<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03257423</url>
  </required_header>
  <id_info>
    <org_study_id>MAPPAC</org_study_id>
    <nct_id>NCT03257423</nct_id>
  </id_info>
  <brief_title>Acute Appendicitis and Microbiota - Etiology of Appendicitis and Antibiotic Therapy Effects</brief_title>
  <acronym>MAPPAC</acronym>
  <official_title>Acute Appendicitis and Microbiota - Ethology of Appendicitis and Effects of the Antimicrobial Treatment - The MAPPAC (Microbiology Appendicitis Acuta) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Turku University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tampere University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oulu University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kuopio University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Jyväskylä Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Turku University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Appendicectomy has been the treatment of acute appendicitis for over a hundred years.&#xD;
      Appendicectomy, however, includes operative and postoperative risks despite being a routine&#xD;
      procedure. Several studies have proved promising results of the safety and efficiency of&#xD;
      antibiotics in the treatment of acute uncomplicated appendicitis. The previous APPAC study by&#xD;
      the investigators, published in 2015 in the Journal of American Medical Association, also&#xD;
      proved promising results with 73% of patients with uncomplicated appendicitis treated&#xD;
      successfully with antibiotics. None of the patients initially treated with antibiotics that&#xD;
      later had appendectomy had major complications. The results of the APPAC trial suggest that&#xD;
      CT proven uncomplicated acute appendicitis is not a surgical emergency and antibiotic therapy&#xD;
      is a safe first-line treatment option. Reducing unnecessary appendectomies has also been&#xD;
      shown to lead to significant economic savings. On the other hand, antibiotic therapies have&#xD;
      been shown to have an effect on the normal gut microbiota and are considered an increasing&#xD;
      global health threat underlining the importance of evaluating both short- and long-term&#xD;
      effects of the antimicrobial treatment in old and new indications.&#xD;
&#xD;
      The aims of this randomized prospective study are:&#xD;
&#xD;
        1. To evaluate the possible role and differences in the microbiological etiology of&#xD;
           complicated and uncomplicated appendicitis.&#xD;
&#xD;
        2. To determine the effects of both antibiotic and placebo treatment on the composition of&#xD;
           gut microbiota, and to evaluate how it recovers after the appendicitis-related&#xD;
           antimicrobial treatment (AMT)&#xD;
&#xD;
        3. To evaluate the effects of the duration of the hospital stay on the AMR reservoir of the&#xD;
           gut microbiota.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Appendectomy has been the treatment of acute appendicitis for over a hundred years.&#xD;
      Appendicectomy, however, includes operative and postoperative risks despite being a routine&#xD;
      procedure. Several studies have proved promising results of the safety and efficiency of&#xD;
      antibiotics in the treatment of acute uncomplicated appendicitis. The previous APPAC study by&#xD;
      the investigators, published in 2015 in the Journal of American Medical Association, also&#xD;
      proved promising results with 73% of patients with uncomplicated appendicitis treated&#xD;
      successfully with antibiotics. None of the patients initially treated with antibiotics that&#xD;
      later had appendectomy had major complications. The results of the APPAC trial suggest that&#xD;
      CT proven uncomplicated acute appendicitis is not a surgical emergency and antibiotic therapy&#xD;
      is a safe first-line treatment option. Reducing unnecessary appendectomies has also been&#xD;
      shown to lead to significant economic savings. On the other hand, antibiotic therapies have&#xD;
      been shown to have an effect on the normal gut microbiota.&#xD;
&#xD;
      Gut microbiota is an extremely complex ecosystem with both high bacterial density and&#xD;
      diversity. Recent scientific evidence emphasizes that the symbiosis between the host and the&#xD;
      balanced gut microbiota supports good health, and contributes to various biochemical and&#xD;
      metabolic functions occurring in host's body. The possible role of the somehow distorted gut&#xD;
      microbiota composition in addition to its metabolites in the etiopathogenesis of many&#xD;
      diseases such as allergy, inflammatory bowel disease, type 1 diabetes and obesity related&#xD;
      disorders, has been recently proposed. Further, detected alterations and perturbations both&#xD;
      in the gut microbiota composition and functionality have been linked to the development of&#xD;
      various malignancies such as colorectal cancer, gastric cancer and hepatocellular carcinoma.&#xD;
      To date, the role of the microbes and especially the members of the commensal microbiota with&#xD;
      their structural compartments and metabolites in the pathogenesis and etiology of&#xD;
      appendicitis have not been clarified in detail, despite the recent knowledge that&#xD;
      uncomplicated acute appendicitis could be treated by antibiotic treatments alone. Further,&#xD;
