Antibiotics vs Appendectomy for Appendicitis: What the Evidence Shows
A synthesis of 12+ randomised trials — including the landmark CODA trial (n=1,552) and a 2025 individual patient data meta-analysis — examining when antibiotics can safely replace surgery and which patients still need the operating room — through 2025.
This is an original evidence synthesis. See References for source studies.
One-Minute Takeaway
One-Minute Takeaway
- The CODA trial (n=1,552) — the largest RCT on this question — found that antibiotics were noninferior to appendectomy for 30-day health status in adults with imaging-confirmed appendicitis. However, 29% of antibiotic-treated patients required appendectomy within 90 days, rising to approximately 46% by 2 years.
- A 2025 individual patient data meta-analysis across multiple RCTs confirmed that antibiotic treatment is safe but less definitive than surgery, with 1-year treatment success of approximately 74% for antibiotics versus 98% for appendectomy.
- The presence of an appendicolith is the single most important predictor of antibiotic failure: in the CODA trial, 41% of patients with an appendicolith required surgery within 90 days versus 25% without, with a significantly higher complication rate (20.2 vs 3.7 per 100 patients).
- Antibiotic-treated patients missed approximately 3.5 fewer workdays than surgical patients — a practical benefit that matters for shared decision-making, especially when patients prioritise avoiding or delaying surgery.
- The American College of Surgeons now describes antibiotic therapy as an accepted first-line treatment for appendicitis, but the evidence does not yet clarify whether delayed appendectomy after failed antibiotics carries higher risk than primary surgery.
Why This Topic Matters
Appendectomy has been the standard treatment for acute appendicitis for over 120 years and remains the most common emergency abdominal operation globally. Yet the question of whether all patients with appendicitis truly need surgery has been debated for decades — and the evidence base has shifted substantially in recent years. The COVID-19 pandemic accelerated interest in non-operative management, as health systems sought to conserve surgical resources, and professional societies including the American College of Surgeons endorsed antibiotic therapy as a reasonable alternative.
The clinical stakes are significant. Appendicitis affects approximately 300,000 people annually in the United States alone, and globally it is among the most resource-intensive surgical conditions. The key question is no longer simply whether antibiotics can work — multiple RCTs confirm they can — but rather for which patients, under what circumstances, and with what long-term trade-offs. This synthesis examines the evidence to help clinicians and patients navigate this increasingly nuanced decision.
What Evidence Was Reviewed
This synthesis draws on the CODA trial and its longer-term follow-up data, the APPAC trial from Finland, a definitive 2025 individual patient data meta-analysis published in The Lancet Gastroenterology & Hepatology, multiple aggregate meta-analyses of RCTs, and the 2020 WSES guidelines on acute appendicitis. Together, these sources encompass over 3,000 randomised patients across multiple countries and healthcare systems, with follow-up extending to 4–5 years in some cohorts.
| Study | Design | n | Population | Key Finding | Quality |
|---|---|---|---|---|---|
| CODA Collaborative 2020 (NEJM) | Multicentre RCT | 1552 | Adults with imaging-confirmed appendicitis (incl. appendicolith) | Antibiotics noninferior at 30 days; 29% had appendectomy by 90 days; appendicolith increased complications | High |
| CODA Longer-Term 2021 (NEJM) | Follow-up of RCT | 1552 | Same cohort as above | 40% appendectomy at 1 year, 46% at 2 years; ~50% at 4 years; complications rare after 30 days | High |
| Salminen et al. 2015 (APPAC, JAMA) | Multicentre RCT | 530 | CT-confirmed uncomplicated appendicitis (no appendicolith) | 73% success with antibiotics at 1 year; long-term follow-up showed 39% eventual appendectomy at 5 years | High |
| Scheijmans et al. 2025 (Lancet GH IPD-MA) | Individual patient data MA | NR | Adults from multiple RCTs | Uniform definitions confirmed antibiotics safe but less effective; appendicolith key predictor of failure | High |
