Supplemental Digital Content



Supplemental Digital Content. Table_1. General characteristics of eligible studies.

Supplemental Digital Content. Table_1. General characteristics of eligible studies.

|Study |Inclusion Criteria |Exclusion Criteria |Sample Size |Pre-intervention | Interventions |Outcomes |

| | | |Calculation |Imaging technique | | |

| | | | | |Antibiotics |Appendectomy | |

|Eriksson S. 1995 |Adult patients with typical |NR |NR |US |I.V. Cefotaxime |OA; antibiotics |Primary Endpoints: |

| |history of AA and clinical signs,| | | |2g/12h+Tinidazole 0.8 |administered for a |hospital stay, |

| |positive findings following US, | | | |g/24h. |period of 24 h, but |complications, pain, |

| |and either increased WBC and CRP | | | |Oral Ofloxacin |only when bowel |analgesic consumption, |

| |values or elevated WBC and CRP | | | |200mg/12h+Tinidazole500 |perforation or |inflammatory laboratory |

| |levels as measured on two | | | |mg/12h for 8 days following|abdominal spillage |tests and body |

| |separate occasions within a | | | |discharge. |occurred. |temperature. |

| |4-hour interval. | | | | | | |

| | | | | | | |Secondary Endpoints: NR |

|Styrud J. 2006 |Male patients (18-50 years) |Women (by decision of the ethics |NR |None |I.V. Cefotaxime |OA or LA, at the |Primary Endpoints: |

| |admitted for suspected AA with |committee), patients with suspicion of | | |2g/12h+Tinidazole 0.8 g/24h|surgeon's discretion. |hospital stay, level of |

| |CRP level > 10mg/l in whom |perforation of the appendix, patients | | | | |pain, sickness, days of |

| |perforation was not suspected. |unwilling to participate, patients with| | |Oral Ofloxacin | |sick leave from work, |

| | |C-reactive protein (CRP) level < | | |200mg/12h+Tinidazole 500 | |complications, |

| | |10mg/l, patients with positive | | |mg/12h for 10 days | |recurrences, diagnosis at |

| | |anamnesis for allergic reaction to the | | |following | |operation. |

| | |antibiotics to be used in the treatment| | |discharge | | |

| | |protocol | | | | |Secondary Endpoints: NR |

|Hansson J. 2009 |Patients older than 18 years with|NR |Yes |US/CT/None |I.V. Cefotaxime 1g/12h |Single dose antibiotic|Primary Endpoints: |

| |assumed AA (diagnosed according | | | |+Metronidazole 1.5g/24h. |prophylaxis, OA or LA,|treatment efficacy, major |

| |to established practice: history,| | | |Oral Ciprofloxacin |and post-operative |complications |

| |clinical status, laboratory tests| | | |500mg/12h+ Metronidazole |antibiotic treatment |(reoperation, abscess |

| |and, in some cases, US and CT | | | |400mg/8h |when the appendix was |formation, bowel |

| |scan) | | | |for 9 days following |gangrenous or |obstruction, wound rupture|

| | | | | |discharge |perforated |or hernia, serious |

| | | | | | | |anaesthesia-related or |

| | | | | | | |cardiac problems). |

| | | | | | | | |

| | | | | | | |Secondary Endpoints: minor|

| | | | | | | |complications, length of |

| | | | | | | |antibiotic therapy, |

| | | | | | | |abdominal pain after |

| | | | | | | |discharge from hospital, |

| | | | | | | |length of hospital stay |

| | | | | | | |and sick leave, total |

| | | | | | | |costs for the primary |

| | | | | | | |hospital stay. |

|Turhan AN. 2009 |Patients with AA, confirmed by |NR |NR |US/CT |I.V. Ampicillin 1g/6h |OA or LA at the |Primary Endpoints: |

| |physical examination, blood cell | | | |+Gentamicin 160mg/24h+ |surgeon's discretion. |Resistence to therapy, |

| |count (leukocytosis), abdominal | | | |Metronidazole 500mg/8h. |82.0% of the patients |recurrence, costs, |

