CODA study - Antibiotics vs Appendectomy for Acute Appendicitis, NEJM (2020) [PubMed abstract]
  • The CODA study enrolled 1552 adults presenting to the ER with acute appendicitis confirmed by imaging
Main inclusion criteria
  • Age ≥ 18 years
  • Acute appendicitis confirmed on imaging
Main exclusion criteria
  • Septic shock
  • Diffuse peritonitis
  • Evidence of severe phlegmon on imaging
  • Walled-off abscess
  • Free air or more than minimal free fluid
Baseline characteristics
  • Average age 38 years
  • Male sex - 63%
  • Average duration of symptoms - 1.7 days
  • Presence of appendicolith - 27%
Randomized treatment groups
  • Group 1 (776 patients): IV antibiotics for at least 24 hours followed by 10 days of oral antibiotics
  • Group 2 (776 patients): Surgical appendectomy
  • Most common antibiotic regimens used for IV therapy were one of the following:
    • Ertapenem
    • Cefoxitin
    • Metronidazole + ceftriaxone, cefazolin, or levofloxacin
  • Most common antibiotics used for oral therapy were metronidazole plus either ciprofloxacin or cefdinir
  • Patients in the antibiotic group were discharged from the emergency department after they had received intravenous antibiotics for 24 hours or with 24 hours of bioavailability. Standard discharge criteria included intake of liquids without difficulty, adequate pain control, and an improving clinical condition.
Primary outcome: 30-day health status, as assessed with the use of the European Quality of Life–5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status). Minimal clinically important difference was predetermined to be 0.05 points.

Duration: 90 days
Outcome Antibiotics Appendectomy Comparisons
Primary outcome 0.92 0.91 diff 0.01 (−0.001 to 0.03)
  • By 90 days, 29% of patients in the antibiotics group had undergone appendectomy, including 41% of those with an appendicolith and 25% of those without an appendicolith
  • Serious adverse events, particularly intra abdominal abscess (27 vs 14), sepsis (11 vs 1), and organ/space infection (7 vs 2), were more common in the antibiotics group. The higher rate in the antibiotics group overall was attributable to those with an appendicolith (20.2 vs. 3.6 per 100 participants) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants).
  • In the antibiotic group, 51% of patients were admitted to the hospital for the index treatment, and 47% were discharged from the ER

Findings: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith.

Antibiotics vs Appendectomy for Acute Appendicitis, JAMA (2015) [PubMed abstract]
  • A study published in the JAMA enrolled 530 patients who presented to the ER with acute appendicitis
Main inclusion criteria
  • 18 - 60 years old
  • Acute uncomplicated appendicitis confirmed with CT scan
Main exclusion criteria
  • Complicated appendicitis defined as presence of an appendicolith, perforation, abscess, or suspicion of a tumor on the CT scan
  • Peritonitis
  • Serious systemic illness
Baseline characteristics
  • Average age 34 years
  • Male sex - 62%
  • Duration of symptoms: 1-6 hours - 6% | 6-12 hours - 13% | 12-18 hours - 22% | >18 hours - 58%
Randomized treatment groups
  • Group 1 (273 patients) - Open surgical appendectomy
  • Group 2 (257 patients) - Ertapenem 1 gram IV once daily for 3 days followed by 7 days of levofloxacin 500 mg once daily + metronidazole 500 mg three times a day
  • Patients in Group 1 received a one-time prophylactic dose of 1.5 g of cefuroxime + 500 mg of metronidazole before surgery. After that, antibiotics were only given for wound infections.
Primary outcome: for patients in the antibiotic group, the primary outcome was resolution of acute appendicitis, resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of 1 year. For the surgical group, the primary outcome was successful appendectomy.

Duration: 1 year
  • In the antibiotic group, 70 patients (27.3%, 95% CI [22.0% to 33.2%]) underwent appendectomy within 1 year. Of these 70 patients, 15 had an appendectomy during the initial hospitalization, and 55 had an appendectomy at a later hospitalization (median time of 102 days). Five appendices were normal on histopathology, and there were 7 cases of complicated appendicitis.
  • In the appendectomy group, 99.6% of patients had a successful appendectomy
  • Antibiotic treatment did not meet the prespecified noninferiority margin of 24%

Findings: Among patients with CT-proven, uncomplicated appendicitis, antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy. Most patients randomized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period, and those who required appendectomy did not experience significant complications.
Antibiotics vs Appendectomy for Acute Appendicitis - 5-year follow-up, JAMA (2018) [PubMed abstract]
  • Patients in the original study detailed above were followed for 5 years total and results were published in 2018
  • In the antibiotic group, 39% (85 patients) of patients underwent appendectomy by the end of 5 years. Of these 85 patients, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis
  • Complications (surgical site infections, incisional hernias, abdominal pain, and obstructive symptoms) occurred more frequently in the appendectomy group (24.4%) than in the antibiotic group (6.5%)
Findings: Among patients who were initially treated with antibiotics for uncomplicated acute appendicitis, the likelihood of late recurrence within 5 years was 39.1%. This long-term follow-up supports the feasibility of antibiotic treatment alone as an alternative to surgery for uncomplicated acute appendicitis.

APPAC II trial - Oral Moxifloxacin vs IV Ertapenem + Oral Levofloxacin/Metronidazole for Uncomplicated Acute Appendicitis, JAMA (2021) [PubMed abstract]
  • The APPAC II trial enrolled 599 adults with acute uncomplicated appendicitis
Main inclusion criteria
  • Age 18 - 60 years
  • Uncomplicated appendicitis on CT scan
Main exclusion criteria
  • Presence of appendicolith
  • Perforation
  • Abscess
  • Suspicion of tumor
  • Renal insufficiency
Baseline characteristics
  • Average age 36 years
  • Female sex - 44%
  • Median duration of symptoms - 20 hours
  • Average appendiceal diameter - 10.8 mm
Randomized treatment groups
  • Group 1 (301 patients): Oral moxifloxacin 400 mg once daily for 7 days
  • Group 2 (298 patients): IV ertapenem sodium 1000 mg once daily X 2 days followed by oral levofloxacin 500 mg once daily + metronidazole 500 mg three times a day for 5 days
  • The first dose of the randomized treatment was given in the ER. Patients followed up at the hospital in 20 - 24 hours, and patients randomized to IV therapy were given their second dose.
  • The clinical condition of the patient was evaluated twice daily, approximately 12 hours after admission by the on-call surgeon. If the patient was suspected of not responding to the antibiotic therapy, the patient underwent laparoscopic appendectomy based on the surgeon’s decision.
Primary outcome: Treatment success at 1 year, defined as resolution of acute appendicitis resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during the 1-year follow-up

Duration: 1 year
Outcome Moxifloxacin Ertapenem + Levo/Metro Comparisons
Primary outcome 70% 73.8% p=0.26
Length of primary hospital stay 28.9 hours 29.9 hours p=0.38
Overall mortality 0% 0% N/A
  • Out of the entire study population, 29 patients failed initial antibiotic therapy and required surgery during their initial appendicitis episode. A secondary analysis of these 29 patients found that appendiceal diameter ≥ 15 mm and fever > 100.4°F (38°C) were the two main predictors of antibiotic failure. [PMID 34613361]

Findings: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics.