Clinical trial NCT05943223: Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA)
Official title: Assessing the Longitudinal Outcomes of Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA): a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Appendicitis Perforated
Keywords: Child
Piperacillin
Ceftriaxone
Metronidazole
Lead sponsor: McMaster Children's Hospital
Sponsor class: OTHER
First posted: 2023-07-13
Enrollment: 16
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Internal pilot study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Length of stay
timeFrame: Index admission
Secondary outcomes:
measure: Percutaneous drain insertion
timeFrame: Within 30 days of surgery
measure: Deep or organ-space surgical site infection
timeFrame: Within 30 days of surgery
measure: Insertion of Peripherally Inserted Central Catheter (PICC)
timeFrame: Within 30 days of surgery
measure: Parenteral nutrition
timeFrame: Within 30 days of surgery
measure: Post-operative ultrasound
timeFrame: Within 30 days of surgery
measure: Clostridium difficile infection
timeFrame: Within 30 days of surgery
measure: Return to the emergency department
timeFrame: Within 30 days of surgery
measure: Readmission to hospital
timeFrame: Within 30 days of surgery
measure: Late complications
timeFrame: Telephone call 3 months after surgery
measure: Exit survey
timeFrame: Telephone call 3 months after surgery
Other outcomes:
measure: Recruitment rate
timeFrame: Through study completion (average of 1 year)
measure: Consent rate
timeFrame: Through study completion (average of 1 year)
measure: Rate of protocol violations
timeFrame: Through study completion (average of 1 year)
measure: Rate of loss to follow-up
timeFrame: Through study completion (average of 1 year)
measure: Cost of trial
timeFrame: Through study completion (average of 1 year)
Locations:
Study officials:
affiliation: McMaster Children's Hospital
name: Michael H Livingston, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.