| |US and CT scan | | | |Oral antibiotics (not |underwent OA and 18.0%|complications, hospital |

| | | | | |specified) for 10 days |LA |stay, histopathologic |

| | | | | |following discharge | |outcome, mortality and |

| | | | | | | |morbidity, Alvarado score.|

| | | | | | | | |

| | | | | | | |Secondary Endpoints: NR |

|Vons C. 2011 |All adults examined in the |Age < 18 years (no upper age limit); |Yes |CT |I.V. |OA or LA at the |Primary Endpoints: 30-day |

| |emergency department and |antibiotic treatment 5 days before; | | |Amoxicillin+Clavulanate |surgeon's discretion. |post therapeutic |

| |suspected to have an AA. |allergy to beta-lactam antibiotics; | | |3g/4g/24h. |65.5% LA and 34.5% |peritonitis; complicated |

| |Diagnosis of uncomplicated AA was|known intolerance to amoxicillin plus | | |Oral |OA. Antibiotic |appendicitis with |

| |assessed by CT imaging |clavulanic acid (nausea, vomiting); | | |Amoxicillin+Clavulanate |prophylaxis with 2 g |peritonitis identified at |

| | |receiving steroids or anticoagulant | | |3g/4g/24h |Amoxicillin+Clavulanat|surgery, postoperative |

| | |treatments; past history of | | |for 8 days following |e. Post-operative |peritonitis. |

| | |inflammatory bowel disease; pregnancy | | |discharge |antibiotics in case of| |

| | |or a positive pregnancy test; life | | | |complicated AA. | |

| | |expectancy less than 1 year; allergy to| | | | |Secondary Endpoints: |

| | |iodine or blood creatinine 200 μmol/L | | | | |number of days with a VAS |

| | |or more; inability to understand | | | | |pain score ≥ 4 (on a 0-10 |

| | |information about the protocol or to | | | | |scale); length of hospital|

| | |sign the consent form. | | | | |stay and absence from |

| | | | | | | |work; incidence of |

| | | | | | | |postoperative wound |

| | | | | | | |abscess, incisional |

| | | | | | | |hernia, adhesive |

| | | | | | | |occlusion. Recurrence of |

| | | | | | | |appendicitis after |

| | | | | | | |antibiotic treatment |

| | | | | | | |(appendicectomy done |

| | | | | | | |between 30 days and 1 year|

| | | | | | | |of follow-up, with |

| | | | | | | |confirmed diagnosis of |

| | | | | | | |appendicitis). |

|Armstrong J. 2014|Classic presentation of AA, less |Imaging not supporting the diagnosis, |NR |US |I.V. |LA in 100% of the |Primary Endpoints: failure|

| |than 48h of symptoms at |duration of symptoms > 48 h, other | | |Ciprofloxacin+Metronidazole|cases. |of initial treatment, |

| |presentation, diagnosis confirmed|indication for operative intervention, | | |or Ampicillin+ | |complications of initial |

| |with imaging. |evidence of perforation on imaging. | | |Gentamycin+Metronidazole. | |treatment (in the A group:|

| | | | | |Oral | |worsening or |

| | | | | |Amoxicillin+Clavulanate for| |non-resolution of symptoms|

| | | | | |1 week (dosing adjusted | |of appendicitis requiring |

| | | | | |for patient weight). | |operation, and perforation|

| | | | | | | |while attempting |

| | | | | | | |non-operative management; |

| | | | | | | |in the S group: |

| | | | | | | |peritonitis requiring |

| | | | | | | |reoperation, surgical site|

| | | | | | | |infections. |

| | | | | | | | |

| | | | | | | |Secondary Endpoints: |

| | | | | | | |length of stay, |

| | | | | | | |recurrences, repeat visits|

| | | | | | | |to hospital with symptoms.|

|Koike Y. 2014 |Patients aged 12 months to 15 |Appendix not detected on US or CT. |NR |US/CT |I.V. Cefoperazone 60 |NR |Primary Endpoints: NR |

