By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC

Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH

SYNOPSIS: A randomized controlled clinical trial found that a seven-day course of oral moxifloxacin was not noninferior to two days of intravenous ertapenem followed by five days of levofloxacin and metronidazole in adults with uncomplicated acute appendicitis.

SOURCE: 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 2021;325:353-362.

There is high quality evidence, including randomized clinical trials and guidelines, that antibiotic therapy can be an effective alternative to surgery in cases of acute uncomplicated appendicitis. However, the optimal regimen remains to be determined. Sippola and colleagues hypothesized that oral antibiotics alone would be as effective as intravenous antibiotics followed by oral antibiotics in the management of acute uncomplicated appendicitis.

The study was a randomized controlled clinical trial conducted at nine hospitals in Finland. Adult patients older than 18 years of age who had uncomplicated acute appendicitis that was confirmed by computed tomography (CT) imaging were included. Uncomplicated acute appendicitis was defined as an appendiceal diameter > 6 mm with a thickened, contrast-enhanced wall, peri-appendiceal edema, and/or minor fluid collection, and the absence of criteria for complicated appendicitis (i.e., presence of appendicolith, perforation, abscess, or tumor). Exclusion criteria included age < 18 years or > 60 years, pregnancy or lactation, allergy to intravenous (IV) contrast dye or study antibiotic therapy, kidney failure, type 2 diabetes and use of metformin, severe systemic illness such as malignancy, or complicated appendicitis.

Participants were randomized 1:1 to receive either oral moxifloxacin 400 mg once a day for seven days or IV ertapenem 1 g IV daily followed by five days of oral levofloxacin 500 mg daily and metronidazole 500 mg three times daily, with treatment begun in the emergency department. Patients who were suspected by a surgeon to not be responding underwent laparoscopic appendectomy. Outcomes were assessed daily in the hospital and after discharge by telephone at one week, two months, and one year. The primary endpoint was treatment success at one year, defined as resolution of acute appendicitis without the need for surgical intervention and no recurrent appendicitis.

The primary analysis included 583 patients, with 295 in the oral moxifloxacin group (oral group) and 288 in the IV ertapenem followed by oral antibiotics group (IV/oral group). Baseline characteristics were similar between the two groups, with a mean age of 36 years (standard deviation, 12 years), and 43.9% were women. The treatment success for the oral group was 70.2% (one-sided 95% confidence interval [CI], 65% to ∞) at one year compared to 73% (one-sided 95% CI, 69.5% to ∞) in the IV/oral group. For the primary outcome, the analysis determined a difference of -3.6% (one-sided 95% CI, -9.7% to ∞; P = 0.26 for noninferiority) between the two groups. Thus, the CI difference exceeded the predefined noninferiority definition of a lower limit of -6%, indicating oral therapy was not noninferior to IV/oral therapy. There were no significant differences between the groups in length of hospital stay or reported pain. No patients died within the one-year hospital follow-up period. Regarding adverse events, two patients in the oral group discontinued treatment (one patient developed eczema with facial swelling and one developed blurry vision), while five in the IV/oral group reported prolonged diarrhea at two months that resolved by one year.

COMMENTARY

Avoiding surgery with acute uncomplicated appendicitis while still achieving a desirable outcome is a worthwhile goal. Antibiotic therapy has emerged as an effective alternative to traditional appendectomy, with little apparent risk or downside. Indeed, studies have shown that patients who ultimately develop recurrent appendicitis and undergo later appendectomy do not experience any adverse outcomes related to the delay. Therefore, the study by Sippola and colleagues is important because it adds to the body of evidence about antibiotic treatment options for acute uncomplicated appendicitis.

Oral moxifloxacin did not reach the predetermined goal of noninferiority compared to IV ertapenem followed by oral levofloxacin and metronidazole. Nevertheless, the majority of patients (70.2%) in the moxifloxacin group were able to avoid surgery. This can be interpreted in a positive light, however, from the perspective of reduced healthcare costs and complications, such as post-operative infection and anesthesia-related adverse events.

So why did moxifloxacin not fare as well as ertapenem followed by levofloxacin and metronidazole? Perhaps some cases of appendicitis were caused by quinolone-resistant Enterobacteriaceae, and two days of ertapenem was sufficient enough to kill a critical threshold of pathogens. This hypothesis is supported by a previous study that found treatment with oral amoxicillin-clavulanate led to inferior outcomes because of the presence of nonsusceptible Escherichia coli. Alternatively, and less likely, perhaps some as-yet-undetermined mechanism leads to synergy between levofloxacin and metronidazole, making them more effective in acute uncomplicated appendicitis than moxifloxacin.

The study had a few limitations. First, it was conducted in a Scandinavian country and the participants were relatively young (mean age, 36 years), which limits the generalizability to other settings. Second, the noninferiority definition of 6% was rather arbitrary. Finally, the duration of symptoms was shorter in the oral moxifloxacin group (median 18 hours) compared to the IV/oral group (median 22 hours), which may have been a confounding factor.

At present, oral moxifloxacin should not be used as therapy for acute uncomplicated appendicitis. Other treatment regimens, especially oral ones, should be investigated further in randomized clinical trials. It is hoped that the appendectomy for acute uncomplicated appendicitis will become a rarity in the not-so-distant future.