Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial

Abstract

Importance: Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known.

Objective: To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis.

Design, setting, and participants: The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019.

Interventions: Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days.

Main outcomes and measures: The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference.

Results: Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin.

Conclusion and relevance: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics.

Trial registration: ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.

Figure 1.. Flow of Patients in a Study of the Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Uncomplicated Acute Appendicitis

^aIncludes appendicolith, perforation, abscess, or suspicion of tumor. ^bThe majority of these patients underwent ultrasonography examination, magnetic resonance imaging, or non–contrast-enhanced computed tomography (CT). Twelve patients underwent an operation without diagnostic imaging. ^cThe alternative diagnoses were as follows: diverticulitis (n = 36), ovarian mass/cyst (n = 25), colitis (n = 24), pelvic inflammatory disease (n = 12), mesenterial lymphadenitis (n = 11), pyelonephritis (n = 8), kidney/ureteral stone (n = 4), bowel obstruction (n = 1), and miscellaneous pathological findings or suspicion of such (n = 55). ^dAdditional exclusion criteria were pregnancy, lactation, allergy to contrast media, kidney insufficiency, use of metformin, systemic illness, and inability to consent. ^eA randomized, placebo-controlled, double-blind, multicenter trial comparing antibiotic therapy with placebo in the treatment of uncomplicated acute appendicitis. ^fPatients who withdrew consent within 24 hours of randomization who received a maximum of 1 dose of the randomized treatment were excluded from the analyses. Two patients, who withdrew their consent 5 and 7 days after randomization, were included in the analyses. ^gPatients erroneously randomized despite a finding of complicated acute appendicitis initially seen on CT imaging were excluded from the analyses according to the study protocol. ^hOperative or histopathological findings of appendicolith, gangrene, perforation, abscess, or tumor were classified as complicated acute appendicitis. ⁱOne patient in the oral antibiotic monotherapy group mistakenly received the treatment intended for the intravenous followed by oral antibiotics group. Four patients received 1 dose of moxifloxacin and thereafter cephalexin and metronidazole (2 due to suspected reactions to moxifloxacin, 1 due to lactation, and 1 to prevent a possible adverse interaction with the patient’s antidepressant).

Figure 2.. Time to Appendectomy After Initial Treatment in a Study of the Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis

A total of 581 of 583 patients (99.7%) were followed up to achievement of the primary outcome or to 1 year and included in this post hoc analysis. The solid dots represent appendectomies of histologically normal appendixes.