| |years with US/CT confirmed | | | |mg/kg/day divided into | | |

| |uncomplicated AA (large external | | | |8-hourly doses, for at | |Secondary Endpoints: NR |

| |appendiceal diameter ≥ 6 mm, | | | |least 48 h. If the CRP | | |

| |without abscess formation. | | | |level was > 1.0 mg/dl at | | |

| | | | | |discharge, oral Cefcapene | | |

| | | | | |pivoxil was prescribed for | | |

| | | | | |3 days. | | |

|Park HC. 2014 |Patients aged ≥ 18 years, with |Complicated AA diagnosed by CT or US, |NR |US/CT |I.V. second-generation |Most LA, but 6 |Primary Endpoints: |

| |right lower quadrant pain and |history of heart disease or cerebral | | |cephalosporin and |patients underwent OA.|treatment failure , rate |

| |diagnosed with AA by CT or US. |vascular disease, previous history of | | |Metronidazole for 48 h and |Patients received |of complicated |

| | |antibiotic treatment in other | | |fasting for 24 h. |prophylactic |appendicitis with |

| | |hospitals, pregnancy. | | |Additional oral antibiotic |antibiotics, and if |peritonitis, recurrent |

| | | | | |therapy for 2 days |there was no sign of |appendicitis, |

| | | | | |following discharge. |infection, antibiotics|complications, length of |

| | | | | | |were discontinued. |hospital stay, total |

| | | | | | |Other antibiotic |costs. |

| | | | | | |regimens were used for| |

| | | | | | |2 or 3 days for | |

| | | | | | |suspected cases of | |

| | | | | | |complicated disease. | |

|Minneci PC. 2015 |Patients aged 7 to 17 years; 48h |Patients with a radiology reading of |Yes |US/CT |I.V. |Prompt initiation of |Primary Endpoints: 1-year |

| |or less of abdominal pain; WBC < |suspected perforation; diffuse | | |Piperacillin-Tazobactam |I.V. antibiotics and |success rate of NOM (not |

| |18.000; radiographic evidence of |peritonitis on clinical examination; | | |sodium or Ciprofloxacin and|LA within 12 h. |having undergone an |

| |nonruptured AA with an |CRP level higher than 40 mg/L if | | |Metronidazole for a minimum| |appendectomy at 1 year) |

| |appendiceal diameter of 1.1 cm or|collected; positive pregnancy test; | | |of 24 h. When tolerating | | |

| |less without fecalith , abscess |history of chronic abdominal pain. | | |oral diet, patients were | |Secondary Endpoints: |

| |or phlegmon on either US or CT; | | | |switched to oral | |complicated appendicitis |

| |surgical consultation confirming | | | |Amoxicillin-Clavulanate (or| |at 1 year, disability day |

| |a clinical diagnosis of AA. | | | |Ciprofloxacin and | |for the child at 1 year, |

| | | | | |Metronidazole). Patients | |disability days for the |

| | | | | |were discharged with oral | |parents at 1 year, health |

| | | | | |antibiotics to complete a | |related quality of life |

| | | | | |10-day total course. | |measures at 1 year, |

| | | | | | | |appendicitis-related total|

| | | | | | | |health costs at 1 year. |

|Salminen P. 2015 |Patients aged 18 to 60 years |Patients with complicated AA (defined |Yes |CT |I.V. Ertapenem 1g/24h. |OA: McBurney (94.5%) |Primary Endpoints: |

| |admitted to the emergency |as the presence of an appendicolith, | | |Oral Levofloxacin |or LA (5.5%). |resolution of acute |

| |department with clinical |perforation, abscess, or suspicion of a| | |500mg/24h+ Metronidazole |Prophylactic |appendicitis, resulting in|

| |suspicion of uncomplicated AA, |tumor on the CT scan). Age younger than| | |500mg/8h |antibiotics (1.5 g of |discharge from the |

| |confirmed by a CT scan. |18 years or older than 60 years; | | |for 7 days following |Cefuroxime and 500 mg |hospital without the need |

| | |contraindications for CT (pregnancy or | | |discharge |of Metronidazole) was |for surgical intervention |