| Podda et al. 2024 (WJES MA + TSA) | MA of 8 RCTs + trial sequential analysis | 3213 | Adults with uncomplicated appendicitis | Antibiotics safe but less effective (RR 0.80); 1-year success 64.6%; similar complications; TSA suggests no further RCTs will change findings | High |
| Li et al. 2023 (BMC Surgery MA) | MA of 12 RCTs | NR | Adults with uncomplicated appendicitis | 1-year complication-free success lower for antibiotics (RR 0.81); appendicolith associated with treatment failure | Moderate |
| Herrod et al. 2022 (BJS Open MA) | MA of 8 RCTs | 3203 | Adults with uncomplicated appendicitis | Earlier complication advantage of antibiotics no longer significant with newer laparoscopic trials | High |
| Long-term Outcomes MA 2024 | MA of 7 RCTs | 3164 | Adults, imaging-confirmed | 1-year success: antibiotics 73.8% vs surgery 98.1%; appendicolith failure up to 46% | Moderate |
Key Findings on Antibiotics vs Appendectomy: Synthesised by Theme
Short-Term Safety: Antibiotics Are Noninferior for Health Status
The CODA trial — the largest and most inclusive RCT on this question — randomised 1,552 adults across 25 US centres to receive either a 10-day antibiotic course or appendectomy. The primary outcome, 30-day health status measured by the EQ-5D, was equivalent between groups (0.92 vs 0.91, difference 0.01, consistent with noninferiority). This finding held in both per-protocol analysis and across subgroups with and without appendicolith. The APPAC trial from Finland and multiple European RCTs have reported similar short-term safety profiles.
However, the CODA data also revealed important nuances. Complications were more common overall in the antibiotics group (8.1 vs 3.5 per 100 participants; rate ratio 2.28), and emergency department visits were approximately double (8.9% vs 4.3%). Crucially, the higher complication rate was almost entirely attributable to patients with an appendicolith (20.2 vs 3.6 per 100) — among those without an appendicolith, complication rates were nearly identical between groups (3.7 vs 3.5 per 100). Antibiotic-treated patients missed significantly fewer workdays (5.3 vs 8.7 days), a practical advantage that is relevant for shared decision-making.
Long-Term Efficacy: A Substantial Proportion Eventually Need Surgery
The longer-term CODA follow-up data, published in the New England Journal of Medicine, showed that among patients initially treated with antibiotics, appendectomy rates rose steadily over time: 40% by 1 year, 46% by 2 years, and approximately 50% by 4 years. The APPAC trial reported a 39% appendectomy rate at 5 years among antibiotic-treated patients. Pooled meta-analyses consistently report 1-year complication-free treatment success of approximately 65–74% for antibiotic therapy versus over 98% for appendectomy.
The 2024 meta-analysis with trial sequential analysis by Podda and colleagues is particularly informative: it concluded that antibiotics are safe and less expensive but definitively less effective than appendectomy (RR 0.80, 95% CI 0.71–0.90, p < 0.00001), and that trial sequential analysis suggests future RCTs are unlikely to change this conclusion. The Herrod et al. 2022 meta-analysis added an important observation: the complication advantage that earlier meta-analyses attributed to antibiotic treatment has been eroded as newer trials have used laparoscopic appendectomy rather than open surgery, narrowing the gap between operative and non-operative approaches.
The Appendicolith Question: The Critical Patient Selection Variable
Across the evidence base, the presence of an appendicolith on cross-sectional imaging emerges as the single most consistent predictor of antibiotic treatment failure. In the CODA trial, patients with an appendicolith had a 41% appendectomy rate by 90 days versus 25% without, with complications 5.7 times higher than in the surgical group (20.2 vs 3.6 per 100; rate ratio 5.69, 95% CI 2.11–15.38). The 2024 meta-analysis confirmed a positive correlation between appendicolith prevalence and antibiotic failure rate on meta-regression.
The 2025 individual patient data meta-analysis by Scheijmans and colleagues was specifically designed to address the variability in patient inclusion across trials, and consistently found that appendicolith status was the most important modifier of treatment effect. This has direct implications for clinical practice: when a CT scan reveals an appendicolith, the evidence strongly supports proceeding with appendectomy rather than offering antibiotic therapy.
