https://orcid.org/0000-0002-8665-9492
Figures
Abstract
Background
Acute appendicitis is the most common indication for emergency surgery in children. In cases of perforation, patients require post-operative intravenous antibiotics in hospital. However, some children fail to respond adequately, resulting in prolonged hospitalization. The optimal antibiotic regimen for perforated appendicitis remains uncertain.
Methods
We propose a double-blind, randomized controlled pilot trial comparing two commonly used antibiotic strategies. Eligible participants include children <18 years undergoing laparoscopic appendectomy for perforated appendicitis. Following surgery, participants will be randomized to receive either: (1) piperacillin/tazobactam; or (2) ceftriaxone and metronidazole. The sample size for the pilot study is 16 participants (i.e., 8 per group). Feasibility outcomes include recruitment rate, protocol adherence, loss to follow-up, and cost per participant.
Discussion
This pilot study will assess the feasibility of conducting a blinded randomized controlled trial of postoperative antibiotic therapy in children with perforated appendicitis. To date, only one randomized trial has addressed this question, but it was limited by its single-center design, lack of blinding, and susceptibility to ascertainment bias and other methodological concerns. Findings from this pilot will inform the design of a larger, multicenter study with rigorous blinding and standardized outcome assessment to determine whether piperacillin-tazobactam or ceftriaxone and metronidazole provides superior outcomes.
Citation: Briatico D, Safa N, Flageole H, Khan S, Pernica J, Eltorki M, et al. (2025) Assessing the Longitudinal outcomes of Piperacillin/tazobactam versus ceftriAxone and metronidazole for Children with perforated Appendicitis (ALPACA): A protocol for a pilot randomized controlled trial. PLoS One 20(11): e0335991. https://doi.org/10.1371/journal.pone.0335991
Editor: Leonard Ighodalo Uzairue,, Federal University Oye-Ekiti, NIGERIA
Received: January 3, 2025; Accepted: October 13, 2025; Published: November 7, 2025
Copyright: © 2025 Briatico et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.
Funding: ML, DB. Hamilton Health Sciences, Pump Up the Volume Competition. Value: $25,000. ML, DB. Department of Surgery, McMaster University. Value: $30,000. Funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Eyal Cohen reports being a member of the Committee to Evaluate Drugs which advises Ontario’s Ministry of Health on public drug funding.
Background
Acute appendicitis is the most common indication for emergency surgery in children [1]. In developed countries, the standard of care includes pre-operative intravenous (IV) antibiotics followed by laparoscopic appendectomy [2]. If the appendix is found to be perforated at the time of surgery, patients must stay in hospital for post-operative IV antibiotics. Patients who do not respond to antibiotic therapy may experience prolonged length of stay, need for additional interventions (e.g., percutaneous drain insertion or parenteral nutrition), or other complications [3]. These outcomes represent significant morbidity for patients and their families.
Historically, children with perforated appendicitis were treated with post-operative ampicillin, gentamicin, and metronidazole (also known as “triple therapy”). In 2008, a randomized controlled trial (RCT) showed that triple therapy was non-inferior to ceftriaxone and metronidazole (CM) in terms of intra-abdominal abscess formation and wound infection [4]. CM is also less expensive and has a simplified dosing regimen. Accordingly, post-operative CM became the standard of care for perforated appendicitis at most children’s hospitals in the United States and Canada [5].
In 2021, an open-label RCT (n = 162) suggested that piperacillin/tazobactam (PT) was more effective than CM for children with perforated appendicitis [6]. Patients randomized to PT had significantly lower rates of intra-abdominal abscess formation (odds ratio [OR] 4.80, p = 0.002), required fewer postoperative imaging studies, and had fewer emergency room visits after discharge [6]. However, the trial had several limitations. It was not blinded, there was no allocation concealment, and the primary outcome—detection of intra-abdominal abscess on postoperative imaging—was subject to potential ascertainment bias. Participants in the CM group underwent imaging more frequently, and the decision to order imaging was left to the treating physician, who was aware of each patient’s antibiotic assignment. This is particularly concerning since postoperative imaging may detect fluid collections that are not clinically significant.