| | |lactating, allergy to contrast media or| | | |administered |and no recurrent |

| | |iodine, renal insufficiency with serum | | | |approximately 30 |appendicitis during a |

| | |creatinine level > 150 μmol/L, actively| | | |minutes before the |minimum follow-up of 1 |

| | |taking metformin), peritonitis, | | | |incision was made. No |year. Treatment success in|

| | |patients unable to cooperate and | | | |further antibiotics |the appendectomy group was|

| | |provide informed consent, presence of | | | |were given to patients|defined as a patient |

| | |serious systemic illness. | | | |in the surgical group |successfully undergoing an|

| | | | | | |unless a wound |appendectomy. |

| | | | | | |infection was | |

| | | | | | |suspected |Secondary Endpoints: |

| | | | | | |postoperatively. |overall postintervention |

| | | | | | | |complications (surgical |

| | | | | | | |site infections, |

| | | | | | | |pneumonia, adverse effects|

| | | | | | | |of the antibiotic |

| | | | | | | |treatment, incisional |

| | | | | | | |hernia, bowel obstruction,|

| | | | | | | |persistent abdominal or |

| | | | | | | |incisional pain), late |

| | | | | | | |recurrence (after 1 year) |

| | | | | | | |of acute appendicitis |

| | | | | | | |after conservative |

| | | | | | | |treatment, length of |

| | | | | | | |hospital stay, sick leave,|

| | | | | | | |postintervention pain |

| | | | | | | |scores and the use of pain|

| | | | | | | |medication. |

|Svensson JF. 2015|All children between 5 and 15 |Suspicion of perforated AA on the basis|Yes |US/CT |I.V. Meropenem (10mg/kg x 3|The modality of |Primary Endpoints: |

| |years of age with a clinical |of generalized peritonitis; appendiceal| | |per 24 h) and Metronidazole|surgery (OA or LA) was|proportion of children in |

| |diagnosis of AA confirmed by |mass, diagnosed by clinical examination| | |(20mg/kg x 1 per 24 h) for |not stipulated in the |each group achieving |

| |US/CT, including those with an |and/or imaging; previous non-operative | | |at least 48 h. Once the |trial protocol. |“resolution of symptoms |

| |appendicolith |treatment of acute appendicitis | | |child was clinically well |Preoperative |without significant |

| | | | | |and tolerating oral intake,|antibiotic prophylaxis|complications”. |

| | | | | |the treatment was changed |with 20mg/kg of |Significant complications |

| | | | | |to oral Ciprofloxacin |Metronidazole. Cases |(length of stay > 7 days):|

| | | | | |(20mg/kg x 2 per 24 h) and |of simple or |abscess formation, need |

| | | | | |Metronidazole (20mg/kg x 2 |phlegmonous AA |for surgery within 48 h in|

| | | | | |per 24 h) for another 8 |received no further |the A group, recurrence of|

| | | | | |days |antibiotics, those |appendicitis, negative |

| | | | | | |with gangrenous AA |appendectomy. |

| | | | | | |received 24 h of I.V. | |

| | | | | | |Trimethoprim/Sulfameto|Secondary Endpoints: time |

| | | | | | |xazol/Metronidazole, |from randomization to |

| | | | | | |and those with |discharge, minor |

| | | | | | |perforated AA received|complications (wound |

| | | | | | |at least 3 days of |infections, wound |

| | | | | | |I.V. |dehiscence, diarrhea, |

| | | | | | |Trimethoprim/Sulfameto|etc), recurrent |

| | | | | | |xazol/Metronidazole, |appendicitis within 1 year|

| | | | | | |depending on clinical |of randomization, total |

| | | | | | |course. |costs of treatment. |

|Hartwich J. 2016 |All children aged 5-18 years with|Symptoms greater than 48h, presence or |Yes |US/MRI |I.V. |NR |Primary Endpoints: |

| |a clinical diagnosis of |suspicion of abscess on imaging, | | |Piperacillin-Tazobactam | |feasibility of NOM in |

| |uncomplicated AA, confirmed by |clinical suspicion of perforated AA, | | |(100mg/kg x 3 or 4 for at | |children, failure rates, |

