Acute Appendicitis and Microbiota - Etiology of Appendicitis and Antibiotic Therapy Effects

NCT03257423 | Unknown

• 1 other identifier: MAPPAC
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Appendicectomy has been the treatment of acute appendicitis for over a hundred years. Appendicectomy, however, includes operative and postoperative risks despite being a routine procedure. Several studies have proved promising results of the safety and efficiency of antibiotics in the treatment of acute uncomplicated appendicitis. The previous APPAC study by the investigators, published in 2015 in the Journal of American Medical Association, also proved promising results with 73% of patients with uncomplicated appendicitis treated successfully with antibiotics. None of the patients initially treated with antibiotics that later had appendectomy had major complications. The results of the APPAC trial suggest that CT proven uncomplicated acute appendicitis is not a surgical emergency and antibiotic therapy is a safe first-line treatment option. Reducing unnecessary appendectomies has also been shown to lead to significant economic savings. On the other hand, antibiotic therapies have been shown to have an effect on the normal gut microbiota and are considered an increasing global health threat underlining the importance of evaluating both short- and long-term effects of the antimicrobial treatment in old and new indications. The aims of this randomized prospective study are:

1. 1.To evaluate the possible role and differences in the microbiological etiology of complicated and uncomplicated appendicitis.
2. 2.To determine the effects of both antibiotic and placebo treatment on the composition of gut microbiota, and to evaluate how it recovers after the appendicitis-related antimicrobial treatment (AMT)
3. 3.To evaluate the effects of the duration of the hospital stay on the AMR reservoir of the gut microbiota.

Conditions

Acute Appendicitis

Keywords

Uncomplicated acute appendicitis; Complicated acute appendicitis; Antibiotic therapy; Microbiological etiology

Outcome Measures

Primary Outcomes (1)

• Microbiology in the etiology of acute appendicitis

  Differences in the microbiological etiology of complicated and uncomplicated appendicitis

  1 day

Secondary Outcomes (2)

• Effects of antimicrobial treatment on gut microbiota

  1 year

• Effects of hospital stay duration on the AMR reservoir of the gut microbiota

  3 days

Study Arms (6)

I.v. + p.o. antibiotics (APPAC II)

ACTIVE COMPARATOR

Patients in this group recruited also in APPAC II trial will receive i.v. antibiotics (ertapenem 1 g twice per day) for 2 days followed by p.o. antibiotics (levofloxacin 500 mg x 1 and metronidazole 500 mg x 3) for 5 days, for a total treatment duration of 7 days. From these patients, rectal swab samples will be collected at day 0 (before treatment) and day 1 (after beginning of treatment), serum sample before treatment initiation.

Drug: Ertapenem followed by levofloxacin and metronidazole

P.o. moxifloxacin (APPAC II)

ACTIVE COMPARATOR

Patients in this group recruited also in APPAC II trial will receive p.o. antibiotics for a total of 7 days, moxifloxacin 400 mg once per day. From these patients, rectal swab samples of faces will be collected at two time points, day 0 (before treatment) and day 1 (after beginning of treatment), serum sample before treatment initiation.

Drug: Moxifloxacin

Placebo treatment (APPAC III)

PLACEBO COMPARATOR

Patients in this group recruited also in APPAC III trial will receive i.v. placebo 3 times per day for 3 days followed by p.o. placebo 3 times per day for 4 additional days. From these patients rectal swab samples will be collected twice during the stay at the research hospital (time points 0 and 1 or 3 d) and three times at home (follow-up at one week, six months and one year). Serum samples are taken prior to treatment initiation and at 10 days after the treatment initiation.

Other: Placebo

Surgery (complicated appendicitis)

OTHER

Patients in this group will undergo appendectomy and are recruited only in the MAPPAC trial. Rectal swab samples and biopsies from the removed appendix will be collected from these patients.

Procedure: Appendectomy

Surgery (uncomplicated appendicitis)

OTHER

Patients in this group will undergo appendectomy either after refusing to participate in the APPAC II or APPAC III trials or after presenting with recurrent appendicitis after antibiotic or placebo therapy. Rectal swab samples of faces and biopsies from the removed appendix will be collected from these patients.

Procedure: Appendectomy

I.v. + p.o. antibiotics (APPAC III)

ACTIVE COMPARATOR

Patients in this group recruited also in APPAC III trial will receive i.v. antibiotics (ertapenem 1 g twice per day) for 3 days followed by p.o. antibiotics (levofloxacin 500 mg x 1 and metronidazole 500 mg x 3) for 4 days, for a total treatment duration of 7 days. From these patients rectal swab samples will be collected twice during the stay at the research hospital (time points 0 and 1 or 3 d) and three times at home (follow-up at one week, six months and one year). Serum samples are taken prior to treatment initiation and at 10 days after the treatment initiation.

