaneous drain insertion by Interventional Radiology | Within 30 days of surgery | 
| Deep or organ-space surgical site infection | Deep or organ-space surgical site infection | Within 30 days of surgery | 
| Insertion of Peripherally Inserted Central Catheter (PICC) | Insertion of Peripherally Inserted Central Catheter (PICC) | Within 30 days of surgery | 
| Parenteral nutrition | Need for parenteral nutrition | Within 30 days of surgery | 
| Post-operative ultrasound | Need for post-operative ultrasound | Within 30 days of surgery | 
| Clostridium difficile infection | Clostridium difficile infection (confirmed with stool sample and requiring treatment) | Within 30 days of surgery | 
| Return to the emergency department | Return to the emergency department within 30 days of surgery | Within 30 days of surgery | 
| Readmission to hospital | Readmission to hospital within 30 days of surgery | Within 30 days of surgery | 
| Late complications | Telephone confirmation of no additional complications related to perforated appendicitis requiring assessment in clinic, emergency department visit, or admission to hospital | Telephone call 3 months after surgery | 
| Exit survey | Parents will complete a descriptive questionnaire about the study by telephone | Telephone call 3 months after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Child, Piperacillin, Ceftriaxone, Metronidazole