In patients with imaging-confirmed uncomplicated appendicitis and no appendicolith, antibiotic treatment produces outcomes that are closest to those of surgery. In the CODA trial, this subgroup had comparable complication rates (3.7 vs 3.5 per 100), a 25% appendectomy rate at 90 days, and a similar perforation rate when appendectomy was eventually performed (14% vs 13%). These patients represent the population most suitable for a genuine shared decision-making discussion, where the trade-offs between avoiding surgery (fewer missed workdays, no surgical risk) and the possibility of recurrence (approximately 1 in 4 within 90 days) can be meaningfully weighed by the patient.
For patients with an appendicolith identified on CT, the evidence consistently favours appendectomy. This subgroup accounts for approximately 25–30% of appendicitis presentations. The CODA trial demonstrated a 41% appendectomy rate within 90 days, a complication rate nearly six times higher than the surgical group, and a substantially higher perforation rate (61% vs 24%) when delayed appendectomy was eventually performed. Although the CODA trial showed noninferiority on the primary health status measure even in this subgroup, the secondary outcome data strongly suggest that appendicolith-positive patients are poorly served by an antibiotics-first strategy. The 2024 meta-regression confirmed this finding across trials.
The RCT evidence for antibiotics versus surgery applies primarily to uncomplicated appendicitis. Patients with perforation, abscess formation, generalised peritonitis, or sepsis were excluded from most trials and should continue to be managed surgically. The 2020 WSES guidelines specifically recommend appendectomy as the primary treatment for complicated appendicitis. In the subset of patients with a contained periappendicular abscess, initial drainage and antibiotics followed by interval appendectomy remains an established approach, but this is a distinct clinical scenario from the antibiotics-first strategy studied in the major RCTs.
A 2025 meta-analysis of 5 RCTs involving 1,423 paediatric patients examined non-operative management for uncomplicated appendicitis in children. The findings showed significantly higher initial treatment failure rates with antibiotics (OR 3.14, 95% CI 2.10–4.71) and higher 1-year post-discharge failure rates compared with surgery. While quality of life appeared similar between groups in the short term, the evidence base remains smaller and less mature than for adults. The CODA investigators have noted that dedicated paediatric trials are ongoing but have not yet reported definitive long-term results. Caution is warranted in extrapolating adult data to children, given differences in appendicitis pathophysiology, diagnostic accuracy, and the practical challenges of antibiotic adherence in younger populations.
The Evolving Context: Laparoscopy Changes the Calculus
An important insight from the most recent meta-analysis by Herrod and colleagues is that the advantage of antibiotic treatment over surgery has narrowed as laparoscopic appendectomy has become the dominant surgical approach. In older trials — particularly the APPAC trial, where 100% of appendectomies were open — antibiotics showed a clearer advantage in terms of post-treatment complications and hospital stay. In the three largest recent RCTs (including CODA), where 90–100% of appendectomies were laparoscopic, this advantage has essentially disappeared. This suggests that the relevant comparison for contemporary practice is antibiotics versus laparoscopic (not open) appendectomy — and in that comparison, the clinical outcomes are much closer than previously appreciated.
Quality & Consistency of Evidence
What the Evidence Does Not Show
Despite the substantial evidence base, several clinically important questions remain unanswered.
Whether delayed appendectomy after failed antibiotic therapy carries greater surgical risk than primary appendectomy has not been addressed by a dedicated randomised comparison. The CODA trial observed higher perforation rates in the appendicolith subgroup who underwent delayed surgery, but this was not a prespecified primary comparison and is subject to confounding. Additionally, CT-based diagnosis of uncomplicated versus complicated appendicitis is imperfect — a recent systematic review estimated CT sensitivity for complicated appendicitis at only 78%, meaning some patients classified as "uncomplicated" may harbour unrecognised perforation or abscess.
The long-term oncological implications of avoiding appendectomy are not well characterised. Appendiceal neoplasms are rare but real — the CODA trial did not systematically report on incidental pathological findings. The risk of missing an appendiceal malignancy with an antibiotics-first approach remains theoretical but unquantified. Furthermore, the optimal antibiotic regimen (choice of agent, duration, inpatient versus outpatient initiation) is not standardised across trials. In the CODA trial, 47% of antibiotic-treated patients were managed entirely as outpatients, but this proportion varied widely across centres, and the evidence does not yet identify which patients can be safely discharged from the emergency department.
