Oral Moxifloxacin vs Intravenous Ertapenem and Oral Levofloxacin for Uncomplicated Appendicitis | Emergency Medicine | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute AppendicitisThe APPAC II Randomized Clinical Trial

Educational Objective
To learn the effect of oral antibiotics alone vs intravenous followed by oral antibiotics for acute uncomplicated appendicitis.
1 Credit CME
Key Points

Question  Is treatment with oral antibiotics alone noninferior to a combination of intravenous and oral antibiotics for treatment of computed tomography–confirmed uncomplicated acute appendicitis?

Findings  This multicenter randomized clinical trial included 583 adults with uncomplicated acute appendicitis who were treated with either 7 days of oral moxifloxacin or 2 days intravenous ertapenem followed by 5 days of levofloxacin and metronidazole. Treatment success (discharge from hospital without need for surgery and no recurrent appendicitis within 1 year) occurred in 70.2% who received oral antibiotics alone vs 73.8% of patients who received intravenous followed by oral antibiotics, with the confidence limit of the difference exceeding the noninferiority margin of 6%.

Meaning  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.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Paulina Salminen, MD, PhD, Department of Surgery, Turku University, Division of Digestive Surgery and Urology, Turku University Hospital, PO Box 52, 20520 Turku, Finland (paulina.salminen@tyks.fi).

Accepted for Publication: December 22, 2020.

Published Online: January 11, 2021. doi:10.1001/jama.2020.23525

Author Contributions: Drs Salminen and Haijanen had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. Drs Sippola and Haijanen contributed equally as co–first authors.

Concept and design: S. Sippola, Haijanen, Gronroos, Rautio, Nordström, Rantanen, Ilves, Löyttyniemi, Hurme, Tammilehto, Marttila, Savolainen, Aarnio, Salminen.

Acquisition, analysis, or interpretation of data: S. Sippola, Haijanen, Gronroos, Rautio, Nordström, Rantanen, Pinta, Ilves, Mattila, Rintala, Löyttyniemi, Hurme, Tammilehto, Meriläinen, Laukkarinen, Sävelä, T. Sippola, Paajanen, Salminen.

Drafting of the manuscript: S. Sippola, Haijanen, Löyttyniemi, Marttila, Salminen.

Critical revision of the manuscript for important intellectual content: S. Sippola, Haijanen, Gronroos, Rautio, Nordström, Rantanen, Pinta, Ilves, Rintala, Löyttyniemi, Hurme, Tammilehto, Marttila, Meriläinen, Laukkarinen, Sävelä, Aarnio, Paajanen.

Statistical analysis: S. Sippola, Haijanen, Löyttyniemi, Hurme, Tammilehto, Salminen.

Obtained funding: S. Sippola, Haijanen, Salminen.

Administrative, technical, or material support: Gronroos, Rautio, Nordström, Rantanen, Pinta, Mattila, Hurme, Tammilehto, Meriläinen, Laukkarinen, Sävelä, Savolainen, Salminen.

Supervision: Rautio, Rantanen, Pinta, Tammilehto, Marttila, Salminen.

Conflict of Interest Disclosures: Dr S. Sippola reported receiving grants from the Orion Research Foundation and the Gastroenterological Research Foundation and a government research grant awarded to Turku University Hospital during the conduct of the study and grants from the Mary and Georg C. Ehrnrooth Foundation and the Finnish Medical Foundation outside the submitted work. Dr Haijanen reported receiving grants from the Orion Research Foundation, a government research grant awarded to Turku University Hospital, and grants from the Gastroenterological Research Foundation during the conduct of the study. Dr Marttila reported receiving European Society of Clinical Microbiology and Infectious Diseases participation fees from Pfizer and personal fees from Merck Sharp and Dohme and Roche Diagnostics outside the submitted work. Dr Salminen reported receiving grants from Mary and Georg C. Ehrnrooth foundation, the Sigrid Juselius foundation, Finnish Academy, and a government research grant (EVO Foundation) during the conduct of the study and personal fees from Merck and Orion Pharma outside the submitted work. No other disclosures were reported.