In contrast, a multicenter observational study (n = 654) found no difference between children treated with PT versus CM in intra-abdominal abscess rates (OR 0.88, 95% CI 0.38–2.03, p = 0.77) or resource utilization, including post-operative imaging, length of stay, and hospital cost [7]. Likewise, another study (n = 1,002) reported comparable rates of organ space infection (17.0% vs 13.1%, p = 0.08), post-operative drainage (11.7% vs 10.7%, p = 0.63), and post-operative length of stay (median 4 vs 4 days, p = 0.26) between groups [8]. Interestingly, the largest multicenter observational study (n = 29,015) found PT to be associated with higher risks of abscess formation (relative risk [RR] 1.35, 99% CI 1.04–1.75) and readmission to hospital (RR 1.38, 99% CI 1.13–1.68) [9]. However, after adjusting for hospitals with high CM utilization (≥75% cases), these differences were no longer statistically significant [9]. Together, these inconsistent results highlight ongoing uncertainty about the optimal antibiotic regimen. Furthermore, all studies were conducted in the United States [6–9], limiting generalizability to Canadian patients who may have different microbial sensitivities and antibiotic resistance patterns [10,11].
Another important consideration is antibiotic stewardship [12]. PT is a broad-spectrum antibiotic with increased effectiveness against Pseudomonas aeruginosa and resistant strains of Escherichia coli. However, the overuse of broad-spectrum antibiotics can promote the emergence of drug-resistant pathogens, which are associated with worse clinical outcomes [13]. Compared with narrow-spectrum agents, broad-spectrum antibiotics are also linked to a higher risk of adverse effects, risks that are often underappreciated by healthcare providers and the general public [14]. Using PT for a routine, community-acquired infection like perforated appendicitis may result in unnecessary exposure to broad-spectrum antibiotics, which appears to be associated with long-term harms [15–17].
At McMaster Children’s Hospital, we reported substantial variation in the type of post-operative antibiotics used among children with perforated appendicitis (n = 71) [18]. In this study, we found that some patients received CM alone (n = 32), others received PT (n = 23), and a subset treated initially with CM were “escalated” to PT when their symptoms did not improve (n = 15). Compared to patients treated with CM only (n = 32), those escalated to PT (n = 15) had worse intra-operative findings at baseline, and also showed an increased need for post-operative ultrasound (67% vs 34%, p = 0.038), parenteral nutrition (33% vs 3%, p = 0.004), peripherally inserted central catheter (PICC) insertion (47% vs 3%, p < 0.001), and greater length of stay (10.7 vs 5.1 days, p < 0.001). There were 3 cases of Clostridioides difficile infection (4%), but all of these occurred in patients treated with CM.
In short, there remains clinical equipoise regarding whether PT or CM is the better option for children with perforated appendicitis. A single-center, unblinded RCT with some risk of bias suggested a benefit with PT [6], while three multicenter, observational studies reported no difference [7–9]. Given the potential harm and unnecessary exposure to broad-spectrum antibiotics, a well-designed RCT is needed to resolve this uncertainty.
Methods
Study design
The Assessing Longitudinal outcomes of Piperacillin/tazobactam versus ceftriAxone and metronidazole for Children with perforated Appendicitis (ALPACA) trial is a pilot study for a multicenter, blinded RCT with two parallel groups. The primary aim of this study is feasibility, not efficacy. Specifically, this pilot will evaluate recruitment, consent, protocol adherence, outcome assessment, and study costs to determine whether a larger multicenter trial can be successfully conducted. The research question for the multicenter trial is: “Among children less than 18 years of age who undergo laparoscopic appendectomy for perforated appendicitis, is post-operative PT superior to CM in terms of length of stay in hospital?” Although we hypothesize that PT may be associated with a shorter length of stay and improvements in other clinically important outcomes, this pilot study is not powered to evaluate efficacy and will not conduct hypothesis testing on clinical endpoints.
Setting
The pilot study will be conducted at McMaster Children’s Hospital, a tertiary children’s hospital located in Hamilton, Ontario, Canada. Our center performs approximately 250 laparoscopic appendectomies per year, including 1–2 cases of perforated appendicitis each week. This study was approved by the Hamilton Integrated Research Ethics Board (HiREB: 16639; May 2024) and Health Canada (HC: 284846; April 2024). The ethics approved protocol can be found in S1 Appendix.
Usual practice
At McMaster Children’s Hospital, all laparoscopic appendectomies in children are performed by pediatric general surgeons with fellowship training in Pediatric Surgery. Patients found to have perforated appendicitis are treated with PT or CM in hospital post-operatively. Pain is controlled with oral acetaminophen, IV ketorolac (or oral ibuprofen), and IV morphine as needed. Maintenance IV fluids are gradually weaned as an oral diet is introduced and bowel function normalizes.
