Antibiotics for Uncomplicated Appendicitis in Adults: What the Evidence Supports
A synthesis of 8 RCTs, the landmark CODA trial, and a 2025 individual patient data meta-analysis of 2,101 patients evaluating antibiotics-first versus appendectomy — clarifying safety, recurrence risk, and the critical role of appendicolith status.
This is an original evidence synthesis. See References for source studies.
One-Minute Takeaway
One-Minute Takeaway
- Antibiotics for uncomplicated appendicitis in adults are a safe alternative to appendectomy — a 2025 individual patient data meta-analysis of 6 RCTs (2,101 patients) found no significant difference in 1-year complication rates using harmonised Clavien-Dindo definitions (Scheijmans et al., Lancet Gastroenterol Hepatol).
- Approximately two-thirds of antibiotic-treated patients avoid appendectomy during the first year; however, at 2 years in the CODA trial, 46% had eventually undergone surgery, and rates approach 49% by 3–4 years.
- Appendicolith status is the strongest identified predictor of antibiotic failure: patients with an appendicolith had a 41–49% appendectomy rate at 90 days in the CODA trial, compared with 25% without appendicolith.
- Delayed appendectomy does not appear to increase the rate of complicated appendicitis beyond the baseline surgical rate (perforation ~20% in both groups), though the risk of missed neoplasm in the non-operated appendix remains an unresolved safety concern.
Why This Topic Matters
Appendectomy has been the standard treatment for acute appendicitis for over a century and remains the most common emergency abdominal procedure worldwide. However, a growing body of randomised evidence — substantially accelerated during the COVID-19 pandemic when surgical resources were constrained — has established antibiotics as a feasible alternative for selected adults with uncomplicated disease. The American College of Surgeons now describes antibiotic treatment as an “accepted first-line treatment” for appropriately selected patients.
Yet the clinical picture is more nuanced than “antibiotics work.” Approximately one-third to one-half of antibiotic-treated patients eventually require appendectomy, and specific subgroups — particularly those with appendicolith — face substantially higher failure rates. This evidence review synthesises the latest data, including the 2025 individual patient data meta-analysis, to clarify which patients are most likely to benefit from non-operative management and where the safety boundaries lie.
What Evidence Was Reviewed
This synthesis draws on the two landmark RCTs (APPAC and CODA), their long-term follow-up publications, the 2025 individual patient data meta-analysis, several aggregate meta-analyses, and secondary analyses examining predictors of antibiotic failure. Studies were included if they randomised adults with imaging-confirmed acute appendicitis to antibiotics versus appendectomy with at least 1-year follow-up.
| Study | Design | n | Population | Key Finding | Quality |
|---|---|---|---|---|---|
| Scheijmans et al. 2025 (Lancet GH) | IPD meta-analysis, 6 RCTs | 2,101 | Adults, imaging-confirmed AA | No difference in 1-yr complications; ~66% avoided surgery; appendicolith: 49% failure | High |
| CODA trial (Flum et al. 2020, NEJM) | Pragmatic multicentre RCT | 1,552 | Adults with/without appendicolith, US | Antibiotics non-inferior (30-day EQ-5D); 29% appendectomy at 90 days | High |
| CODA 2-yr (Davidson et al. 2021, NEJM) | RCT long-term follow-up | 1,552 | CODA cohort | 46% appendectomy at 2 yr; perforation rate comparable at delayed surgery (~20%) | High |
| APPAC (Salminen et al. 2015, JAMA) | Multicentre RCT | 530 | CT-confirmed, no appendicolith, Finland | 73% antibiotic success at 1 yr; 39% appendectomy by 5 yr | High |
| Herrod et al. 2022 (BJS Open) | MA of 8 RCTs | 3,203 | Uncomplicated AA | Complication advantage of antibiotics no longer apparent with laparoscopic surgery | Moderate |
| Prechal et al. 2024 (WJES) | MA + TSA, 8 RCTs | 3,213 | Uncomplicated AA | Antibiotics safe but less effective (65% 1-yr success); TSA confirms stable evidence | Moderate |
| CODA secondary (Davidson et al. 2023) | Exploratory analysis | 776 | CODA antibiotics arm | Baseline severity features not strongly predictive of 30-day to 1-yr appendectomy | Moderate |
| Long-term outcomes MA (2025) | MA of 7 RCTs | 3,164 | Adults, imaging-confirmed | 1-yr success: antibiotics 73.8% vs surgery 98.1%; appendicolith failure up to 46% | Moderate |
Key Findings: Antibiotics for Uncomplicated Appendicitis in Adults
Safety: Complication Rates Are Comparable
The central safety finding across the evidence base is that antibiotic treatment does not increase the risk of complications compared with appendectomy at 1 year. The 2025 individual patient data meta-analysis — which harmonised outcomes across 6 RCTs using Clavien-Dindo classification — found no significant difference in overall, major, or minor complication rates between treatment groups. Importantly, this held true even when appendectomy performed in the antibiotics group was not counted as a “complication.” Earlier meta-analyses had suggested a complication advantage for antibiotics, but the Herrod et al. (2022) updated analysis showed this advantage disappeared once the majority of appendectomies were performed laparoscopically — suggesting that the benefit of avoiding surgery is smaller when surgery itself is minimally invasive.
