By Jake Scott, MD
Assistant Clinical Professor of Medicine, Stanford University
SYNOPSIS: In a pragmatic, open-label, randomized trial conducted at 15 hospitals in the Netherlands, two days of postoperative intravenous antibiotics for complex appendicitis was found to be noninferior to five days in terms of infectious complications and mortality within 90 days.
SOURCE: de Wijkerslooth EML, Boerma EG, van Rossem CC, et al. 2 days versus 5 days of postoperative antibiotics for complex appendicitis: A pragmatic, open-label, multicentre, non-inferiority randomised trial. Lancet 2023;401:366-376.
The antibiotics following appendicectomy in complex appendicitis (APPIC) trial, which was conducted at 15 hospitals in the Netherlands, compared two days of postoperative intravenous (IV) antibiotic treatment to five days of treatment. Complex appendicitis, which accounts for roughly 20% to 30% of appendicitis cases at the time of presentation, was defined by the study authors as the intraoperative identification of necrosis, perforation, or abscess. This pragmatic, open-label, randomized controlled trial assessed whether two days of IV antibiotics was noninferior to five days of antibiotics, using a noninferiority margin of 7.5%. A composite endpoint of infectious complications and mortality within a 90-day postoperative period was chosen as the primary endpoint. Secondary endpoints included the duration of postoperative antibiotics, rates of intra-abdominal abscess and surgical site infections, all postoperative complications, hospital readmission, length of hospital stay, number and types of postoperative imaging studies, and costs.
Participants diagnosed with complex appendicitis who were at least 8 years of age and who had adequate source control achieved during surgery were eligible for inclusion. Patients were excluded if they had an American Society of Anesthesiologists (ASA) classification of IV (i.e., patient with severe systemic disease that is a constant threat to life) or higher, or if they were pregnant, immunocompromised, or had a contraindication to the trial drugs. Participants were randomized within 24 hours of appendectomy in a 1:1 ratio to either two days or five days of post-operative antibiotics, which included cefuroxime (1,500 mg three times daily) or ceftriaxone (2,000 mg once daily), in combination with metronidazole (500 mg three times daily). Treating physicians and patients were not masked to the group allocation.
The two groups were well matched in terms of baseline characteristics, duration of symptoms, vital signs, preoperative management, type of surgical procedure performed, operating time, and operative findings. The majority (89%) of patients were 18 years of age or older, and the mean age was 51 years. Fifty-seven percent of patients were male, and the mean body mass index was 26 kg/m2. The baseline health status of patients, as determined by ASA classification, was matched between the groups: 47% of patients in each group had an ASA classification of I (i.e., normal healthy patient) and 43% had a classification of II (i.e., patient with mild systemic disease without substantive functional limitations). Only 10% in each group had an ASA classification of III (i.e., patient with severe systemic disease with substantive functional limitations). The mean duration of baseline symptoms was two days in both groups. Slightly more patients in the five-day group were found to have had gangrenous appendicitis compared to the two-day group — 283 (56%) of 503 vs. 264 (53%) of 502 patients, respectively. Most patients in both groups had localized pus or peritonitis (84% in the two-day group and 87% in the five-day group); diffuse peritonitis was only noted in 10% in the two-day group and 9% in the five-day group.