| |US/MRI |significant comorbidities, inability or| | |least 24 h). Oral | |recurrence, cost-utility, |

| | |unwillingness to complete 7 days of | | |Amoxicillin+Clavulanate | |quality of life. |

| | |oral antibiotics, allergy to | | |(50mg/kg/day in 3 divided | | |

| | |Penicillin, inability to return to the | | |doses) for 1 week following| |Secondary Endpoints: NR |

| | |hospital in a timely fashion if | | |discharge | | |

| | |symptoms recurred or persisted | | | | | |

|Mahida JB. 2016 | Patients aged 7 to 17 years, |Findings of diffuse peritonitis, |Yes |US/CT |I.V. |I.V. |Primary Endpoints: percent|

| |abdominal pain for less than or |positive urine pregnancy test, history | | |Piperacillin-Tazobactam |Piperacillin-Tazobacta|of patients who were |

| |equal to 48 h, WBC less than |of chronic intermittent abdominal pain,| | |(Ciprofloxacin and |m (Ciprofloxacin and |successfully managed |

| |18.000 cells/μL, clinical history|CRP greater than 4mg/dL (if obtained) | | |Metronidazole if penicillin|Metronidazole if |nonoperatively with |

| |and examination consistent with | | | |allergic) for a minimum of |Penicillin allergic) |success defined ad not |

| |AA as determined by surgeon, and | | | |24 h. Patients who showed |and appendectomy |undergoing appendectomy by|

| |radiographic evidence of | | | |improvement and were | |1 year after discharge. |

| |nonruptured AA on US or CT with a| | | |tolerating regular diet at | | |

| |maximum appendiceal diameter less| | | |24 h after initiation of | |Secondary Endpoints: |

| |than or equal to 1.1 cm with an | | | |I.V. antibiotics were given| |percent of patients found |

| |appendicolith, but without | | | |a trial of | |to have complicated |

| |phlegmon or abscess | | | |Amoxicillin+Clavulanate | |appendicitis (gangrenous |

| | | | | |(oral Ciprofloxacin and | |or perforated) on |

| | | | | |Metronidazole if penicillin| |pathologic examination |

| | | | | |allergic) while in the | | |

| | | | | |hospital. Patients were | | |

| | | | | |discharged with oral | | |

| | | | | |antibiotics and completed a| | |

| | | | | |7 days course of | | |

| | | | | |antibiotics) | | |

|Tanaka Y. 2016 |Uncomplicated AA confirmed by |Pan-peritonitis, abscess, phlegmon, |NR |US/CT |I.V. Cefmetazole 100 |LA on the day of or |Primary Endpoints: |

| |US/CT |other complications | | |mg/kg/24h (maximum 4g/d) |the day after |Recurrence of |

| | | | | |followed by |admission. |appendicitis, |

| | | | | |Sulbactam/Ampicillin 200 |Prophylactic |complications, hospital |

| | | | | |mg/kg/24h (maximum 6g/d) |antibiotics were |stay, operative time |

| | | | | |and Ceftazidime 150 |administered | |

| | | | | |mg/kg/24h (maximum 4g/d) if|intravenously until 48| |

| | | | | |WBC did not decreased by |h after surgery | |

| | | | | |25% in 2 days, or Meropenem| | |

| | | | | |or Imipenem Cilast 60 | | |

| | | | | |mg/kg/24h (maximum 2g/d) | | |

| | | | | |and Gentamicin 5 mg/kg/24h | | |

| | | | | |(maximum 120 mg/d) | | |

|Allievi N. 2017 |Adult patients (aged more than |Appendectomy performed as an elective |NR |US/CT |I.V. Ertapenem 1g/24h or |LA or OA, depending on|Primary Endpoints: |

| |18) admitted with a diagnosis of |procedure (appendectomy during other | | |Piperacillin-Tazobactam |the on-call surgeon's |in-hospital length of stay|

| |AA. Diagnosis confirmed by |abdominal surgical procedures), | | |4.5mg/8h or Ceftriaxone |decision |at first admission, |

