Are Antibiotics the Answer to Treating Appendicitis?

Managing uncomplicated acute appendicitis can involve two treatment pathways—surgery or antibiotics—and is a clinical decision that has been rigorously debated in recent years, driven by data from several prominent clinical trials.

Surgical appendectomy has been the first-line option for treating uncomplicated appendicitis for more than 120 years,¹ although nonoperative management may be a safe alternative for a select patient population. Notably, in the US, only 6% of patients are treated with antibiotics for uncomplicated appendicitis, while the vast majority of patients are managed by laparoscopic appendectomy.²

However, for some patients, particularly those who are not in a physical state that is conducive for surgery or are located in settings where resources are limited, such as during the COVID-19 pandemic, nonoperative management for uncomplicated appendicitis is a viable alternative.³

Before engaging in any patient-centered decision-making regarding treatment options, it is important to identify if the appendicitis is uncomplicated or complicated, as each disease presents varying degrees of severity.² Radiologic assessments, primarily a computed tomography (CT) scan, can quite reliably rule out complicated acute appendicitis and confirm that the patient’s appendix doesn’t have an appendicolith, abscess, or perforation and is, therefore, most likely the uncomplicated form of the disease.

“I was taught to operate on every single patient who was suspected of having acute appendicitis. At that time, we did not use imaging,” said Paulina Salminen, MD, PhD, FACS(Hon), professor of surgery at the University of Turku and Turku University Hospital in Finland. “So, we ended up having 30% to 40% negative appendectomies, especially in young female patients.”

Dr. Salminen also is the lead investigator of the Appendicitis Acuta (APPAC) randomized trials, which focus on the treatment of uncomplicated acute appendicitis.

“The main point I want everybody to internalize is the fact that we are talking about two very different diseases,” explained Dr. Salminen. “After you decide that the patient has acute appendicitis, you have to figure out whether it’s the milder form, which is approximately 60% to 70% of cases, or if it is the more difficult form.” She said a primary goal of the inclusion criteria for the APPAC trials (and also clinically) was to rule out patients with complicated acute appendicitis.

Evidence for Antibiotics

The three APPAC trials function as a continuation of research stemming from the initial trial that compared nonoperative management with appendectomy in adults with CT-verified uncomplicated acute appendicitis.

The 5-year follow-up of the first trial (November 2009 to June 2012 in Finland) was completed in September 2017. Among the 530 patients who were selected for the randomized clinical trial, 257 individuals were in the antibiotics group. At the 1-year mark, 70 patients in the group received an appendectomy, with 30 additional patients requiring the procedure between 1 and 5 years.⁴ The cumulative recurrence rate evaluated by appendectomy mandated by the study protocol for suspected recurrence was 34% at 2 years, 35.2% at 3 years, 37.1% at 4 years, and 39.1% at 5 years.²

“Surgery is always a big deal, and everything we do carries risk,” said Drew Gunnells Jr., MD, FACS, assistant professor in the Division of Gastrointestinal Surgery at The University of Alabama at Birmingham. “Although an appendectomy is one of the more straightforward procedures we do, there's still risk associated with it. And, so, can we avoid surgical intervention for a disease that for a long time has been treated with surgery?”

According to Dr. Gunnells, as long as the chance for the patient with uncomplicated appendicitis requiring an operation in the future is minimal, treatment with antibiotics may be a safe option. “I think, based on the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trials and the APPAC trials, you’re not putting the patients at risk of undue harm by treating them with antibiotics. The question in my mind is: What's the recurrence rate of appendicitis, and are those patients going to need surgery in the future?”

CODA, a large, randomized clinical trial of antibiotics for appendicitis, was conducted at 25 US medical centers. From May 2016 to February 2020, 1,552 adults with appendicitis were randomly assigned to receive either antibiotics or appendectomies. According to findings presented at ACS Clinical Congress 2020 and published simultaneously in The New England Journal of Medicine, approximately half of the patients in the trial did not require an appendectomy up to 4 years after receiving antibiotics.⁵

Despite these findings, clinicians are encouraged to review the data with a critical eye. “We need to have an evidence-based approach to treating uncomplicated appendicitis and not an eminence-based approach,” suggested Dr. Salminen, underscoring the importance of carefully assessing new and existing research in this area.