Patients who are unable to tolerate an oral diet for 7 days (including both pre- and post-operative days) are often considered for PICC insertion and parenteral nutrition. However, decisions about the timing of PICC insertion and initiating parenteral nutrition are ultimately left to the attending surgeon. At our institution, the duration of IV antibiotics is based on clinical criteria. These include: (1) resolution of pain and localized tenderness; (2) resolution of fevers (i.e., any documented temperature greater than 38.0 degrees); (3) resolution of diarrhea; and (4) ability to tolerate an oral diet. If symptoms resolve within one week of surgery, patients are discharged home with a course of oral antibiotics, typically amoxicillin and clavulanic acid.
Patients with persistent symptoms up to one week after surgery typically undergo an abdominal ultrasound to assess for the presence of a phlegmon (i.e., inflamed soft tissue) or drainable abscess (i.e., organized collection of purulent fluid). Patients with a large abscess (i.e., typically greater than 5 cm in maximal dimension) are often considered for percutaneous drain insertion by a pediatric interventional radiologist. In children, this procedure requires a general anesthetic and the drain is left in place for a few days to allow the abscess to evacuate completely. These patients remain in hospital on IV antibiotics until the drain is removed and symptoms resolve.
When patients are discharged home, they are advised to contact our office or return to the emergency department if they have fevers, persistent diarrhea (which may be a sign of an intra-abdominal abscess or Clostridioides difficile infection), abdominal pain, or inability to tolerate an oral diet. Some of the patients who return to the emergency department require readmission to hospital for additional IV antibiotics and possible percutaneous drain insertion.
Participants
Participants in this pilot study will include children treated with laparoscopic appendectomy for perforated appendicitis. The inclusion and exclusion criteria are listed below.
Inclusion criteria:
- Age less than 18 years
- 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 the peritoneal cavity)
Exclusion criteria:
- Non-operative treatment (since patients managed non-operatively have a different clinical course and outcomes compared to those undergoing immediate appendectomy)
- Interval laparoscopic appendectomy (since patients undergo interval laparoscopic appendectomy as a day procedure and do not receive post-operative antibiotics)
- Conversion to open procedure (since this is rare in children undergoing laparoscopic appendectomy, and those requiring open surgery tend to experience prolonged stay in hospital due to more severe disease at baseline, greater need for post-operative pain management, slower return of gastrointestinal function, etc.)
- Non-perforated appendicitis (since children with non-perforated appendicitis do not require post-operative antibiotics)
- Confirmed or suspected allergy to penicillins or cephalosporins (since allergic reactions would compromise safety and necessitate switching post-operative antibiotics to non-study alternatives)
- Renal impairment (since PT may be associated with increased odds of acute kidney injury in critically ill children [19]. Moreover, renal dysfunction alters drug clearance, potentially leading to toxicity or adverse drug reactions [20])
- Weight less than 10 kilograms (since small children have unique physiological and clinical conditions [21]. Antibiotic dosing protocols may not be generalizable to the broader pediatric population)
Interventions
Participants will be randomized to receive one of the following post-operative antibiotic regimens:
- Piperacillin/tazobactam 100 mg/kg IV q8h (to a maximum of 4.5 g IV q8h) and normal saline (i.e., placebo) once daily.
- Ceftriaxone 50 mg/kg IV once daily (to a maximum of 2 g IV daily) and metronidazole 10 mg/kg IV q8h (to a maximum of 500 mg IV q8h).
To maintain blinding, all study participants will receive one study treatment every 8 hours (either PT or metronidazole) and one study treatment every 24 hours (either ceftriaxone or normal saline).
Outcomes
Feasibility outcomes.
The feasibility outcomes for the pilot study include:
- Recruitment rate (i.e., mean number of participants randomized per month)
- Consent rate (i.e., number of participants who consent to participate divided by those who are approached for consent)
- Rate of protocol violations (i.e., 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)
- Rate of loss to follow-up (i.e., number of participants who cannot be contacted by phone 3 months after discharge from hospital divided by those randomized)
- Study costs per participant randomized (i.e., total cost of pilot study in Canadian dollars divided by the number of participants randomized)
Our criteria for feasibility are recruitment rate ≥1 new participant per month, consent rate >30%, rate of protocol violations <20%, rate of loss to follow-up <20%, and study costs <3000 Canadian dollars per participant randomized. A similar RCT of children with appendicitis reported a consent rate of 50% [22]. This increased from 38% to 72% throughout the course of the study with focused training of clinical and research personnel.