| |abdominal examination, blood |previous hospitalization for acute | | |1g/24h and Metronidazole | |cumulative individual |

| |tests sampling (including CRP, |appendicitis treated conservatively, | | |500mg/8h or Ciprofloxacin | |length of stay, number of |

| |WBC, polymorphonuclear cells |pregnancy status | | |500mg/12h and Metronidazole| |post-discharge lost work |

| |count), calculation of the AIR | | | |500mg/8h. Oral Amoxicillin | |days, failure rate, and |

| |score | | | |+Clavulanate 1g/8h for 5 | |length of stay |

| | | | | |days following discharge | | |

|Gorter RR. 2017 |Children aged 7-17 years old with|Children with signs of severe general |NR |US |I.V. |Immediate appendectomy|Primary Endpoints: |

| |a simple AA confirmed by imaging |illness, with a faecalith, or with | | |Amoxicillin+Clavulanate |with pre-, peri- and |percentage of patients |

| |studies |sonographic features of complex AA, | | |250/25 mg/kg/6h and |postoperative care |experiencing complications|

| | |significant co-morbidity, and those | | |Gentamicin 7mg/kg/24h. |(surgeons with |after initially NOM, as |

| | |with a known type 1 allergy for | | |Oral |extensive experience |compared to immediate |

| | |antibiotic used | | |Amoxicillin+Clavulanate |in treating children |appendectomy during the |

| | | | | |500/125mg/8h for 4 days |with appendicitis) |period of at least 1 year |

| | | | | |following discharge | |after initial treatment, |

| | | | | | | |total number of patients |

| | | | | | | |who underwent appendectomy|

| | | | | | | |after initially NOM during|

| | | | | | | |follow-up. |

| | | | | | | | |

| | | | | | | |Secondary Endpoints: |

| | | | | | | |recurrent appendicitis, |

| | | | | | | |interval appendectomy, |

| | | | | | | |faecalith (number of |

| | | | | | | |patients who underwent |

| | | | | | | |appendectomy due to the |

| | | | | | | |fact that a faecalith was |

| | | | | | | |noted by US after 48 h |

| | | | | | | |after start of the |

| | | | | | | |initially NOM, total |

| | | | | | | |appendectomies (total |

| | | | | | | |number of patients who |

| | | | | | | |underwent appendectomy |

| | | | | | | |after initially NOM during|

| | | | | | | |follow-up |

|Lee SL. 2017 |Age 3-17 years, ≤ 5 days of |Age < 3 years, positive pregnancy test,|NR |US/CT |I.V. Ceftriaxone and |Prompt initiation of |Primary Endpoints: |

| |abdominal pain, radiographic |history of immunodeficiency or | | |Metronidazole or |I.V. antibiotics and |initial failure rate of |

| |evidence of non-perforated AA (US|cirrhosis, cognitive impairment, | | |Ciprofloxacin and |timely LA |NOM. |

| |or CT), evaluation by a surgeon |inability to follow-up, diffuse | | |Metronidazole. | | |

| |confirming clinical suspicion of |peritonitis, evidence of severe | | |Oral | |Secondary Endpoints: |

| |non-perforated AA, willingness to|sepsis/septic shock on clinical | | |Amoxicillin+Clavulanate or | |rate of complicated |

| |participate. Imaging confirmation|evaluation, I.V. antibiotic within 24 h| | |Ciprofloxacin and | |appendicitis, length of |

| |was not required if the attending|of presentation, evidence of | | |Metronidazole or | |hospitalization, days to |

| |pediatric surgeon diagnosed the |intra-abdominal abscess greater than 5 | | |Cefdinir+Metronidazole for | |normal activity, days of |

| |patient with non-perforated AA |cm or perforated AA on imaging, | | |a 10-day total course | |pain medication, quality |

| |(PAS ≥ 6) |clinical concern for perforated AA | | | | |of life score at 30 days, |

