One Versus Five Days of Antibiotics After Appendectomy (SSI-IAA)

Background and Rationale

Acute appendicitis remains one of the most common indications for emergency abdominal surgery worldwide. While perioperative prophylactic antibiotics are universally recommended for appendectomy, the optimal duration of postoperative antibiotic therapy for uncomplicated (non-perforated, non-gangrenous) acute appendicitis remains poorly defined. Current clinical practice varies widely, with some surgeons prescribing no postoperative antibiotics, others recommending 24 hours of therapy, and many continuing a traditional five- to seven-day course. This variation persists despite growing evidence that prolonged antibiotic exposure may offer no additional clinical benefit while increasing the risks of antimicrobial resistance, adverse drug events, Clostridioides difficile infection, and healthcare costs.

Antimicrobial resistance has been declared a top global public health threat by the World Health Organization, with estimates suggesting 10 million annual deaths attributable to AMR by 2050. Surgical specialties, including general surgery, have been identified as high-priority targets for antimicrobial stewardship interventions due to historically high rates of antibiotic prescribing. Shortening postoperative antibiotic courses when clinically appropriate represents a key stewardship strategy that can reduce selective pressure on resistant organisms while maintaining or improving patient outcomes.

Study Objectives

Primary Objective:

To demonstrate that 24 hours of postoperative intravenous antibiotics is non-inferior to a five-day regimen (one day intravenous followed by four days oral) in preventing a composite outcome of infectious complications (surgical site infection or intra-abdominal abscess) following appendectomy for uncomplicated acute appendicitis.

Study Design

This is a prospective, randomized controlled, open-label (non-blinded), non-inferiority trial. A non-inferiority design was selected because shortening antibiotic duration is expected to offer important secondary benefits (reduced side effects, lower cost, decreased antimicrobial resistance selection pressure) even if it is not superior to the longer course. The non-inferiority margin is set at 5%, meaning the one-day regimen will be considered non-inferior if the upper bound of the 95% confidence interval for the difference in primary outcome rates (five-day minus one-day) is less than 5 percentage points.

Study Setting

The trial will be conducted in the General Surgery Department at Fayoum General Hospital, Fayoum, Egypt. This is a tertiary care hospital serving a mixed urban and rural population. All appendectomy procedures will be performed by or under the supervision of attending general surgeons within the department.

Participant Enrollment and Consent

Potential participants will be identified upon admission to the General Surgery Department with a diagnosis of acute appendicitis. After surgical evaluation and decision to proceed with appendectomy, eligible patients (or their legally authorized representatives, for minors aged 10-17 years) will be approached by a study investigator or trained research coordinator. The study will be explained in full, and written informed consent will be obtained prior to any study-related procedures, including randomization. For participants under 18 years of age, parental or guardian consent will be required, and assent will be obtained from the minor participant when appropriate to their developmental level. The informed consent form has been approved by the institutional review board and includes all required elements per local regulations and international ethical guidelines.

Randomization and Allocation

Eligible and consented participants will be randomly assigned in a 1:1 ratio to either the short-course (24-hour) or standard-course (five-day) antibiotic regimen. Randomization will be performed using computer-generated random numbers created in R. The allocation sequence will be generated by a biostatistician not involved in participant recruitment or outcome assessment. Allocation concealment will be achieved using sequentially numbered, opaque, sealed envelopes. Envelopes will be opened by the treating physician only after the participant has been confirmed eligible and enrolled.

Blinding

This is an open-label trial. Blinding of participants or treating clinicians to antibiotic duration is not feasible due to obvious differences in the duration of intravenous therapy and the transition to oral antibiotics in the five-day arm. However, outcome assessment will be performed by study personnel who are not involved in direct patient care; while they will not be formally blinded to treatment allocation, the primary outcome (surgical site infection, intra-abdominal abscess, or mortality) is objective and unlikely to be influenced by knowledge of assignment. No sham procedures or placebo medications will be used.

Interventions

Short-course arm (experimental):

Participants randomized to the short-course arm will receive intravenous ampicillin/sulbactam (dosage according to hospital formulary and weight-based guidelines) for a total duration of 24 hours following completion of the appendectomy procedure. No oral antibiotics will be prescribed as part of the study protocol after the 24-hour intravenous period, unless clinically indicated for treatment of a documented postoperative infection.

Standard-course arm (active comparator):

Participants randomized to the standard-course arm will receive intravenous ampicillin/sulbactam for the first 24 hours following appendectomy, using the same dosing regimen as the short-course arm. After completion of 24 hours of intravenous therapy, participants will transition to oral amoxicillin/clavulanic acid (dosage according to hospital formulary) to complete a total antibiotic course of five days (one day intravenous plus four days oral). Oral antibiotics will be administered either in the hospital if the participant remains admitted, or as outpatient therapy if the participant has been discharged.

In both arms, antibiotic selection (ampicillin/sulbactam intravenous, followed by amoxicillin/clavulanic acid oral) follows the Fayoum General Hospital formulary and local antimicrobial susceptibility patterns for community-acquired intra-abdominal infections.