Progression criteria will serve as key benchmarks to evaluate the feasibility of conducting a larger RCT. While each criterion is important, we recognize that feasibility is a multifaceted assessment and we will not base the decision to proceed on any single factor.
Primary clinical outcome.
The primary outcome for the multicenter RCT is length of stay in hospital. This is because patients who respond to post-operative antibiotics typically remain in hospital for 5 days or less. Patients who experience prolonged stays in hospital often do so because of persistent infectious symptoms. These include fever, abdominal pain, diarrhea, and/or poor oral intake. The treatment of this subset of patients includes prolonged IV antibiotics, post-operative imaging, possible percutaneous drain insertion, PICC line insertion, and/or parenteral nutrition. This often results in a length of one to two weeks (or longer).
Secondary clinical outcomes.
Another goal of the pilot study is to ensure that we can reliably assess secondary outcomes. These are likely to be affected by the type of antibiotic therapy and have been used in other trials of children with perforated appendicitis. The secondary outcomes include:
- Post-operative imaging (i.e., ultrasound or computed tomography)
- Deep or organ-space SSI (i.e., intra-abdominal abscess formation) [23]
- Percutaneous drain insertion
- Clostridioides difficile infection (confirmed with stool sample and requiring treatment)
- Parenteral nutrition
- PICC line insertion
- Return to the emergency department within 30 days of surgery
- Readmission to hospital within 30 days of surgery
Patient-reported outcomes.
The Research Coordinator for this study will phone participant family members 3 months after discharge to ensure that they have not experienced any additional complications related to perforated appendicitis. Family members will also complete a questionnaire by phone regarding patient satisfaction and rank the relative importance of the primary and secondary outcomes.
Sample size for pilot study
The sample size of the pilot study will be 16 participants (i.e., 8 per treatment arm). This number is approximately 10% of the total sample size for the multicenter RCT and should be sufficient to assess feasibility and cost [24–26].
Sample size for multicenter trial
The sample size for the multicenter RCT is 180 participants (i.e., 90 per treatment arm). In our recent quality assurance project, the average length of stay for participants treated with PT only (n = 23) was 5.9 days (standard deviation 2.9 days), compared to 6.9 days (standard deviation 4.2 days) for those who received CM first (n = 32) [18]. The standard deviation for the entire sample (n = 71) was 3.8 days [18].
A parallel two-group design will be used to test whether the PT location (distribution center) is different from the CM location (H0: μ1 - μ2 = 0 versus H1: μ1 - μ2 ≠ 0). The comparison will be made using a two-sided, two-sample Mann-Whitney U test, with a Type I error rate (α) of 0.05. The common standard deviation for both groups is assumed to be 3.8, and the underlying data distribution is assumed to be Normal. To detect a difference in means of 2 with 90% power, the number of needed subjects will be 81 in Group 1 and 81 in Group 2. The sample size was computed using PASS 2024, version 24.0.5. Assuming a dropout rate of approximately 10%, we plan to increase the total sample size to 180 participants.
Recruitment
Participants for the ALPACA trial will be identified by the attending pediatric surgeon or pediatric surgical fellow. After consent is obtained for surgery (i.e., “laparoscopic possibly open appendectomy”), the patient and family will be asked if they are agreeable to learn more about the study. If so, they will be approached by a member of the research team for possible study enrollment. Informed consent will be obtained from the parent or legal guardian. Participants who are not consented before surgery will not be enrolled. Assent will be obtained from the patient whenever possible.
Patients who decline to participate will receive usual clinical care. This includes pre-operative IV antibiotics followed by laparoscopic appendectomy. If the appendix is not perforated during surgery, the patient will be discharged home. Conversely, if the appendix is found to be perforated, patients will receive PT or CM post-operatively (with the type of antibiotics left to the discretion of the attending pediatric surgeon).
Patients and families who consent to participate in the ALPACA trial will also proceed with surgery as per usual clinical care. If the appendix is found to be perforated at the time of surgery, they will then be randomized to receive PT or CM post-operatively. If the appendix is not perforated, the patient will not be randomized or receive any study treatments. They will return to usual clinical care, which typically involves being discharged home with no further oral antibiotics.