The intention-to-treat (ITT) analysis included 1,005 patients — 502 in the two-day group and 503 in the five-day group. Adherence to the study protocol was 86% in the two-day group and 92% in the five-day group. The primary endpoint occurred in 51 (10%) of 502 patients in the two-day group and 41 (8%) of 503 in the five-day group; the absolute risk difference, adjusted for age and appendicitis severity, was 2.0% (95% confidence interval [CI], -1.6 to 5.6). Postoperative intra-abdominal abscesses were found in 43 (9%) of 502 patients in the two-day group and 36 (7%) of 503 patients in the five-day group, and surgical site infections were found in 10 (2%) vs. five (1%) patients, respectively. One patient in the two-day group died on postoperative day 84 from metastatic esophageal cancer complications; there were no treatment-related deaths. A total of 955 (95%) of the 1,005 patients in the ITT analysis underwent laparoscopic procedures. Only 50 (5%) of the 1,005 patients underwent open appendectomy — 22 (4.4%) of 502 patients in the two-day group and 28 (5.6%) of 503 patients in the five-day group. For those patients who underwent laparoscopic appendectomy, there was no statistically significant association between treatment allocation and the primary endpoint (adjusted odds ratio [OR], 1.128 [95% CI, 0.719 to 1.769]; P = 0.599). Allocation to the two-day group was reported to be an independent predictor of infectious complications among the small subgroup of patients who underwent open appendectomy (OR, 10.825; 95% CI, 1.231 to 95.201); six (27%) of 22 patients in the two-day group developed an infectious complication, compared to one (4%) of 28 patients in the five-day group.
There was no significant difference between the two-day and five-day groups in rates of re-interventions, in terms of any re-intervention (6% vs. 4%; OR, 1.563 [0.888 to 2.749]), percutaneous drainage (4% vs. 3%; OR, 1.402 [0.679 to 2.892]), or re-operation (3% vs. 2%; OR, 1.518 [0.676 to 3.413]). The median length of hospital stay was two days shorter in the two-day group (3.0 days vs. 5.0 days), and fewer patients in the two-day group were observed to have had adverse effects attributed to antibiotics (9% in the two-day group compared to 22% in the five-day group). A greater portion of patients in the two-day group had complications that required hospital readmission compared to those in the five-day group — 50 (13%) of 388 patients in the two-day group and 26 (7%) of 387 patients in the five-day group (unadjusted OR, 2.054; 95% CI, 1.250 to 3.375). Of note, one-third of readmissions in the two-day group occurred within five days of appendectomy.
COMMENTARY
Acute appendicitis is the most common abdominal surgical emergency in the world, occurring most frequently in the second and third decades of life, with a lifetime risk of 8.6% in men and 6.7% in women.1 For complex appendicitis, achieving adequate source control surgically is essential but can be challenging. Postoperative infectious complications occur in approximately 20% of cases.2 There has been little consensus on the optimal duration of postoperative antibiotic therapy for complex appendicitis because of a paucity of consistent and robust data.3 When adequate source control has been achieved, guidelines typically recommend four to seven days of antibiotics in patients who have appropriate clinical responses.
In a Dutch observational cohort study of 267 patients with complicated appendicitis, there was no significant difference in terms of intra-abdominal abscesses or wound infections in those treated with three days of postoperative antibiotics compared to patients who were given five days of antibiotics.4
Restricting the administration of antibiotic therapy to the shortest duration necessary for maximum efficacy is a core element of antimicrobial stewardship, yet the optimal duration of therapy is a moving target. This study by de Wijkerslooth and colleagues provides good evidence that there are important benefits provided by a short, two-day course of postoperative antibiotics for patients with complicated appendicitis who undergo laparoscopic appendectomy with successful source control compared to a longer, five-day course, and that shorter courses are relatively safe. The findings of this trial pertain mainly to relatively healthy immunocompetent adults who have access to well-resourced healthcare facilities that can provide rapid preoperative diagnoses and perform laparoscopic procedures, and can promptly identify and manage postoperative complications. Further similar studies are needed in low- and middle-income settings and in patients who are immunocompromised.
REFERENCES
- Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol 1990;132:910-925.
- Inui T, Haridas M, Claridge JA, Malangoni MA. Mortality for intra-abdominal infection is associated with intrinsic risk factors rather than the source of infection. Surgery 2009;146:654-661.
- Ramson DM, Gao H, Penny-Dimri JC, et al. Duration of post-operative antibiotic treatment in acute complicated appendicitis: Systematic review and meta-analysis. ANZ J Surg 2021;91:1397-1404.
- van Rossem CC, Schreinemacher MHF, Treskes K, et al. Duration of antibiotic treatment after appendicectomy for acute complicated appendicitis. Br J Surg 2014;101:715-719.