      there is only limited amount of evidence on the appendix microbial composition in humans.&#xD;
&#xD;
      Microbial overgrowth has been speculated to serve as a secondary consequence in appendicitis.&#xD;
      However, recent accumulating evidence suggests that primary bacterial infection may actually&#xD;
      be an initiating event in the pathogenesis of the disease. Interestingly, it has been&#xD;
      postulated that the appendix could serve as a microbial reservoir for repopulating the&#xD;
      gastrointestinal tract in times of necessity thus gut microbiota may act as a source for&#xD;
      these pathogenic intruders. Further it has been reported that certain members of the gram&#xD;
      negative Fusobacteria especially F. nucleatum and necrophorum are present in most&#xD;
      appendicitis samples.&#xD;
&#xD;
      Additionally, antimicrobial resistance (AMR) is considered an increasing global threat.&#xD;
      According to the WHO (World Health Organisation), in 2050s more people will be killed by AMR&#xD;
      bacteria than by all cancers.The use of antimicrobials in humans and especially in animal&#xD;
      health care and production industry are the major causes of increasing AMR worldwide; the&#xD;
      prudent use of antimicrobials is essential to prevent increasing AMR. Antimicrobials are&#xD;
      known to decrease the gut microbiota diversity, richness and species variation and cause the&#xD;
      perturbation of its overall balance and even a short-term antimicrobial treatment has a&#xD;
      long-term impact on its composition underlining the importance of evaluating both short- and&#xD;
      long-term effects of the antimicrobial treatment in old and new indications.&#xD;
&#xD;
      The aims of this randomized prospective study are:&#xD;
&#xD;
        1. To evaluate the possible role and differences in the microbiological etiology of&#xD;
           complicated and uncomplicated appendicitis. The bacterial composition of the complicated&#xD;
           appendix will be compared to the gut microbiota composition determined from the fecal&#xD;
           sample collected from the same individual. Additionally, these results will be compared&#xD;
           to the gut microbiota composition of patients with uncomplicated acute appendicitis.&#xD;
&#xD;
        2. To determine the effects of both antibiotic and placebo treatment on the composition of&#xD;
           gut microbiota, and to evaluate how it recovers after the appendicitis-related&#xD;
           antimicrobial treatment (AMT). The bacterial composition and AMR reservoir of the gut&#xD;
           microbiota will be evaluated both pre and post treatment in patients receiving&#xD;
           antibiotic or placebo treatment for uncomplicated acute appendicitis. Additionally, the&#xD;
           recovery of gut microbiota composition and disappearance of AMR will be evaluated. We&#xD;
           will compare two variations (i.v.and p.o.) of antibiotic treatment with the placebo&#xD;
           treatment.&#xD;
&#xD;
        3. To evaluate the effects of the duration of the hospital stay on the AMR reservoir of the&#xD;
           gut microbiota. According to the study protocols of the APPAC II and III trials,&#xD;
           patients will spend either 1 or 3 days in the hospital in order to receive treatment&#xD;
           before continuing the selected treatment at home. We will evaluate the effects of length&#xD;
           of stay on the AMR reservoir of gut microbiota as well as evaluating if and when&#xD;
           possible colonization occurs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">April 4, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>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</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Microbiology in the etiology of acute appendicitis</measure>
    <time_frame>1 day</time_frame>
    <description>Differences in the microbiological etiology of complicated and uncomplicated appendicitis</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effects of antimicrobial treatment on gut microbiota</measure>
    <time_frame>1 year</time_frame>
    <description>Determining 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 evaluated by rectal swabs pre- and post treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects of hospital stay duration on the AMR reservoir of the gut microbiota</measure>
    <time_frame>3 days</time_frame>
    <description>The effect of length of hospital stay (days) on the AMR reservoir of gut microbiota and colonization occurrence evaluated by analysing rectal swabs microbiota pre- and post-treatment at 0, 1 and 3 days.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Acute Appendicitis</condition>
  <arm_group>
    <arm_group_label>I.v. + p.o. antibiotics (APPAC II)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>P.o. moxifloxacin (APPAC II)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo treatment (APPAC III)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Surgery (complicated appendicitis)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Surgery (uncomplicated appendicitis)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>I.v. + p.o. antibiotics (APPAC III)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ertapenem followed by levofloxacin and metronidazole</intervention_name>
    <description>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)</description>
