Evolving Issues in the Use of Antibiotics for the Treatment of Uncomplicated Appendicitis | Emergency Medicine | JAMA | JAMA Network
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Editorial
January 11, 2021

Evolving Issues in the Use of Antibiotics for the Treatment of Uncomplicated Appendicitis

Author Affiliations
  • 1Center for Surgical Outcomes Research, Abigail Wexner Research Institute and the Department of Surgery, Nationwide Children's Hospital, Columbus, Ohio
JAMA. Published online January 11, 2021. doi:10.1001/jama.2020.23607

Over the past decade there has been considerable discussion regarding whether antibiotics alone should be offered as a treatment option to patients with uncomplicated appendicitis. Recent evidence has suggested the answer to this question is yes. Results from several large trials, including the Appendicitis Acuta (APPAC) II trial reported in this issue of JAMA, have generated robust evidence for the effectiveness and safety for nonoperative management of uncomplicated appendicitis for both adults and children.1-4

In 2015, the initial APPAC trial that compared surgery (n = 273 [272 included in the primary analysis]) vs antibiotics alone (n = 257 [256 included in primary analysis]) in the treatment of uncomplicated appendicitis in adults demonstrated that nonoperative management had a 1-year success rate of 72.7%, had fewer treatment-associated complications (2.8% vs 20.5%), and conferred a shorter median length of sick leave (7 days vs 19 days) compared with surgery.1 Subsequent follow-up results from this trial demonstrated a 5-year success rate of nonoperative management (246 of 257 patients [96%] completed 5-year follow-up) of 60.9%. Compared with surgery (246 of 272 patients [90%] completed 5-year follow-up), nonoperative management had shorter sick leave (11 days vs 2 days) and a continued lower rate of treatment-associated complications (6.5% vs 24.4%) at 5 years.5 Furthermore, the difference in long-term quality of life between surgery (217 of 273 patients [79%] complete 7-year follow-up) and nonoperative management (206 of 257 patients [80%] completed 7-year follow-up) was not significant at the 7-year follow-up (median health index value of 1.0 in both groups).6 The APPAC trial results were the first to definitively show that patients with uncomplicated appendicitis could be successfully treated with antibiotics alone without an increased risk of treatment-associated complications.

Earlier in 2020, a multi-institutional nonrandomized clinical intervention study demonstrated similar outcomes for antibiotic therapy alone vs laparoscopic appendectomy for uncomplicated appendicitis in children.2 This study of 1068 children treated at 10 US children’s hospitals demonstrated that nonoperative management with antibiotics alone (n = 370) had a 1-year success rate of 67.1%. Compared with surgery, nonoperative management was associated with fewer mean disability days for both the child (6.6 vs 10.9) and caregivers (3.3 vs 4.1), with high health care satisfaction and satisfaction with the initial decision in both groups. In addition, results from a 2020 multicenter randomized clinical trial of adults with appendicitis (n = 1552) in the US further confirmed the safety and effectiveness of nonoperative management of appendicitis (676 of 776 participants [87%] completed 90-day follow-up), with a 90-day success rate of 71%. Compared with surgery (656 of 776 participants [85%] completed 90-day follow-up), nonoperative management was associated with decreased disability (5.3 vs 8.7 missed worked days) and similar treatment-associated complications (3% vs 3%) and quality of life (European Quality of Life–5 Dimensions scores at 30 days: 0.92 vs 0.91).3

The APPAC II trial results published in this issue of JAMA further confirm and extend the effectiveness of antibiotics alone as a treatment for uncomplicated appendicitis. The objective of this study was to assess whether treatment with oral antibiotics alone (7 days of oral moxifloxacin; n = 295) was noninferior to a combination of intravenous and oral antibiotics (2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole; n = 288) for treatment of adults (mean age, 36 years) with computed tomography–confirmed uncomplicated acute appendicitis. Treatment success was defined as discharge from the hospital without surgery and no recurrent appendicitis during 1-year follow-up, and the noninferiority margin was 6% for the between-group difference. The authors hypothesized that (1) treatment success for each group would be greater than or equal to 65% at 1 year and (2) oral antibiotics alone would be noninferior to the combination of intravenous and oral antibiotics.

At 1 year, treatment success rate was 70.2% for patients treated with oral antibiotics and 73.8% for patients treated with intravenous followed by oral antibiotics, with a between-group difference of −3.6% ([1-sided 95% CI, −9.7% to ∞]; P = .26 for noninferiority) and the confidence limit exceeding the noninferiority margin. These results successfully satisfied the authors’ first hypothesis with the success rate being greater than 65% in both groups, but did not meet the prespecified criteria for oral antibiotics to be considered noninferior. Appendectomy during initial hospitalization occurred in 27 patients (9.2%) in the oral antibiotic group and 22 patients (7.6%) in the intravenous followed by oral antibiotics group. An additional 61 patients (20.7%) underwent an appendectomy for suspected recurrent appendicitis after a median (interquartile range) of 87 (39-154) days in the oral antibiotic group vs 53 patients (18.5%) after a median (interquartile range) of 120 (76-211) days in the intravenous followed by oral antibiotics group.

The results from these large trials are remarkably consistent, with a success rate for antibiotic treatment of appendicitis of approximately 70%, less disability, and similar treatment-associated complications. Collectively, these trials represent a substantial and definitive body of evidence that supports incorporating nonoperative management as a standard treatment option for uncomplicated appendicitis.