Randomization
Participants will be randomized to treatment groups using a computer-generated randomization list. This will consist of random blocks of multiple sizes ranging from 2 to 6 individuals, created by a biostatistician. Participants will be randomized in a 1:1 parallel design, with an equal chance of being allocated PT or CM.
Concealment mechanism
The randomization scheme will be housed in Research Electronic Data Capture (REDCap), a secure web-based application [27]. Participants will be randomized by the research pharmacy at McMaster Children’s Hospital once they have been enrolled in the study, assuring allocation concealment from study investigators and the clinical team. The inpatient pharmacist will possess a study key to determine which study arm the patient is assigned to. The assigned treatments will be crosschecked against the master linkage key at the end of the study.
Blinding
All participants, caregivers, clinical staff, and outcome assessors will remain blinded throughout the trial. The only reason for emergency unblinding is if a participant develops signs of a moderate to severe allergic reaction (i.e., hives, anaphylaxis, etc.). This will allow the clinical team to determine if the reaction was due to a penicillin (i.e., piperacillin) or cephalosporin (i.e., ceftriaxone). Allergic reactions to IV metronidazole are rare. In addition to unblinding, the participant’s IV antibiotics will be changed to an alternative regimen. At our center, the usual alternative regimen for children with allergies is ciprofloxacin and metronidazole, but the decision will be left to the attending surgeon.
Follow-up
There should be no loss to follow-up while study participants remain in hospital. After discharge, two National Surgical Quality Improvement Program (NSQIP) data abstractors routinely review the electronic medical record of all children who undergo laparoscopic appendectomy for perforated appendicitis. There is a possibility that participants could develop a complication and present to the emergency department at a different hospital. To capture this, our Research Coordinator will call patient families 3 months after discharge from our center.
Data collection
The Research Coordinator will be responsible for storing signed consent forms and entering baseline data. Feasibility outcomes will also be assessed by the Research Coordinator. The NSQIP data abstractors will be responsible for assessing and recording the primary and secondary outcomes.
Data management
All study data will be stored in a REDCap database [27], designed specifically for the purposes of this trial. Data entered into REDCap will be de-identified, with participant identifiers replaced with unique study identification numbers. Any electronic files containing patient identifiers, including the master list linking medical record numbers (MRNs) to study identification numbers, will be password-protected and stored on the secure drive for the Department of Surgery at McMaster University. This drive is protected by the McMaster University firewall, and only research staff directly involved in the conduct of this trial will have access to these files. Paper consent forms will be kept in a locked cabinet within the secure office space for the Department of Surgery. Only research staff directly involved in the conduct of this trial will have access to this cabinet.
To ensure data accuracy, data completeness checks will be conducted throughout the trial. The first check will occur after five participants are randomized, with an additional check upon completion of the pilot study.
Statistical analysis
The purpose of this pilot study is to assess the feasibility of conducting a full-scale RCT. Accordingly, no hypothesis testing will be performed on any of the primary or secondary clinical outcomes, as the study is not powered to detect statistically significant differences. All analyses will be descriptive.
Feasibility outcomes (which include recruitment rate, consent rate, frequency of protocol violations, loss to follow-up, and cost per participant) will be summarized using descriptive statistics. The primary clinical outcome, length of hospital stay, will be described using measures of central tendency and dispersion (mean, median, standard deviation, and range). Secondary outcomes will be summarized as counts and proportions. Patient-reported outcomes (e.g., satisfaction and outcome rankings) will be summarized descriptively using frequencies and proportions.
Cost per participant randomized will be estimated in Canadian dollars. This estimate will include personnel costs associated with consent, randomization, outcome assessment, and pharmacy services. These data will be used to estimate the budget required for recruitment and implementation of the full-scale trial.
All statistical analyses will be performed using SPSS (IBM Corp., Armonk, NY, USA). A summary of each outcome and corresponding summary statistics can be found in Table 1.
Data monitoring
This study will have a Steering Committee. The Steering Committee members will be responsible for overseeing the conduct of the trial. The Steering Committee will meet monthly and will include the study co-investigators from Pediatric Surgery, Pediatric Infectious Disease, and Pediatric Emergency Medicine.