| | | | | | | |recurrent appendicitis |

| | | | | | | |during the follow-up |

|Mudri M. 2017 |Clinical diagnosis of AA, |Symptoms > 48 h as well as clinical |NR |US |I.V. Ceftriaxone and |One preoperative dose |Primary Endpoints: |

| |symptoms less than 48 h, |and/or radiographic evidence of | | |Metronidazole. Oral |of I.V. Ceftriaxone |Length of hospital stay, |

| |localized peritonitis, US |perforated AA | | |Amoxicillin+Clavulanate for|and Metronidazole |costs, failure rate |

| |confirmation of AA | | | |7 days following discharge |before appendectomy | |

|Poillucci G. 2017|Signed informed consent for the |Pregnancy or lactating, non-consenting |Yes |US/CT/None |I.V. Ertapenem 1g/24h or |LA or OA, depending on|Primary Endpoints: |

| |treatment of personal and |patients, positive diagnosis of | | |Piperacillin-Tazobactam |the on-call surgeon's |complication-free |

| |sensible data, age range 18-65, |inflammatory bowel disease clinical | | |4.5mg/8h or Ceftriaxone |decision |treatment success based on|

| |diagnosis of AA made using the |diagnosis of diffuse peritonitis, | | |1g/24h and Metronidazole | |1-year follow-up |

| |AIR score, eventually confirmed |confirmed by CT scan, appendectomy | | |500mg/8h or Ciprofloxacin | | |

| |by US and/or CT scan in selected |performed as an elective procedure, | | |500mg/12h and Metronidazole| |Secondary Endpoints: |

| |patients, depending on the |appendectomy performed during other | | |500mg/8h. | |index admission antibiotic|

| |on-call surgeon's judgement |abdominal surgical procedures, previous| | |Oral | |therapy failure, |

| | |hospitalization for AA treated | | |Amoxicillin+Clavulanate | |recurrence at 1-year |

| | |conservatively | | |1g/8h for 4 days following | |follow-up, |

| | | | | |discharge | |post-intervention |

| | | | | | | |complications, |

| | | | | | | |post-operative |

| | | | | | | |complications, length of |

| | | | | | | |primary hospital stay, |

| | | | | | | |time to return to normal |

| | | | | | | |activities |

|Talan DA. 2017 |Age 5 years or older, |Inability to return or be contacted for|NR |US/CT |I.V. Ertapenem 1g/24h. Oral|Urgent LA or OA |Primary Endpoints: |

| |radiographic diagnosis of |follow-up visits, evidence of severe | | |Cefdinir 300mg/12h and |according to the |one-month major |

| |uncomplicated AA by CT and/or US |sepsis or septic shock, high-risk | | |Metronidazole 500mg/8h for |surgeon's preference. |complication rate. |

| |as read by an attending |diabetes, immunodeficiency, suspicion | | |8 days following discharge |Patients received 1 | |

| |radiologist and performed within |of acute coronary syndrome, congestive | | | |dose of I.V. Ertapenem|Secondary Endpoints: |

| |24 hours of consent, clinical |heart failure, or active chronic liver | | | |Additional |appendectomy rate in the |

| |diagnosis of uncomplicated AA by |disease, chronic renal insufficiency, | | | |preoperative |antibiotic-first group, |

| |a surgical teaching service |hepatic cirrhosis or failure, acute | | | |antibiotic treatment |quality of life both at 2 |

| |supervised by an attending |inflammatory bowel disease or | | | |was at the discretion |weeks and 1 month, days |

| |surgeon, ability to provide a |malignancy, pregnant, nursing or | | | |of the treating |unable to perform normal |

| |written informed consent in |expectation of becoming pregnant within| | | |clinicians |activities and work or |

| |English or Spanish |10 days, concurrent illness that would | | | | |school, days of analgesic |