Additional studies related to nonoperative management of appendicitis no longer need to focus on the effectiveness of the treatment, but on further defining optimal treatment strategies. This includes antibiotic duration, mode of antibiotic delivery, the need for in-patient observation, and how to disseminate and promote implementation of nonoperative treatment choices across various practice types and patient demographics. Implications related to the adoption and success of nonoperative management across a range of health literacy, access to surgical care, racial and ethnic groups, and non–English-speaking populations are also in need of additional study.

The APPAC II trial begins to address some of these more nuanced questions. This is a critical first study related to better defining treatment strategies because it opens up a larger potential area of application in the outpatient setting. Comparison of outcomes after oral vs combined intravenous and oral antibiotics can help identify an equally effective oral regimen that would allow for outpatient management. Additional studies have investigated outpatient management with intravenous and oral antibiotics after a period of observation in the emergency department. Reported results with this strategy in adult trials have been promising.3,7 With increasing evidence and experience, the management of appendicitis may evolve similarly to that of early diverticulitis, which changed from inpatient surgical management to initial outpatient medical management. An effective oral antibiotic alone regimen to manage uncomplicated appendicitis would be particularly relevant in the current coronavirus disease 2019 (COVID-19) pandemic because it would allow for patients to be treated without admitting them to the hospital. This would help relieve strain on the health care system by limiting inpatient bed use during a time of shortage and alleviate patient anxiety related to COVID-19 exposure during a hospital admission.

Nonoperative management and surgery for the treatment of uncomplicated appendicitis should both be offered as part of an informed decision-making process in clinical care. Eligible patient populations can be easily identified through information collected routinely as part of clinical care, and treatment protocols can easily be incorporated into clinical practice. However, there are still significant potential barriers to implementing this evidence into appendicitis care. These include persistent dogma related to the inevitability of acute appendicitis progressing in severity if untreated with an operation; physicians, trainees, and other medical staff being unfamiliar with the available evidence to support both treatment choices; patients and families being unfamiliar with nonoperative management as a potential alternative to appendectomy; and the challenge of integrating a shared decision-making process into the acute care setting. Methods to help overcome these barriers include use of a decision aid and a standardized script to explain the treatment options to patients and their families in a concise, understandable, and objective way; examples of both were provided in a previous report.2

The current evidence supports that patients with uncomplicated appendicitis should be offered a treatment choice between surgery and antibiotics alone. The key to moving forward is getting that evidence into practice. Successful implementation studies that address and mitigate these barriers will promote evidence uptake and allow for an informed decision-making process as part of clinical care.

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Article Information

Corresponding Author: Peter C. Minneci, MD, MHSc, Center for Surgical Outcomes Research, Abigail Wexner Research Institute and the Department of Surgery, Nationwide Children's Hospital, 700 Children’s Dr, Columbus, OH 43205 (peter.minneci@nationwidechildrens.org).

Published Online: January 11, 2021. doi:10.1001/jama.2020.23607

Conflict of Interest Disclosures: None reported.

References
1.
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.2015.6154PubMedGoogle ScholarCrossref
2.
Minneci  PC, Hade  EM, Lawrence  AE,  et al; Midwest Pediatric Surgery Consortium.  Association of nonoperative management using antibiotic therapy vs laparoscopic appendectomy with treatment success and disability days in children with uncomplicated appendicitis.   JAMA. 2020;324(6):581-593. doi:10.1001/jama.2020.10888PubMedGoogle ScholarCrossref
3.
Flum  DR, Davidson  GH, Monsell  SE,  et al; CODA Collaborative.  A randomized trial comparing antibiotics with appendectomy for appendicitis.   N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320PubMedGoogle ScholarCrossref
4.
Sippola  S, Haijanen  J, Grönroos  J,  et al.  Effect of oral moxifloxacin vs intravenous ertapenem plus oral levofloxacin for treatment of uncomplicated acute appendicitis: the APPAC II randomized clinical trial.   JAMA. Published online January 11, 2021. doi:10.1001/jama.2020.23525Google Scholar
5.
Salminen  P, Tuominen  R, Paajanen  H,  et al.  Five-year follow-up of antibiotic therapy for uncomplicated acute appendicitis in the APPAC randomized clinical trial.   JAMA. 2018;320(12):1259-1265. doi:10.1001/jama.2018.13201PubMedGoogle ScholarCrossref
6.
Sippola  S, Haijanen  J, Viinikainen  L,  et al.  Quality of life and patient satisfaction at 7-year follow-up of antibiotic therapy vs appendectomy for uncomplicated acute appendicitis: a secondary analysis of a randomized clinical trial.   JAMA Surg. 2020;155(4):283-289. doi:10.1001/jamasurg.2019.6028PubMedGoogle ScholarCrossref
7.
Talan  DA, Saltzman  DJ, Mower  WR,  et al; Olive View–UCLA Appendicitis Study Group.  Antibiotics-first versus surgery for appendicitis: a US pilot randomized controlled trial allowing outpatient antibiotic management.   Ann Emerg Med. 2017;70(1):1-11.e9. doi:10.1016/j.annemergmed.2016.08.446PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Non-Operative Management of Appendicitis
    John Waldron, MD | Marshfield Clinic, retired
    I hope on-going studies count the number of subsequent CT scans of abdomen in the operative and non-operative groups.
    CONFLICT OF INTEREST: None Reported
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