Serious adverse events
SAE reporting will adhere to the guidelines set out by HiREB, which requires reporting of all SAE that are unexpected and related to study treatments (or possibly related). If an unexpected SAE occurs, the Principal Investigator will notify the Data Safety Monitoring Board (DSMB) within 48 hours. The only SAE that will be reviewed by the DSMB are allergic reactions possibly related to study medications. The DSMB will also review any cases of mortality within 30 days of surgery. All unexpected SAEs associated with the drug but are not fatal or life-threatening will be reported to Health Canada within 15 calendar days. Any unexpected SAEs associated with a drug that are fatal or life-threatening will be reported to Health Canada within 7 calendar days, followed by a complete written report within 15 calendar days.
Data Safety Monitoring Board
This study will have a DSMB made up of three healthcare professionals, independent of the Steering Committee, who will monitor patient safety throughout the study. Their role is to review all SAEs that are unexpected and determine if they are related or possibly related to study treatments. The DSMB will submit a summary report to the Steering Committee and HiREB. Based on these reports, the DSMB will recommend either continuing or discontinuing the trial due to harm.
Timeline
At McMaster Children’s Hospital, approximately 60 pediatric patients undergo laparoscopic appendectomy for perforated appendicitis each year. As such, it is estimated that recruitment for the pilot study will require at least one year to complete enrollment. This is based on an estimated recruitment rate of 2–3 participants randomized per month and an estimated consent rate of 50% [22]. Recruitment began on September 9, 2024. A detailed schedule of enrolment, interventions, and assessments for the ALPACA trial can be found in Fig 1. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist can be found in S2 Appendix.
Dissemination
The results of the pilot study will be published in a peer-reviewed journal and presented at relevant academic meetings. These include the annual meeting for the Canadian Association of Pediatric Surgeons and the Canadian Pediatric Society. To improve the quality of reporting, findings will be presented in accordance with the CONSORT 2010 extended statement for randomized pilot and feasibly trials [28].
Confidentiality
Patient medical information will be kept strictly confidential and handled in accordance with Good Clinical Practice (GCP) and the Personal Health Information Protection Act (PHIPA). Only personal identifiers essential for the success of this study will be collected. All data will be anonymized for validation and analysis purposes. Access to de-identified data or the participant master list will be restricted to research staff directly involved in the study.
Discussion
Perforated appendicitis remains a common cause of morbidity among otherwise healthy children [3]. To date, the optimal antibiotic regimen following laparoscopic appendectomy remains uncertain. While one non-blinded RCT suggested improved outcomes with PT [6], three observational studies found no difference [7–9]. These conflicting findings highlight the need for a rigorously designed RCT. Importantly, the prior RCT lacked blinding and allocation concealment, raising concerns about potential bias and limiting the reliability of its conclusions [6].
RCTs are considered the highest level of evidence [29], but their strength depends on methodological rigor, including adequate blinding, allocation concealment, and unbiased outcome assessment [30]. Despite their importance, less than 2% of the pediatric surgical literature is derived from RCTs [31,32], leaving even common conditions such as appendicitis without robust, high-level evidence.
Given the complexity of conducting surgical trials in pediatric populations [33,34], a feasibility study is an essential first step. Challenges include timely identification and enrollment of patients before emergency surgery, obtaining informed consent in urgent settings, maintaining blinding and allocation concealment, and ensuring accurate delivery of study medications. Establishing feasibility in these domains is critical before undertaking a fully powered multicenter RCT.
A unique strength of this pilot study is the inclusion of a post-discharge questionnaire administered to families 3 months after surgery. The questionnaire will capture participants’ perspectives on outcomes they consider most meaningful, identifying areas potentially overlooked by clinical endpoints alone. In doing so, the study seeks to achieve not only methodological rigor but also enhanced clinical and patient-centered relevance.
Finally, this work has important implications for antibiotic stewardship. PT provides broader coverage but risks promoting antimicrobial resistance and unnecessary adverse effects if not demonstrably superior to CM. Establishing whether PT offers true clinical benefit—or simply broader but avoidable exposure—is critical for balancing effectiveness with long-term safety.
To the best of our knowledge, ALPACA will be the first double-blind RCT comparing PT and CM in children with perforated appendicitis. This pilot study will determine whether a full multicenter trial is feasible and, ultimately, whether broad-spectrum therapy is justified in this common pediatric condition.
Acknowledgments
The authors acknowledge and thank the members of the Data Safety and Monitoring Board.
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