Risk of Recurrence

Benjamin H. Stone, MD, MBA, FACS, a general surgeon at The University of Kansas in Kansas City, also suggested focusing on the success and failure rates for both treatment options.

“We’ve had 100+ years of operative therapy for acute appendicitis—so we have a good track record to benchmark other management modalities,” Dr. Stone said. “Surgical therapy is at least 96% effective for this disease. We need to be candid and open about the fact that these results are not the same for nonoperative management. Most of the best studies, when we look at long-term data, have about a 25% failure rate compared to maybe a 1% to 4% failure rate for operative therapy.”

For example, the long-term data for the CODA trial revealed that 40% of patients who were prescribed antibiotics underwent subsequent appendectomy at 1 year and 46% received the procedure at 2 years, rising to 49% at 3 and 4 years.⁵

“If you look at the patients with an appendicolith on their initial presentation in the CODA trial who ended up getting an appendectomy, it was about 50% in 2 years,” added Dr. Gunnells. “That number is fairly high in my mind, and those patients probably just need to have their appendices out to decrease their risk of recurrence in the future.”

While the APPAC and CODA trials demonstrated that it is likely safe to treat the first episode of uncomplicated appendicitis with antibiotics, clinicians are advised to have honest and straightforward conversations with patients about potential recurrence rates.

“The more data we accrue long-term, we find that the recurrence rates continue to go up,” added Dr. Stone. “Those early benchmarks for near equivalence or non inferiority don't seem to hold up over time. I also think it’s important to keep in mind that patients don’t read these studies in depth, if at all, and there are exclusion criteria that need to be considered.”

Exclusion criteria for nonoperative management could include comorbid conditions and other concomitant acute presentations, chronic conditions such as Crohn’s disease, patients taking immunosuppressants or undergoing chemotherapy, as well as patients who are pregnant.

“We’re not trying to omit appendectomy,” explained Dr. Salminen. “We’re just trying to select the patients who would be best off with surgery and others who actually could do without surgery. The majority of recurrences happened during the first year and a half—and that’s quick. If you want to do nonoperative treatment with antibiotics, you need to inform the patients that if they have a recurrence or experience similar symptoms, they need to inform their next surgeon that they’ve already had one round of antibiotics to successfully treat the disease.”

Paradigm Shifts: Past and Future

Over the last century, a couple of key paradigm shifts regarding the management of appendicitis have happened. After Reginald Herber Fitz published a study on appendicitis in 1886, where he officially named the procedure, Charles McBurney proposed an innovative muscle-splitting operation in 1893.⁶

At that time, it was thought that all patients with appendicitis required an appendectomy. “We know that is not true. That realization was the first paradigm shift,” Dr. Salminen said, referring to nonoperative treatment. The second major paradigm that could occur in the future—exploring whether antibiotics can be omitted for uncomplicated acute appendicitis—would result from the findings of the APPAC IV trial, which is currently underway.

“What we’re trying to prove now with APPAC IV is whether or not we even need antibiotics,” said Dr. Salminen, noting that an optimized nonoperative treatment does not currently exist. Typically, nonoperative management begins with intravenous antibiotics followed by as many as 7 days or more of oral antibiotics.⁷

“If symptomatic treatment is sufficient with results similar to antibiotics—this really will change the field because then we have a disease that for some patients actually resolves by itself without any specific treatment. So, if you don’t even need antibiotics, you really cannot justify operating on all the patients. That’s not good, evidenced-based medicine,” she said.

