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Antibiotics could be alternative first line treatment for appendicitis.

NIHR Signal Antibiotics may be an alternative first-line treatment for uncomplicated appendicitis

Published on 22 January 2019

doi: 10.3310/signal-000716

Appendicectomy surgery could potentially be avoided for around 60% of adults with uncomplicated appendicitis if they receive antibiotics first.

Adults in Finland with appendicitis were randomised to have appendicectomy or a course of antibiotics. In 6 out of 10 the appendicitis settled and did not return over the five years they were followed. Of those who did go on to need surgery most did so in the first year.

If the findings from the study could be applied to the UK, it is estimated that up to 24,000 appendicectomies might be avoided in England each year.

In the UK, appendicitis is usually managed by appendicectomy, so shifting to antibiotic therapy as a first choice would require major changes in clinical practice.

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Why was this study needed?

Around 40,000 people a year are admitted to hospital in England with acute appendicitis. The usual treatment for acute appendicitis (and suspected appendicitis) is removal of the appendix, to avoid the risk of rupture or sepsis.

Recent advances in diagnostic imaging mean it is now easier to diagnose uncomplicated appendicitis. This has allowed trials of other treatments, including antibiotics and observation. However, most of the trials have had relatively short follow-up, meaning some cases of recurrence of appendicitis after antibiotic treatment may have been missed.

This study intended to report on the long-term outcomes for patients enrolled on a trial of antibiotics or appendicectomy.

What did this study do?

The APPAC randomised controlled trial recruited 530 patients from six hospitals. They were aged 18 to 60 years with uncomplicated appendicitis, confirmed by CT scan. Participants were randomised to open appendicectomy (273) or antibiotics (257). Antibiotic treatment consisted of intravenous ertapentem for three days, followed by oral metronidazole (500mg three times per day) and levofloxin (500mg) for seven days.

Researchers followed patients up for five years, to see how many patients initially randomised to antibiotic treatment subsequently underwent appendicectomy. They also looked at rates of complication, hospital stay and time off work.

As surgeons could use their clinical judgement to carry out an appendicectomy in the antibiotic group if they thought it necessary, personal preference may have affected the results.

What did it find?

  • The study found that 70/257 (27%) patients who initially received antibiotics had appendicectomy in the first year, 15 of them during the initial hospitalisation. In the subsequent four years, an additional 30 patients had appendicectomy. The incidence of recurrent appendicitis was 39.1% after five years (95% confidence interval [CI] 33.1 to 45.3).
  • Of the 85 patients who had appendicectomy after antibiotics, 76 had uncomplicated appendicitis, two had complicated appendicitis (at least two years after the initial infection), and seven were found not to have had appendicitis at all.
  • After five years, 24% (95% CI 19.2 to 30.3) of people in the surgery group and 6.5% (95% CI 3.8 to 10.4) of people in the antibiotic group had complications. Complications were defined as surgical site infections, incisional hernias, abdominal pain and obstructive symptoms.
  • There were three deaths, but they were unrelated to appendicitis.
  • Both groups stayed in hospital for on average three days. Average time for sick leave was 22 days for people who’d had appendicectomy, compared with 11 days after antibiotic therapy.

What does current guidance say on this issue?

Appendicectomy is the treatment of choice for appendicitis according to the 2015 NICE Clinical Knowledge Summary.

The Association of Surgeons of Great Britain and Ireland emergency general surgery guideline updated in 2017 recommends laparoscopy or imaging followed by appendicectomy for suspected appendicitis.

What are the implications?

The possibility that some of the appendicectomies carried out in the UK might be avoided by use of antibiotics is enticing. Avoiding surgery and surgical complications and reducing time off work is likely to be popular with patients.

However, a number of issues would need to be resolved before that becomes a possibility. All the people in the study had abdominal CT scans to confirm uncomplicated appendicitis while different imaging techniques may be used in the UK.

Open surgery was performed rather than the laparoscopic (keyhole) technique that is common practice in the UK, so the complication rate for surgery may be different.

Diagnostic procedures and protocols to ensure people were followed up carefully would need to be developed to ensure patient safety. Finally, there is the issue of antibiotic stewardship as ertapenem, the antibiotic used in this trial is currently reserved for severe infections.