Efficacy: Two-Thirds Avoid Surgery, But Recurrence Is Substantial
Across the evidence base, antibiotic treatment successfully avoids appendectomy in approximately 65–75% of patients at 1 year. However, this success rate erodes over time. In the CODA trial, 40% had undergone appendectomy at 1 year, 46% at 2 years, and approximately 49% at 3–4 years. The APPAC trial, which excluded patients with appendicolith, reported a 5-year appendectomy rate of 39%. Trial sequential analysis in the Prechal et al. (2024) meta-analysis confirmed that these efficacy estimates are stable and unlikely to change substantially with further trials.
A critical perspective shift is required: antibiotic treatment is best understood not as a cure for appendicitis but as a strategy that offers the majority of patients a period of surgery avoidance, with the understanding that a meaningful minority will eventually need appendectomy. For patients whose priority is avoiding surgery entirely, the long-term data should inform expectations.
The Appendicolith Question: The Most Important Risk Modifier
The presence of an appendicolith consistently emerges as the strongest predictor of antibiotic failure. In the CODA trial, patients with an appendicolith had a 41% appendectomy rate at 90 days versus 25% without — a difference that was most pronounced in the first 48 hours (HR 2.9 for early appendectomy). The 2025 IPD meta-analysis confirmed that patients with appendicolith treated with antibiotics had significantly higher complication rates and nearly half required subsequent surgery. A separate meta-regression across 7 RCTs confirmed a positive correlation between appendicolith prevalence in a study and the overall antibiotic failure rate.
A central safety concern with antibiotics-first management is whether delay to eventual appendectomy allows uncomplicated appendicitis to progress to perforation. The available evidence is reassuring but not definitive. In the CODA trial, perforation was found in approximately 20% of patients in both the antibiotics group who underwent delayed appendectomy and the primary appendectomy group. The 2025 IPD meta-analysis reported that 25% of patients undergoing delayed appendectomy had complicated appendicitis at surgery — similar to the rate found in the upfront surgery groups.
However, there are important caveats. The definition of “complicated” appendicitis at delayed surgery may capture both true progression and sampling of patients who had more severe disease initially (and therefore failed antibiotics). Additionally, CT sensitivity for detecting complicated appendicitis is estimated at only 78%, meaning some patients classified as “uncomplicated” at presentation may have had undetected perforation or gangrene. The evidence does not suggest that antibiotic treatment meaningfully increases the risk of a more dangerous operation if surgery is eventually required, but this remains a theoretical concern, particularly beyond 2 years of follow-up where data are sparse.
An underappreciated concern with non-operative management is the potential for missed appendiceal neoplasm. In the CODA trial, 9 neoplasms were identified in appendectomy specimens — a finding that could not have been detected by CT alone. Although patients with imaging features suggestive of a mass were excluded, some tumours (particularly low-grade mucinous neoplasms and neuroendocrine tumours) present identically to simple appendicitis on imaging.
The clinical significance of this finding remains uncertain. Appendiceal neoplasms are uncommon (estimated 0.5–1.5% of appendectomy specimens), and it is unknown whether delayed detection in a minority of antibiotic-treated patients affects long-term oncological outcomes. However, this concern is particularly relevant in older adults (over 40–50 years), where the incidence of appendiceal neoplasm rises, and some expert guidelines recommend a lower threshold for appendectomy in this age group even when antibiotics are otherwise appropriate.
The CODA trial used the EQ-5D as its primary outcome and demonstrated noninferiority of antibiotics at 30 days (0.92 vs 0.91). Both treatment groups showed similar resolution of symptoms — pain, tenderness, and fever — at 7, 14, and 30 days. Patients treated with antibiotics missed fewer work days (5.3 vs 8.7 days), consistent with the APPAC trial findings. Nearly half of antibiotic-treated patients avoided hospitalisation entirely, being managed as outpatients.
However, the antibiotics group had more subsequent emergency department visits (8.9% vs 4.3%) and more hospital readmissions, reflecting the need for retreatment or eventual surgery. Decisional regret and patient satisfaction data are limited but suggest that patients who actively chose antibiotics and were counselled about the possibility of eventual surgery tend to report higher satisfaction than those who were surprised by recurrence. The CODA investigators developed an online shared decision-making tool (appyornot.org) to help standardise patient counselling.
