Oral antibiotic monotherapy: Yes or no for acute uncomplicated appendicitis?

A 7-day course of oral moxifloxacin monotherapy successfully treated uncomplicated acute appendicitis, though it did not appear to be noninferior to an intravenous (IV) ertapenem plus oral levofloxacin/metronidazole treatment regimen, according to results of the APPAC* II trial.

The investigators enrolled 583 adults aged 18–60 years (mean age 36 years, 43.9 percent female) with computed tomography-confirmed uncomplicated acute appendicitis from nine hospitals in Finland. The patients were randomized 1:1 to receive either oral moxifloxacin monotherapy (400 mg QD) for 7 days (n=295) or IV ertapenem (1 g QD) for 2 days followed by oral levofloxacin (500 mg/day) and metronidazole (500 mg TID) for 5 days (n=288). If patients were suspected of not responding to antibiotic therapy, surgeons could arrange for them to undergo laparoscopic appendectomy.

Both treatment groups met the criteria for success of treatment at 1 year (≥65 percent), defined as resolution of acute appendicitis leading to discharge from hospital without the need for surgery and no recurrent appendicitis during 1-year follow-up (70.2 percent [1-sided 95 percent confidence interval (CI), 65.8 percent to ∞] vs 73.8 percent [1-sided 95 percent CI, 69.5 percent to ∞] for oral antibiotic monotherapy vs IV plus oral antibiotics).

However, the outcomes failed to demonstrate noninferiority between the two regimens (difference, -3.6 percent, 1-sided 95 percent CI, -9.7 percent to ∞**; p_{noninferiority}=0.26). [JAMA 2021;325:353-362]

Twenty-seven and 22 patients assigned to oral antibiotic monotherapy and IV–oral antibiotics, respectively, underwent appendectomy at primary hospitalization, while 61 and 53, respectively, underwent appendectomy due to suspected recurrence during 1-year follow-up.

Of those who underwent appendectomy at primary hospitalization, 18 and 11 assigned to oral antibiotic monotherapy and IV–oral antibiotics, respectively, had complicated appendicitis at surgery, resulting in a true primary failure rate of 6.1 and 3.8 percent, respectively (difference, 2.3 percent; p=0.25).

Five and eight patients assigned to oral antibiotic monotherapy and IV–oral antibiotics, respectively, who underwent appendectomy during 1-year follow-up were found to not have appendicitis (based on histopathological specimen), resulting in a true recurrence rate of 20.9 and 16.7 percent, respectively (difference, 4.2 percent; p=0.22).

Among patients who underwent appendectomy for suspected appendicitis recurrence, time to surgery was a median 87 days in the oral antibiotic monotherapy group vs 120 days in the IV–oral antibiotic group.

Duration of primary hospitalization did not differ between the oral antibiotic monotherapy and the IV–oral antibiotic groups (median 28.9 vs 29.9 days; p=0.38), nor did overall hospitalization over 1-year follow up (median 36.5 vs 35.7 days; p=0.91) or duration of sick leave (median 7 days in both groups).

There were no deaths over the follow-up period. Adverse events (AEs) occurred in 4.8 and 7.3 percent of patients in the oral antibiotic monotherapy and the IV–oral antibiotic groups, respectively. Two patients in the oral antibiotic monotherapy group discontinued treatment due to suspected antibiotic-related AEs, while five patients in the IV–oral antibiotic group reported prolonged diarrhoea at 2 months, though none at 1-year follow-up.

A non-surgical approach the way forward?

“It is well established that nonoperative management of appendicitis with IV antibiotics is a suitable alternative to appendectomy. The aim of the current study was to avoid the use of IV antibiotics by replacing them with oral antibiotics,” said the authors.

In addition, the authors wished to look at regimens that could avoid hospitalization, which has become particularly important during the COVID-19 pandemic.

“[In this study,] patients with acute, uncomplicated appendicitis treated with oral antibiotics alone met the prespecified threshold for treatment success but failed to demonstrate noninferiority relative to systemic antibiotics followed by oral antibiotics,” they said.

Nonetheless, these results add to the evidence suggesting the efficacy and safety of a non-surgical approach for uncomplicated appendicitis, said Drs Peter Minneci and Katherine Deans from the Nationwide Children’s Hospital, Columbus, Ohio, US, in an editorial. [JAMA 2021;325:351-352]

As such, they called for further research into identifying not the efficacy of non-surgical treatment, but the optimal treatment regimen for uncomplicated appendicitis, including duration and mode of antibiotic treatment.

“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,” noted Minneci and Deans.