Citation and Funding

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):1259-65.

The study was funded by the Mary and Georg C Erhnrooth Foundation and Turku University.

Bibliography

ASGBI. Commissioning guide: Emergency general surgery (acute abdominal pain). London: Association of Surgeons of Great Britain and Ireland; 2014.

Edward H Livingston. Antibiotic treatment for uncomplicated appendicitis really works. JAMA. 2018;320(12):1245-66.

NICE. Appendicitis. Clinical Knowledge Summary. London: National Institute for Health and Clinical Excellence; 2015.

Why was this study needed?

Around 40,000 people a year are admitted to hospital in England with acute appendicitis. The usual treatment for acute appendicitis (and suspected appendicitis) is removal of the appendix, to avoid the risk of rupture or sepsis.

Recent advances in diagnostic imaging mean it is now easier to diagnose uncomplicated appendicitis. This has allowed trials of other treatments, including antibiotics and observation. However, most of the trials have had relatively short follow-up, meaning some cases of recurrence of appendicitis after antibiotic treatment may have been missed.

This study intended to report on the long-term outcomes for patients enrolled on a trial of antibiotics or appendicectomy.

What did this study do?

The APPAC randomised controlled trial recruited 530 patients from six hospitals. They were aged 18 to 60 years with uncomplicated appendicitis, confirmed by CT scan. Participants were randomised to open appendicectomy (273) or antibiotics (257). Antibiotic treatment consisted of intravenous ertapentem for three days, followed by oral metronidazole (500mg three times per day) and levofloxin (500mg) for seven days.

Researchers followed patients up for five years, to see how many patients initially randomised to antibiotic treatment subsequently underwent appendicectomy. They also looked at rates of complication, hospital stay and time off work.

As surgeons could use their clinical judgement to carry out an appendicectomy in the antibiotic group if they thought it necessary, personal preference may have affected the results.

What did it find?

  • The study found that 70/257 (27%) patients who initially received antibiotics had appendicectomy in the first year, 15 of them during the initial hospitalisation. In the subsequent four years, an additional 30 patients had appendicectomy. The incidence of recurrent appendicitis was 39.1% after five years (95% confidence interval [CI] 33.1 to 45.3).
  • Of the 85 patients who had appendicectomy after antibiotics, 76 had uncomplicated appendicitis, two had complicated appendicitis (at least two years after the initial infection), and seven were found not to have had appendicitis at all.
  • After five years, 24% (95% CI 19.2 to 30.3) of people in the surgery group and 6.5% (95% CI 3.8 to 10.4) of people in the antibiotic group had complications. Complications were defined as surgical site infections, incisional hernias, abdominal pain and obstructive symptoms.
  • There were three deaths, but they were unrelated to appendicitis.
  • Both groups stayed in hospital for on average three days. Average time for sick leave was 22 days for people who’d had appendicectomy, compared with 11 days after antibiotic therapy.

What does current guidance say on this issue?

Appendicectomy is the treatment of choice for appendicitis according to the 2015 NICE Clinical Knowledge Summary.

The Association of Surgeons of Great Britain and Ireland emergency general surgery guideline updated in 2017 recommends laparoscopy or imaging followed by appendicectomy for suspected appendicitis.

What are the implications?

The possibility that some of the appendicectomies carried out in the UK might be avoided by use of antibiotics is enticing. Avoiding surgery and surgical complications and reducing time off work is likely to be popular with patients.

However, a number of issues would need to be resolved before that becomes a possibility. All the people in the study had abdominal CT scans to confirm uncomplicated appendicitis while different imaging techniques may be used in the UK.

Open surgery was performed rather than the laparoscopic (keyhole) technique that is common practice in the UK, so the complication rate for surgery may be different.

Diagnostic procedures and protocols to ensure people were followed up carefully would need to be developed to ensure patient safety. Finally, there is the issue of antibiotic stewardship as ertapenem, the antibiotic used in this trial is currently reserved for severe infections.

Citation and Funding

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):1259-65.

The study was funded by the Mary and Georg C Erhnrooth Foundation and Turku University.