The cost comparison between antibiotics and appendectomy is complex and depends on the healthcare setting. The APPAC trial’s 5-year cost analysis showed that antibiotic treatment was less expensive than appendectomy overall, driven by the avoidance of surgery in the majority of patients. However, the patients who failed antibiotics and required delayed appendectomy incurred higher cumulative costs than those who underwent primary surgery.
In the Prechal et al. (2024) meta-analysis, the authors concluded that antibiotic therapy was “less expensive” but also “less effective” than surgery — an important framing for shared decision-making. The cost-effectiveness calculation changes substantially depending on the proportion of patients expected to eventually need surgery (higher in patients with appendicolith) and the cost of managing recurrent episodes, ED visits, and readmissions. In resource-limited settings where surgical capacity is constrained, the economic argument for antibiotics-first management may be more compelling.
Quality and Consistency of Evidence
What the Evidence Does Not Show
No RCT has followed patients beyond 5 years after antibiotic treatment. The lifetime recurrence rate of appendicitis after successful antibiotic treatment — and whether it eventually approaches 100% — remains unknown. Additionally, the clinical significance of missed appendiceal neoplasms in patients who never undergo appendectomy has not been studied.
The evidence base has significant limitations. All major RCTs are unblinded (the nature of the intervention makes blinding impractical), introducing performance and detection bias. Only approximately 30% of eligible patients agreed to randomisation in the CODA trial, creating potential selection bias toward patients comfortable with either treatment. CT is used for diagnosis in virtually all trial patients, but in many healthcare settings, CT is not routinely performed for suspected appendicitis in young adults — limiting the generalisability of the imaging-based inclusion criteria.
Antibiotic regimens varied substantially across trials (IV versus oral, different agents, different durations), and the optimal antibiotic protocol has not been established. Whether fully outpatient oral antibiotic therapy is equivalent to a strategy that includes initial IV therapy remains uncertain, though the CODA trial permitted both. Finally, the interaction between antibiotic treatment and antimicrobial resistance has not been adequately studied — a concern that becomes more relevant as the proportion of appendicitis patients treated with antibiotics increases.
Practical Implications
Based on the current evidence, several considerations emerge for clinicians managing adults with suspected uncomplicated acute appendicitis. These reflect what the data support rather than directive recommendations.
For adults with CT-confirmed uncomplicated appendicitis without appendicolith, antibiotic treatment is associated with similar complication rates to appendectomy at 1 year, with approximately 65–75% avoiding surgery. This represents a genuine alternative for patients who prefer to avoid an operation, with the understanding that eventual appendectomy remains a meaningful possibility.
Patients with an appendicolith face nearly double the risk of antibiotic failure and higher complication rates. The evidence supports using appendicolith status as the primary imaging-based criterion for patient selection. While antibiotics remain non-inferior to surgery even in this subgroup for the primary outcome, the high failure rate limits the practical benefit.
The evidence does not establish superiority of either approach — both are safe with different trade-off profiles. Patients should understand: antibiotics offer avoidance of surgery for the majority, with fewer missed work days and no anaesthetic risk, but carry a 30–50% chance of eventual surgery, more ED visits, and uncertainty about recurrence. Structured decision tools like the CODA trial’s appyornot.org can facilitate this conversation.
The risk of appendiceal neoplasm increases with age. While the absolute risk remains low, the potential for missed neoplasm in non-operated patients is a consideration that may lower the threshold for recommending appendectomy in older adults, particularly when the clinical presentation is atypical or imaging findings are equivocal.
Evidence Grade and Bottom Line
Overall Evidence Grade: Strong (safety) / Moderate (long-term efficacy and patient selection)
The safety of antibiotic treatment for uncomplicated appendicitis in adults is now well established through multiple RCTs, an IPD meta-analysis, and trial sequential analysis. However, the evidence for optimal patient selection, long-term recurrence rates beyond 5 years, and the clinical implications of missed neoplasm remains less certain.
- Antibiotic treatment is a safe alternative to appendectomy for uncomplicated appendicitis in adults, with comparable complication rates at 1 year confirmed by IPD meta-analysis.
- Approximately two-thirds of patients avoid surgery at 1 year, but this erodes to roughly half by 2–4 years — framing antibiotics as a surgery-delaying rather than surgery-replacing strategy for many patients.
- Appendicolith is the strongest predictor of antibiotic failure and should be the primary imaging-based criterion in patient selection discussions.
- The complication advantage of antibiotics over surgery that was seen in earlier meta-analyses has largely disappeared now that most appendectomies are performed laparoscopically.
- Long-term recurrence data beyond 5 years, the risk of missed neoplasm, and the impact of widespread antibiotic use on resistance patterns remain unresolved and require further study.
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
- 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
- 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
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- Prechal D, Post S, Gfrörer S, 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
- Davidson GH, Monsell SE, Gundel SJ, et al. Factors associated with recurrent appendicitis after successful treatment with antibiotics. BJS. 2023;110(12):1768–1776. DOI: 10.1093/bjs/znad292
- 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
- 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