Study Procedures and Participant Timeline

Screening and Baseline (Day 0, pre-randomization):

• Review of inclusion and exclusion criteria
• Informed consent and randomization

Surgery (Day 0):

• Appendectomy performed via open or laparoscopic approach as determined by the attending surgeon
• Intraoperative confirmation of uncomplicated acute appendicitis (non-phlegmonous, non-gangrenous, non-perforated, no abscess)
• If intraoperative findings indicate complicated appendicitis, the participant will be excluded from the trial post-randomization and treated according to standard clinical practice

Intervention Period (Day 0 to Day 5):

• Short-course arm: IV antibiotics for 24 hours, then no further study antibiotics
• Standard-course arm: IV antibiotics for 24 hours, then oral antibiotics for 4 days
• Daily monitoring for adverse events, clinical status, and signs of infection

Follow-up Period (Day 30 post-surgery):

- Post-operative visits at 7, 14, and 30 days to assess surgical site infection (superficial, deep, or organ/space) and intra-abdominal abscess.

Early Termination:

Participants may withdraw from the study at any time for any reason without penalty or loss of medical care. The investigator may also withdraw a participant if continued participation would be unsafe (e.g., development of a serious adverse event, need for prohibited concomitant antibiotics, or intraoperative finding of complicated appendicitis).

Data Collection and Management

Data will be collected by google forms filled by the surgeons. Data points include demographic information, medical history, surgical details (approach, operative findings, duration), antibiotic administration records, daily clinical status, adverse events, and 30-day follow-up outcomes are collected manually by the clinical pharmacist and research coordinators. All data will be entered into a secure, password-protected database. Paper records will be stored in locked filing cabinets in a restricted-access research office at Fayoum General Hospital. Participant confidentiality will be maintained by assigning unique study identification numbers; personal identifiers (name, national ID number) will be stored separately from clinical data.

Missing data will be minimized through standardized data collection procedures and regular audits. For participants lost to follow-up or with incomplete data, multiple attempts at telephone contact will be made. No imputation for missing primary outcome data is planned; a complete-case analysis will be performed, and the potential impact of missing data will be addressed in the limitations section of the final report.

Sample Size Calculation

Assuming a baseline infectious complication rate of 5% in both treatment arms, a non-inferiority margin of 5%, a one-sided alpha of 0.025, and a power of 90%, the required sample size is 100 participants per arm (200 total). This calculation was performed using standard non-inferiority sample size formulas for binary outcomes. Accounting for an anticipated 10% dropout or exclusion rate (e.g., due to intraoperative conversion to complicated appendicitis, withdrawal of consent, or loss to follow-up), the target enrollment is 220 participants (110 per arm). The dropout rate estimate is based on prior surgical trials conducted in similar settings.

Statistical Analysis Plan

Primary Analysis:

The primary analysis will be performed on the intention-to-treat population, which includes all randomized participants regardless of whether they completed the assigned antibiotic regimen or were later found to have complicated appendicitis. The primary outcome (composite of surgical site infection and intra-abdominal abscess) will be compared between two arms. Non-inferiority of the one-day regimen will be declared if the upper limit of this confidence interval is less than 5 percentage points.

Statistical analysis:

1. Univariate analysis is done for different demographic variables for both groups. Categorical variables are expressed as frequencies or proportions and continuous variables are expressed as mean ± SD or median and IQR (with 95% CI) according to the distribution of data
2. Bivariate analysis using Chi-square test for categorical variables. Calculate (RR) ,(OR).
3. Multivariate logistic regression for binary outcomes to adjust for residual potential confounders.
4. Statistical significance is set at p values < 0.05 , Power is set as 80% and apla error 0.05.

Subgroup Analyses (exploratory):

• By age group (10-17 years vs. ≥18 years)
• By sex
• By surgical approach (laparoscopic vs. open)

Interim Analyses:

No formal interim analyses for efficacy or futility are planned due to the relatively short enrollment period and low expected event rate. An independent data safety monitoring committee will review serious adverse events semiannually.

Safety Monitoring

All adverse events, serious adverse events, and suspected unexpected serious adverse reactions will be recorded from the time of randomization through the 30-day follow-up period. Serious adverse events include death, life-threatening events, prolongation of hospitalization beyond expected duration (excluding routine extended stay for antibiotic administration in the standard-course arm), persistent or significant disability, intra-abdominal abscess requiring drainage, reoperation, or readmission. The principal investigator is responsible for reporting all serious adverse events to the institutional review board within 24 hours and to the relevant regulatory authorities per local requirements.

Ethical and Regulatory Considerations

This trial will be conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice guidelines, and all applicable Egyptian national regulations for clinical research. The protocol and informed consent form have been approved by the Institutional Review Board of The Ministry of Health and Population. (approval number: 11-2025/23). Any modifications to the protocol will be submitted as amendments for review and approval prior to implementation.

Dissemination Plan

Results of this trial, regardless of whether the primary hypothesis is demonstrated, will be submitted for publication in a peer-reviewed general medical or surgical journal. Authorship will follow International Committee of Medical Journal Editors guidelines. The complete dataset and statistical code will be made available to other researchers upon reasonable request following publication. There is no plan for commercial distribution of results.

Trial Status

The trial is currently in the pre-enrollment phase. Enrollment is expected to begin following final regulatory approvals and is anticipated to be completed within 12 months. The estimated primary completion date is 30 October 2026.