Practical Implications
Based on the current evidence, the following considerations emerge for clinicians managing patients with acute appendicitis.
Evidence Grade + Bottom Line
Overall Evidence Grade: Strong
The comparison of antibiotics versus appendectomy for acute appendicitis is supported by the CODA trial (n=1,552), a 2025 individual patient data meta-analysis, and trial sequential analysis across 8+ RCTs confirming that the core findings are robust and unlikely to change. Short-term safety of antibiotics is well-established; lower long-term efficacy is equally well-established. Appendicolith as a predictor of failure is consistently replicated.
A "strong" evidence grade reflects that the central question — can antibiotics safely treat uncomplicated appendicitis? — has been answered: yes, in selected patients, with trade-offs. The remaining questions involve refining patient selection, understanding long-term oncological implications, and optimising antibiotic protocols. The clinical challenge has shifted from evidence generation to evidence application through effective shared decision-making.
- Antibiotics are noninferior to appendectomy for short-term health status in imaging-confirmed uncomplicated appendicitis, but approximately 25–50% of patients eventually require surgery within 2–4 years.
- Appendicolith on imaging is the strongest predictor of antibiotic failure and is associated with a 5- to 6-fold increase in complications — these patients are best served by appendectomy.
- The complication advantage of antibiotics over surgery has narrowed as laparoscopic appendectomy has become standard, reducing the margin between the two approaches.
- Shared decision-making is essential: patients who prioritise avoiding surgery and accepting recurrence risk may reasonably choose antibiotics; those who prioritise definitive treatment should undergo appendectomy.
- The evidence does not yet clarify the long-term oncological risk of avoiding appendectomy, the safety of delayed surgery after antibiotic failure, or the optimal outpatient antibiotic protocol.
Article Information
For Educational Purposes Only. This is an original evidence synthesis informed by the studies listed below. It does not replace clinical judgement. Drug dosages should be verified against current prescribing information.
References
- CODA Collaborative; Flum DR, Davidson GH, Monsell SE, et al. A randomized trial comparing antibiotics with appendectomy for appendicitis. N Engl J Med. 2020;383(20):1907–1919. DOI: 10.1056/NEJMoa2014320
- Davidson GH, Flum DR, Talan DA, et al. Antibiotics versus appendectomy for acute appendicitis — longer-term outcomes. N Engl J Med. 2021;385(25):2395–2397. DOI: 10.1056/NEJMc2116018
- Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA. 2015;313(23):2340–2348. DOI: 10.1001/jama.2015.6154
- Scheijmans JCG, Haijanen J, Flum DR, et al. Antibiotic treatment versus appendicectomy for acute appendicitis in adults: an individual patient data meta-analysis. Lancet Gastroenterol Hepatol. 2025;10(3):222–233. DOI: 10.1016/S2468-1253(24)00349-2
- Podda M, et al. A meta-analysis and trial sequential analysis comparing nonoperative versus operative management for uncomplicated appendicitis. World J Emerg Surg. 2024;19:3. DOI: 10.1186/s13017-023-00531-6
- Li Z, et al. Comparison of the efficacy and safety of antibiotic treatment and appendectomy for acute uncomplicated appendicitis: a systematic review and meta-analysis. BMC Surg. 2023;23:210. DOI: 10.1186/s12893-023-02108-1
- Herrod PJJ, Kwok AT, Lobo DN. Randomized clinical trials comparing antibiotic therapy with appendicectomy for uncomplicated acute appendicitis: meta-analysis. BJS Open. 2022;6(4):zrac100. DOI: 10.1093/bjsopen/zrac100
- Di Saverio S, Podda M, De Simone B, et al. Diagnosis and treatment of acute appendicitis: 2020 update of the WSES Jerusalem guidelines. World J Emerg Surg. 2020;15:27. DOI: 10.1186/s13017-020-00306-3
- Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011;377(9777):1573–1579. DOI: 10.1016/S0140-6736(11)60410-8
- Wang Y, et al. The safety and efficacy of appendectomy, endoscopic retrograde appendicitis therapy, and antibiotic treatment for acute uncomplicated appendicitis: a systematic review and network meta-analysis of RCTs. BMC Surg. 2025;25:435. DOI: 10.1186/s12893-025-02750-x