Funding/Support: The APPAC II study was supported by research grants from the Mary and Georg C. Ehrnrooth Foundation (Salminen), the Sigrid Juselius Foundation (Salminen), the Finnish Academy (Salminen), the Orion Research Foundation (Sippola, Haijanen), and the Gastroenterological Research Foundation (Sippola, Haijanen) and a government research grant awarded to Turku University Hospital (Salminen, Sippola, Haijanen).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank Susanna Kulmala, MHA (Division of Digestive Surgery and Urology, Turku University Hospital), our research coordinator, and Teemu Kemppainen, BBA (Department of biostatistics, University of Turku), for statistical and data monitoring assistance, both of whom received compensation for their role in the study. We also thank all of the surgeons on-call who took part in the enrollment of trial patients. None of the surgeons who participated in the study received compensation.

References
1.
Salminen  P , Paajanen  H , Rautio  T ,  et al.  Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial.   JAMA. 2015;313(23):2340-2348. doi:10.1001/jama.2015.6154PubMedGoogle ScholarCrossref
2.
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):1259-1265. doi:10.1001/jama.2018.13201PubMedGoogle ScholarCrossref
3.
Sippola  S , Grönroos  J , Tuominen  R ,  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. doi:10.1002/bjs.10575PubMedGoogle ScholarCrossref
4.
Haijanen  J , Sippola  S , Tuominen  R ,  et al.  Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis: 5-year results of the APPAC randomized clinical trial.   PLoS One. 2019;14(7):e0220202. doi:10.1371/journal.pone.0220202PubMedGoogle Scholar
5.
Talan  DA , Saltzman  DJ , DeUgarte  DA , Moran  GJ .  Methods of conservative antibiotic treatment of acute uncomplicated appendicitis: A systematic review.   J Trauma Acute Care Surg. 2019;86(4):722-736. doi:10.1097/TA.0000000000002137PubMedGoogle ScholarCrossref
6.
Di Saverio  S , Podda  M , De Simone  B ,  et al.  Diagnosis and treatment of acute appendicitis: 2020 update of the WSES Jerusalem guidelines.   World J Emerg Surg. 2020;15(1):27. doi:10.1186/s13017-020-00306-3PubMedGoogle ScholarCrossref
7.
 COVID 19: Elective Case Triage Guidelines for Surgical Care. American College of Surgeons; 2020. Updated December 8, 2020. https://www.facs.org/covid-19/clinical-guidance/elective-case/emergency-surgery
8.
Sippola  S , Haijanen  J , Viinikainen  L ,  et al.  Quality of life and patient satisfaction at 7-year follow-up of antibiotic therapy vs appendectomy for uncomplicated acute appendicitis: a secondary analysis of a randomized clinical trial.   JAMA Surg. 2020;155(4):283-289. doi:10.1001/jamasurg.2019.6028PubMedGoogle ScholarCrossref
9.
Minneci  PC , Sulkowski  JP , Nacion  KM ,  et al.  Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children.   J Am Coll Surg. 2014;219(2):272-279. doi:10.1016/j.jamcollsurg.2014.02.031PubMedGoogle ScholarCrossref
10.
Ehlers  AP , Talan  DA , Moran  GJ , Flum  DR , Davidson  GH .  Evidence for an antibiotics-first strategy for uncomplicated appendicitis in adults: a systematic review and gap analysis.   J Am Coll Surg. 2016;222(3):309-314. doi:10.1016/j.jamcollsurg.2015.11.009PubMedGoogle ScholarCrossref
11.
Hansson  J , Körner  U , Khorram-Manesh  A , Solberg  A , Lundholm  K .  Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients.   Br J Surg. 2009;96(5):473-481. doi:10.1002/bjs.6482PubMedGoogle ScholarCrossref