    <arm_group_label>I.v. + p.o. antibiotics (APPAC II)</arm_group_label>
    <arm_group_label>I.v. + p.o. antibiotics (APPAC III)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Moxifloxacin</intervention_name>
    <description>Moxifloxacin 400 mg once a day for seven days (APPAC II + MAPPAC)</description>
    <arm_group_label>P.o. moxifloxacin (APPAC II)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Appendectomy</intervention_name>
    <description>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).</description>
    <arm_group_label>Surgery (complicated appendicitis)</arm_group_label>
    <arm_group_label>Surgery (uncomplicated appendicitis)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo i.v. once a day for three days (APPAC III + MAPPAC) followed by placebo capsules three times a day for four days.</description>
    <arm_group_label>Placebo treatment (APPAC III)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-60 years&#xD;
&#xD;
          -  CT confirmed uncomplicated or complicated acute appendicitis&#xD;
&#xD;
          -  Ability to give consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age under 18 years or over 60 years&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Allergy to contrast media or iodine&#xD;
&#xD;
          -  Allergy or contraindication to antibiotic therapy&#xD;
&#xD;
          -  Renal insufficiency&#xD;
&#xD;
          -  Metformin medication&#xD;
&#xD;
          -  Severe systemic illness (for example malignancy, medical condition requiring&#xD;
             immunosuppressant medication)&#xD;
&#xD;
          -  Inability to co-operate and give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paulina Salminen, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Turku University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Turku University Hospital</name>
      <address>
        <city>Turku</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>August 2, 2017</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>November 9, 2020</last_update_submitted>
  <last_update_submitted_qc>November 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Turku University Hospital</investigator_affiliation>
    <investigator_full_name>Paulina Salminen</investigator_full_name>
    <investigator_title>MD, PhD, Chief of Acute Care Surgery</investigator_title>
  </responsible_party>
  <keyword>Uncomplicated acute appendicitis</keyword>
  <keyword>Complicated acute appendicitis</keyword>
  <keyword>Antibiotic therapy</keyword>
  <keyword>Microbiological etiology</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Appendicitis</mesh_term>
    <mesh_term>Acute Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Moxifloxacin</mesh_term>
    <mesh_term>Metronidazole</mesh_term>
    <mesh_term>Levofloxacin</mesh_term>
    <mesh_term>Ertapenem</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03257423
org study id: MAPPAC
nct id: NCT03257423
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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. To evaluate the possible role and differences in the microbiological etiology of
           complicated and uncomplicated appendicitis.

        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. To evaluate the effects of the duration of the hospital stay on the AMR reservoir of the
           gut microbiota.
Appendectomy 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.

      Gut microbiota is an extremely complex ecosystem with both high bacterial density and
      diversity. Recent scientific evidence emphasizes that the symbiosis between the host and the
      balanced gut microbiota supports good health, and contributes to various biochemical and
      metabolic functions occurring in host's body. The possible role of the somehow distorted gut
      microbiota composition in addition to its metabolites in the etiopathogenesis of many
      diseases such as allergy, inflammatory bowel disease, type 1 diabetes and obesity related
      disorders, has been recently proposed. Further, detected alterations and perturbations both
      in the gut microbiota composition and functionality have been linked to the development of
      various malignancies such as colorectal cancer, gastric cancer and hepatocellular carcinoma.
      To date, the role of the microbes and especially the members of the commensal microbiota with
      their structural compartments and metabolites in the pathogenesis and etiology of
      appendicitis have not been clarified in detail, despite the recent knowledge that
      uncomplicated acute appendicitis could be treated by antibiotic treatments alone. Further,
      there is only limited amount of evidence on the appendix microbial composition in humans.

      Microbial overgrowth has been speculated to serve as a secondary consequence in appendicitis.
      However, recent accumulating evidence suggests that primary bacterial infection may actually
      be an initiating event in the pathogenesis of the disease. Interestingly, it has been
      postulated that the appendix could serve as a microbial reservoir for repopulating the
      gastrointestinal tract in times of necessity thus gut microbiota may act as a source for
      these pathogenic intruders. Further it has been reported that certain members of the gram
      negative Fusobacteria especially F. nucleatum and necrophorum are present in most
      appendicitis samples.