Another key component of the APPAC IV trial that could drive a major paradigm shift is the fact that researchers, led by Dr. Salminen, are conducting intravenous antibiotic therapy in the outpatient setting. The majority of patients in the trial will be discharged directly from the ER, which will help determine whether hospitalization can be avoided, saving resources and cutting costs.

Comparing Costs

Studies comparing the costs associated with nonoperative versus operative treatment are somewhat limited at this point. However, one study demonstrated higher medical costs for surgical treatment of uncomplicated appendicitis with a difference of $1,067 per patient.^2,8

Costs also were discovered to be higher for patients treated operatively in the APPAC trial, at both the 1- and 5-year follow-ups, where the costs were reportedly 1.6 and 1.4 times higher, respectively.² These costs included factors related to hospital length of stay and sick time as it correlated to productivity loss.

“This difference in costs to both the service providers and society overall strongly encourages further evaluation of antibiotic therapy as the first-line treatment for uncomplicated acute appendicitis,” noted Dr. Salminen and coauthors in a 2017 article published in the British Journal of Surgery that provided an economic evaluation of both treatment modalities in the APPAC trial.⁹

Other clinicians assert that the appendectomy, considered the gold standard treatment, is the least expensive option because of its success rate.

“The reason that it’s the cheapest is because often it’s very effective,” said Dr. Stone. “I think it's the single most effective way of dealing with acute appendicitis as the lowest failure rate. We don't yet have the long-term follow-up that we need with nonoperative therapy to make certain these people aren't recurring, and we know they are, with up to 30% and 40% relapse rates.”

Dr. Stone, who currently practices in a community hospital setting, also highlighted the relevance of some other cost factors that are not routinely discussed in these economic evaluations.

“Something that is not always discussed when we’re comparing these studies are the resources that are required as far as money, personnel, and time, especially considering all the follow-up that is required for nonoperative management. Not everyone practices under those circumstances,” he said, emphasizing the need for more detailed cost analysis of both treatment modalities.

While managing uncomplicated appendicitis with antibiotics is a safe, cost-effective alternative with potentially fewer complications than surgical treatment, appendectomies have a higher efficacy rate. Clinicians are encouraged to stay current on new research findings and have frank and open discussions with patients regarding the realities of each treatment option.

Tony Peregrin is the Managing Editor of Special Projects in the ACS Division of Integrated Communications in Chicago, IL.

References

1. Newhall K, Albright B, Tosteson A, Ozanne E, Trus T, Goodney PP. Cost-effectiveness of prophylactic appendectomy: A Markov model. Surg Endosc. 2017;31(9):3596-3604.
2. Alajaimi J, Almansoor M, Almutawa A, Almusalam MM, et al. Are antibiotics the new appendectomy? Cureus. 2023 Sep 1;15(9):e44506.
3. Blair J. Is surgery the only safe option for acute uncomplicated appendicitis? Medscape. August 3, 2022. Available at: https://www.medscape.com/viewarticle/978512. Accessed January 26, 2024.
4. Salminen P, Tuominen R, Paajanen H, Rautio T, 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.
5. CODA Collaborative. Antibiotics versus appendectomy for acute appendicitis—longer-term outcomes. Correspondence. December 16, 2021. N Engl J Med;2021;385(25):2395-2397.
6. Meljnikov I, Radojcić B, Grebeldinger S, Radojcić N. [History of surgical treatment of appendicitis]. Med Pregl. 2009 Sep-Oct;62(9-10):489-492.
7. Galzier E, Ko E. Doctors may opt for nonoperative management of appendicitis. UCLA Health. February 7, 2023. Available at: https://www.uclahealth.org/news/doctors-may-opt-nonoperative-management-appendicitis. Accessed January 26, 2024.
8. Park HC, Kim MJ, Lee BH. The outcome of antibiotic therapy for uncomplicated appendicitis with diameters ≤10 mm. Int J Surg. 2014;12(9):897-900.
9. Sippola S, Grönroos JR, Tuominen R, Paajanen H, et al. Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial. Br J Surg. 2017;104(10):1355-1361.