12.
Talan  DA , Saltzman  DJ , Mower  WR ,  et al.  Antibiotics-first versus surgery for appendicitis: a US pilot randomized controlled trial allowing outpatient antibiotic management.   Ann Emerg Med. 2017;70(1):1-11. doi:10.1016/j.annemergmed.2016.08.446PubMedGoogle ScholarCrossref
13.
Minneci  PC , Hade  EM , Lawrence  AE ,  et al; Midwest Pediatric Surgery Consortium.  Association of nonoperative management using antibiotic therapy vs laparoscopic appendectomy with treatment success and disability days in children with uncomplicated appendicitis.   JAMA. 2020;324(6):581-593. doi:10.1001/jama.2020.10888PubMedGoogle ScholarCrossref
14.
Flum  DR , Davidson  GH , Monsell  SE ,  et al; CODA Collaborative.  A randomized trial comparing antibiotics with appendectomy for appendicitis.   N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320PubMedGoogle ScholarCrossref
15.
Kaji  AH , Lewis  RJ .  Noninferiority trials: is a new treatment almost as effective as another?   JAMA. 2015;313(23):2371-2372. doi:10.1001/jama.2015.6645PubMedGoogle ScholarCrossref
16.
De Waele  JJ , Tellado  JM , Alder  J ,  et al.  Randomised clinical trial of moxifloxacin versus ertapenem in complicated intra-abdominal infections: results of the PROMISE study.   Int J Antimicrob Agents. 2013;41(1):57-64. doi:10.1016/j.ijantimicag.2012.08.013PubMedGoogle ScholarCrossref
17.
Goldstein  EJ , Solomkin  JS , Citron  DM , Alder  JD .  Clinical efficacy and correlation of clinical outcomes with in vitro susceptibility for anaerobic bacteria in patients with complicated intra-abdominal infections treated with moxifloxacin.   Clin Infect Dis. 2011;53(11):1074-1080. doi:10.1093/cid/cir664PubMedGoogle ScholarCrossref
18.
Solomkin  JS , Mazuski  JE , Bradley  JS ,  et al.  Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America.   Surg Infect (Larchmt). 2010;11(1):79-109. doi:10.1089/sur.2009.9930PubMedGoogle ScholarCrossref
19.
Dindo  D , Demartines  N , Clavien  PA .  Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.   Ann Surg. 2004;240(2):205-213. doi:10.1097/01.sla.0000133083.54934.aePubMedGoogle ScholarCrossref
20.
Sippola  S , Grönroos  J , Sallinen  V ,  et al.  A randomised placebo-controlled double-blind multicentre trial comparing antibiotic therapy with placebo in the treatment of uncomplicated acute appendicitis: APPAC III trial study protocol.   BMJ Open. 2018;8(11):e023623. doi:10.1136/bmjopen-2018-023623PubMedGoogle Scholar
21.
Haijanen  J , Sippola  S , Grönroos  J ,  et al; APPAC study group.  Optimising the antibiotic treatment of uncomplicated acute appendicitis: a protocol for a multicentre randomised clinical trial (APPAC II trial).   BMC Surg. 2018;18(1):117. doi:10.1186/s12893-018-0451-yPubMedGoogle ScholarCrossref
22.
Styrud  J , Eriksson  S , Nilsson  I ,  et al.  Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial.   World J Surg. 2006;30(6):1033-1037. doi:10.1007/s00268-005-0304-6PubMedGoogle ScholarCrossref
23.
Vons  C , Barry  C , Maitre  S ,  et al.  Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial.   Lancet. 2011;377(9777):1573-1579. doi:10.1016/S0140-6736(11)60410-8PubMedGoogle ScholarCrossref
24.
Harnoss  JC , Probst  P , Büchler  MW , Diener  MK .  Antibiotics versus appendicectomy for the treatment of uncomplicated acute appendicitis: an updated meta-analysis of randomised controlled trials by Rollins et al.   World J Surg. 2017;41(9):2411. doi:10.1007/s00268-016-3864-8PubMedGoogle ScholarCrossref