Bibliography

ASGBI. Commissioning guide: Emergency general surgery (acute abdominal pain). London: Association of Surgeons of Great Britain and Ireland; 2014.

Edward H Livingston. Antibiotic treatment for uncomplicated appendicitis really works. JAMA. 2018;320(12):1245-66.

NICE. Appendicitis. Clinical Knowledge Summary. London: National Institute for Health and Clinical Excellence; 2015.

Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial

Published on 29 September 2018

Salminen, P.,Tuominen, R.,Paajanen, H.,Rautio, T.,Nordstrom, P.,Aarnio, M.,Rantanen, T.,Hurme, S.,Mecklin, J. P.,Sand, J.,Virtanen, J.,Jartti, A.,Gronroos, J. M.

Jama Volume 320 Issue 12 , 2018

Importance: Short-term results support antibiotics as an alternative to surgery for treating uncomplicated acute appendicitis, but long-term outcomes are not known. Objective: To determine the late recurrence rate of appendicitis after antibiotic therapy for the treatment of uncomplicated acute appendicitis. Design, Setting, and Participants: Five-year observational follow-up of patients in the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotic therapy, in which 530 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were randomized to undergo an appendectomy (n = 273) or receive antibiotic therapy (n = 257). The initial trial was conducted from November 2009 to June 2012 in Finland; last follow-up was September 6, 2017. This current analysis focused on assessing the 5-year outcomes for the group of patients treated with antibiotics alone. Interventions: Open appendectomy vs antibiotic therapy with intravenous ertapenem for 3 days followed by 7 days of oral levofloxacin and metronidazole. Main Outcomes and Measures: In this analysis, prespecified secondary end points reported at 5-year follow-up included late (after 1 year) appendicitis recurrence after antibiotic treatment, complications, length of hospital stay, and sick leave. Results: Of the 530 patients (201 women; 329 men) enrolled in the trial, 273 patients (median age, 35 years [IQR, 27-46]) were randomized to undergo appendectomy, and 257 (median age, 33 years, [IQR, 26-47]) were randomized to receive antibiotic therapy. In addition to 70 patients who initially received antibiotics but underwent appendectomy within the first year (27.3% [95% CI, 22.0%-33.2%]; 70/256), 30 additional antibiotic-treated patients (16.1% [95% CI, 11.2%-22.2%]; 30/186) underwent appendectomy between 1 and 5 years. The cumulative incidence of appendicitis recurrence was 34.0% (95% CI, 28.2%-40.1%; 87/256) at 2 years, 35.2% (95% CI, 29.3%-41.4%; 90/256) at 3 years, 37.1% (95% CI, 31.2%-43.3%; 95/256) at 4 years, and 39.1% (95% CI, 33.1%-45.3%; 100/256) at 5 years. Of the 85 patients in the antibiotic group who subsequently underwent appendectomy for recurrent appendicitis, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis. At 5 years, the overall complication rate (surgical site infections, incisional hernias, abdominal pain, and obstructive symptoms) was 24.4% (95% CI, 19.2%-30.3%) (n = 60/246) in the appendectomy group and 6.5% (95% CI, 3.8%-10.4%) (n = 16/246) in antibiotic group (P < .001), which calculates to 17.9 percentage points (95% CI, 11.7-24.1) higher after surgery. There was no difference between groups for length of hospital stay, but there was a significant difference in sick leave (11 days more for the appendectomy group). Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01022567.

Expert commentary

Before we consider routinely using antibiotics instead of open surgical or laparoscopic appendicectomy for uncomplicated acute appendicitis, several questions need answering.

How should we manage the 34% of antibiotic-treated patients whose appendicitis recurs within two years? What is the risk of recurrent appendicitis in the much longer term? How should we treat age groups excluded from this study (younger than 18 years or older than 60 years)? How can we avoid overlooking cancers presenting with appendicitis? Could the antibiotics be given in the community, avoiding hospital admission? And what would be the cost implications of a switch from surgical to antibiotic treatment?

David Rampton, Professor of Clinical Gastroenterology, Barts and The London School of Medicine and Dentistry

The commentator declares no conflicting interests