      Additionally, antimicrobial resistance (AMR) is considered an increasing global threat.
      According to the WHO (World Health Organisation), in 2050s more people will be killed by AMR
      bacteria than by all cancers.The use of antimicrobials in humans and especially in animal
      health care and production industry are the major causes of increasing AMR worldwide; the
      prudent use of antimicrobials is essential to prevent increasing AMR. Antimicrobials are
      known to decrease the gut microbiota diversity, richness and species variation and cause the
      perturbation of its overall balance and even a short-term antimicrobial treatment has a
      long-term impact on its composition 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. To evaluate the possible role and differences in the microbiological etiology of
           complicated and uncomplicated appendicitis. The bacterial composition of the complicated
           appendix will be compared to the gut microbiota composition determined from the fecal
           sample collected from the same individual. Additionally, these results will be compared
           to the gut microbiota composition of patients with uncomplicated acute appendicitis.

        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). The bacterial composition and AMR reservoir of the gut
           microbiota will be evaluated both pre and post treatment in patients receiving
           antibiotic or placebo treatment for uncomplicated acute appendicitis. Additionally, the
           recovery of gut microbiota composition and disappearance of AMR will be evaluated. We
           will compare two variations (i.v.and p.o.) of antibiotic treatment with the placebo
           treatment.

        3. To evaluate the effects of the duration of the hospital stay on the AMR reservoir of the
           gut microbiota. According to the study protocols of the APPAC II and III trials,
           patients will spend either 1 or 3 days in the hospital in order to receive treatment
           before continuing the selected treatment at home. We will evaluate the effects of length
           of stay on the AMR reservoir of gut microbiota as well as evaluating if and when
           possible colonization occurs.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: 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
primary purpose: Other
masking: None (Open Label)
measure: Microbiology in the etiology of acute appendicitis
time frame: 1 day
description: Differences in the microbiological etiology of complicated and uncomplicated appendicitis
measure: Effects of antimicrobial treatment on gut microbiota
time frame: 1 year
description: Determining 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 evaluated by rectal swabs pre- and post treatment
measure: Effects of hospital stay duration on the AMR reservoir of the gut microbiota
time frame: 3 days
description: The effect of length of hospital stay (days) on the AMR reservoir of gut microbiota and colonization occurrence evaluated by analysing rectal swabs microbiota pre- and post-treatment at 0, 1 and 3 days.
arm group label: I.v. + p.o. antibiotics (APPAC II)
arm group type: Active Comparator
description: 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.
arm group label: P.o. moxifloxacin (APPAC II)
arm group type: Active Comparator
description: 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.
arm group label: Placebo treatment (APPAC III)
arm group type: Placebo Comparator
description: 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.
arm group label: Surgery (complicated appendicitis)
arm group type: Other
description: 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.
arm group label: Surgery (uncomplicated appendicitis)
arm group type: Other
description: 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.
arm group label: I.v. + p.o. antibiotics (APPAC III)
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Ertapenem followed by levofloxacin and metronidazole
description: 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)
arm group label: I.v. + p.o. antibiotics (APPAC II)
arm group label: I.v. + p.o. antibiotics (APPAC III)
intervention type: Drug
intervention name: Moxifloxacin
description: Moxifloxacin 400 mg once a day for seven days (APPAC II + MAPPAC)
arm group label: P.o. moxifloxacin (APPAC II)
intervention type: Procedure
intervention name: Appendectomy
description: 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).
arm group label: Surgery (complicated appendicitis)
arm group label: Surgery (uncomplicated appendicitis)
intervention type: Other
intervention name: Placebo
description: Placebo i.v. once a day for three days (APPAC III + MAPPAC) followed by placebo capsules three times a day for four days.
arm group label: Placebo treatment (APPAC III)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Paulina Salminen, MD, PhD
role: Principal Investigator
affiliation: Turku University Hospital
facility: 
country: Finland
responsible party type: Principal Investigator
investigator affiliation: Turku University Hospital
investigator full name: Paulina Salminen
investigator title: MD, PhD, Chief of Acute Care Surgery
mesh term: Appendicitis
mesh term: Acute Disease
mesh term: Moxifloxacin
mesh term: Metronidazole
mesh term: Levofloxacin
mesh term: Ertapenem
sharing ipd: No