25.
Sallinen  V , Akl  EA , You  JJ ,  et al.  Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis.   Br J Surg. 2016;103(6):656-667. doi:10.1002/bjs.10147PubMedGoogle ScholarCrossref
26.
Sakran  JV , Mylonas  KS , Gryparis  A ,  et al.  Operation versus antibiotics—the “appendicitis conundrum” continues: a meta-analysis.   J Trauma Acute Care Surg. 2017;82(6):1129-1137. doi:10.1097/TA.0000000000001450PubMedGoogle ScholarCrossref
27.
Podda  M , Gerardi  C , Cillara  N ,  et al.  Antibiotic treatment and appendectomy for uncomplicated acute appendicitis in adults and children: a systematic review and meta-analysis.   Ann Surg. 2019;270(6):1028-1040. doi:10.1097/SLA.0000000000003225PubMedGoogle ScholarCrossref
28.
Ielpo  B , Podda  M , Pellino  G ,  et al; ACIE Appy Study Collaborative.  Global attitudes in the management of acute appendicitis during COVID-19 pandemic: ACIE Appy Study.   Br J Surg. Published online October 8, 2020. doi:10.1002/bjs.11999PubMedGoogle Scholar
29.
Chabok  A , Påhlman  L , Hjern  F , Haapaniemi  S , Smedh  K , Group  AS ; AVOD Study Group.  Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis.   Br J Surg. 2012;99(4):532-539. doi:10.1002/bjs.8688PubMedGoogle ScholarCrossref
30.
Daniels  L , Ünlü  Ç , de Korte  N ,  et al; Dutch Diverticular Disease (3D) Collaborative Study Group.  Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis.   Br J Surg. 2017;104(1):52-61. doi:10.1002/bjs.10309PubMedGoogle ScholarCrossref
31.
de Korte  N , Kuyvenhoven  JP , van der Peet  DL , Felt-Bersma  RJ , Cuesta  MA , Stockmann  HB .  Mild colonic diverticulitis can be treated without antibiotics. A case-control study.   Colorectal Dis. 2012;14(3):325-330. doi:10.1111/j.1463-1318.2011.02609.xPubMedGoogle ScholarCrossref
32.
Isacson  D , Smedh  K , Nikberg  M , Chabok  A .  Long-term follow-up of the AVOD randomized trial of antibiotic avoidance in uncomplicated diverticulitis.   Br J Surg. 2019;106(11):1542-1548. doi:10.1002/bjs.11239PubMedGoogle ScholarCrossref
33.
Isacson  D , Thorisson  A , Andreasson  K , Nikberg  M , Smedh  K , Chabok  A .  Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study.   Int J Colorectal Dis. 2015;30(9):1229-1234. doi:10.1007/s00384-015-2258-yPubMedGoogle ScholarCrossref
34.
Mali  JP , Mentula  PJ , Leppäniemi  AK , Sallinen  VJ .  Symptomatic treatment for uncomplicated acute diverticulitis: a prospective cohort study.   Dis Colon Rectum. 2016;59(6):529-534. doi:10.1097/DCR.0000000000000579PubMedGoogle ScholarCrossref
35.
Park  HC , Kim  MJ , Lee  BH .  Randomized clinical trial of antibiotic therapy for uncomplicated appendicitis.   Br J Surg. 2017;104(13):1785-1790. doi:10.1002/bjs.10660PubMedGoogle ScholarCrossref
36.
Livingston  EH , Woodward  WA , Sarosi  GA , Haley  RW .  Disconnect between incidence of nonperforated and perforated appendicitis: implications for pathophysiology and management.   Ann Surg. 2007;245(6):886-892. doi:10.1097/01.sla.0000256391.05233.aaPubMedGoogle ScholarCrossref
37.
Kim  HY , Park  JH , Lee  SS , Jeon  JJ , Yoon  CJ , Lee  KH .  Differentiation between complicated and uncomplicated appendicitis: diagnostic model development and validation study.   Abdom Radiol (NY). Published online September 10, 2020. doi:10.1007/s00261-020-02737-7PubMedGoogle Scholar
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