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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Appendicitis Perforated
• Intervention / Treatment: Drug: Piperacillin/tazobactam; Drug: Normal saline; Drug: CefTRIAXone Injection; Drug: Metronidazole Injection

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daniel Briatico, MSc; Phone Number: 75231 9055212100; Email: briaticd@mcmaster.ca
• Study Contact Backup: Name: Michael H Livingston, MD, MSc; Phone Number: 75231 9055212100; Email: livingm@mcmaster.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Number of participants randomized per month	Through study completion (average of 1 year)
Consent rate	Number of participants who consent to participate divided by those who are approached for consent	Through study completion (average of 1 year)
Rate of protocol violations	Number of participants who do not receive study treatments within 8 hours of surgery, miss a scheduled study treatment, and/or experience treatment crossover divided by those randomized	Through study completion (average of 1 year)
Rate of loss to follow-up	Number of participants who cannot be contacted by phone 3 months after discharge from hospital divided by those randomized	Through study completion (average of 1 year)
Cost of trial	Total cost of internal pilot study in Canadian dollars divided by the number of participants randomized	Through study completion (average of 1 year)

Collaborators and Investigators

• Sponsor: McMaster Children's Hospital
• Investigators: Principal Investigator: Michael H Livingston, MD, MSc, McMaster Children's Hospital

Publications and helpful links

General Publications

• St Peter SD, Snyder CL. Operative management of appendicitis. Semin Pediatr Surg. 2016 Aug;25(4):208-11. doi: 10.1053/j.sempedsurg.2016.05.003. Epub 2016 May 10.
• Linnaus ME, Ostlie DJ. Complications in common general pediatric surgery procedures. Semin Pediatr Surg. 2016 Dec;25(6):404-411. doi: 10.1053/j.sempedsurg.2016.10.002. Epub 2016 Oct 29.
• St Peter SD, Tsao K, Spilde TL, Holcomb GW 3rd, Sharp SW, Murphy JP, Snyder CL, Sharp RJ, Andrews WS, Ostlie DJ. Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial. J Pediatr Surg. 2008 Jun;43(6):981-5. doi: 10.1016/j.jpedsurg.2008.02.018.
• Lee J, Garvey EM, Bundrant N, Hargis-Villanueva A, Kang P, Osuchukwu O, Dekonenko C, Svetanoff WJ, St Peter SD, Padilla B, Ostlie D. IMPPACT (Intravenous Monotherapy for Postoperative Perforated Appendicitis in Children Trial): Randomized Clinical Trial of Monotherapy Versus Multi-drug Antibiotic Therapy. Ann Surg. 2021 Sep 1;274(3):406-410. doi: 10.1097/SLA.0000000000005006.
• Kashtan MA, Graham DA, Melvin P, Hills-Dunlap JL, Anandalwar SP, Rangel SJ. Ceftriaxone with Metronidazole versus Piperacillin/Tazobactam in the management of complicated appendicitis in children: Results from a multicenter pediatric NSQIP analysis. J Pediatr Surg. 2022 Oct;57(10):365-372. doi: 10.1016/j.jpedsurg.2021.11.009. Epub 2021 Nov 20.
• Gerber JS, Jackson MA, Tamma PD, Zaoutis TE; COMMITTEE ON INFECTIOUS DISEASES, PEDIATRIC INFECTIOUS DISEASES SOCIETY. Antibiotic Stewardship in Pediatrics. Pediatrics. 2021 Jan;147(1):e2020040295. doi: 10.1542/peds.2020-040295.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 26, 2023
• First Submitted That Met QC Criteria: July 4, 2023
• First Posted (Actual): July 13, 2023

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 4, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Child; Metronidazole; Ceftriaxone; Piperacillin
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Appendicitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; beta-Lactamase Inhibitors; Metronidazole; Ceftriaxone; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination
• Other Study ID Numbers: McmasterCH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No