Drug: Ertapenem followed by levofloxacin and metronidazole

Interventions

Ertapenem followed by levofloxacin and metronidazole DRUG

Ertapenem 1 g i.v. daily for either 2 days (MAPPAC + APPAC II patients) or 3 days (MAPPAC + APPAC III) followed by p.o. levofloxacin 500 mg x 1 + metronidazole 500 mg x 3 for either 5 days (APPAC II + MAPPAC) or 4 days (APPAC III + MAPPAC)

I.v. + p.o. antibiotics (APPAC II); I.v. + p.o. antibiotics (APPAC III)

Moxifloxacin DRUG

Moxifloxacin 400 mg once a day for seven days (APPAC II + MAPPAC)

P.o. moxifloxacin (APPAC II)

Appendectomy PROCEDURE

Primarily laparoscopic appendectomy for either complicated acute appendicitis or uncomplicated acute appendicitis (refusing to participate in APPAC II or III trials or recurrent acute appendicitis).

Surgery (complicated appendicitis); Surgery (uncomplicated appendicitis)

Placebo OTHER

Placebo i.v. once a day for three days (APPAC III + MAPPAC) followed by placebo capsules three times a day for four days.

Placebo treatment (APPAC III)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-60 years
• CT confirmed uncomplicated or complicated acute appendicitis
• Ability to give consent to participate in the study

You may not qualify if:

• Age under 18 years or over 60 years
• Pregnancy or lactation
• Allergy to contrast media or iodine
• Allergy or contraindication to antibiotic therapy
• Renal insufficiency
• Metformin medication
• Severe systemic illness (for example malignancy, medical condition requiring immunosuppressant medication)
• Inability to co-operate and give informed consent

Sponsors & Collaborators

• Turku University Hospital: lead
• Tampere University Hospital: collaborator
• Oulu University Hospital: collaborator
• Kuopio University Hospital: collaborator
• Helsinki University Central Hospital: collaborator
• Jyväskylä Central Hospital: collaborator

Study Sites (1)

Turku University Hospital

Turku, Finland

Location

Related Publications (3)

• Vanhatalo S, Makila E, Hakanen AJ, Munukka E, Salonen J, Saarinen T, Gronroos J, Sippola S, Salminen P. Appendicolith classification: physical and chemical properties of appendicoliths in patients with CT diagnosed acute appendicitis - a prospective cohort study. BMJ Open Gastroenterol. 2024 Aug 19;11(1):e001403. doi: 10.1136/bmjgast-2024-001403.

  PMID: 39160081 DERIVED

• Vanhatalo S, Munukka E, Kallonen T, Sippola S, Gronroos J, Haijanen J, Hakanen AJ, Salminen P. Appendiceal microbiome in uncomplicated and complicated acute appendicitis: A prospective cohort study. PLoS One. 2022 Oct 14;17(10):e0276007. doi: 10.1371/journal.pone.0276007. eCollection 2022.

  PMID: 36240181 DERIVED

• Vanhatalo S, Munukka E, Sippola S, Jalkanen S, Gronroos J, Marttila H, Eerola E, Hurme S, Hakanen AJ, Salminen P; APPAC collaborative study group. Prospective multicentre cohort trial on acute appendicitis and microbiota, aetiology and effects of antimicrobial treatment: study protocol for the MAPPAC (Microbiology APPendicitis ACuta) trial. BMJ Open. 2019 Sep 6;9(9):e031137. doi: 10.1136/bmjopen-2019-031137.

  PMID: 31494621 DERIVED

MeSH Terms

Conditions

Appendicitis

Interventions

Metronidazole; Moxifloxacin; Appendectomy

Condition Hierarchy (Ancestors)

Intraabdominal Infections; Infections; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Cecal Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Digestive System Surgical Procedures; Surgical Procedures, Operative

Study Officials

• Paulina Salminen, MD, PhD

  Turku University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Chief of Acute Care Surgery

Model Details: Patients are enrolled in conjuction with APPAC II (NCT03236961) and APPAC III (NCT 03234296) trials, all patients with uncomplicated or complicated acute appendicitis are evaluated for MAPPAC enrollment. MAPPAC study groups: complicated acute appendicitis (samples: rectal swabs, serum, removed appendix), APPAC II patients in two groups according to APPAC II randomized antibiotic therapy (uncomplicated acute appendicitis, samples: rectal swabs, serum and in cases of antibiotic treatment failure or appendicitis recurrence also removed appendix), APPAC III patients in two groups according to APPAC III randomized group of antibiotc or placebo therapy (uncomplicated acute appendicitis, samples: rectal swabs, serum and in cases of antibiotic or placebo treatment failure or appendicitis recurrence also removed appendix), and patients with uncomplicated acute appendicitis declining to participate in APPAC II or III trials undergoing appendectomy

Study Record Dates

• First Submitted: August 2, 2017
• First Posted: August 22, 2017
• Study Start: April 4, 2017
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2025
• Last Updated: November 10, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1)