| | |mandate hospitalization, imaging | | | | |use, pain scores at and |

| | |findings suggesting a mass or mucocele,| | | | |24 hours before each |

| | |severe allergy or reaction to study | | | | |visit, total hours in the |

| | |drugs or drugs similar to them, | | | | |emergency department and |

| | |receiving warfarin, another infection | | | | |hospital at the initial |

| | |requiring antibiotic treatment, | | | | |visit from triage until |

| | |incarceration and police custody, | | | | |discharge, total hours in |

| | |abdominal or pelvic surgery within the | | | | |the hospital through 1 |

| | |last month, current long-term-care | | | | |month, Alvarado scores, |

| | |resident, expected use of an | | | | |hospital charges |

| | |investigational treatment, intravenous | | | | | |

| | |drug use in the preceding month, | | | | | |

| | |expected concurrent hemodialysis, | | | | | |

| | |peritoneal dialysis, received | | | | | |

| | |parenteral antibiotics greater than or | | | | | |

| | |equal to 6 and less than or equal 48 | | | | | |

| | |hours before screening, received | | | | | |

| | |Ertapenem within 24 hours before | | | | | |

| | |screening, previous study enrollment | | | | | |

A=Antibiotic group. S=Surgery group. NR=Not Reported. AA=Acute Appendicitis. US=Ultrasound Scan. CT=Computed Tomography. MRI=Magnetic Resonance Imaging. I.V.=Intravenous. OA=Open Appendectomy. LA=Laparoscopic Appendectomy. PAS=Pediatric Appendicitis Score. NOM=Non-Operative Management. AIR=Appendicitis Inflammatory Response.

Supplemental Digital Content. Table_2. Risk of Bias in the published Randomized Controlled Trials (By the Cochrane Risk of Bias Tool, and in the Non-Randomized Studies of Interventions (By the Risk Of Bias In Non-Randomised Studies – of Interventions - ROBINS-I Tool).

Supplemental Digital Content. Table_2. Risk of Bias in the published Randomized Controlled Trials (By the Cochrane Risk of Bias Tool, and in the Non-Randomized Studies of Interventions (By the Risk Of Bias In Non-Randomised Studies – of Interventions - ROBINS-I Tool).

|Study |Study type|Random sequence |Allocation |Blinding of Patients, Personnel, and |Adequate Assessment |Selective Outcome |Other Potential Bias |Incomplete Outcome | Final Judgement |

| | |generation |concealment |Outcome Assessors |of Each Outcome |Reporting Avoided | |Data | |

| |

| | | Pre-intervention | At intervention | Post-intervention | Final Judgement |

|Study |Study type|Bias due to confounding|Bias in selection of |Bias in classification of |Bias due to |Bias due to missing |Bias in measurement|Bias in selection of | |

| | | |participants into the |interventions |deviations from |data |of outcomes |the reported results | |

| | | |study | |intended | | | | |

| | | | | |interventions | | | | |

|Armstrong J. (2014)|RCS |Low Risk |Moderate Risk |Low Risk |Low Risk |Serious Risk |Moderate Risk |Serious Risk |Serious Risk |

|Koike Y. (2014) |RCS |Low Risk |High Risk |Moderate Risk |High Risk |Low Risk |Moderate Risk |Moderate Risk |Serious Risk |

|Park HC. (2014) |PCS |Low Risk |Moderate Risk |Low Risk |High Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Tanaka Y. (2015) |PCS |Low Risk |Moderate Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Hartwich J. (2016) |PCS |Moderate Risk |Moderate Risk |Low Risk |Moderate Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Mahida JB. (2016) |PCS |Serious Risk |Moderate Risk |Low Risk |Low Risk |Low Risk |Moderate Risk |Low Risk |Serious Risk |

|Minneci PC. (2016) |PCS |Low Risk |Moderate Risk |Low Risk |Low Risk |Moderate Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Allievi N. (2017) |PCS |Low Risk |Low risk |Moderate Risk |Low Risk |Low Risk |Moderate Risk |Low Risk |Low or Moderate Risk |

|Gorter RR. (2017) |PCS |Low Risk |Moderate Risk |Low Risk |Serious Risk |Low Risk |Moderate Risk |Low Risk |Serious Risk |

|Lee SL. (2017) |PCS |Low Risk |Moderate Risk |Low Risk |Moderate Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Mudri M. (2017) |RCS |Moderate Risk |Serious Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

|Poillucci G. (2017)|RCS |Low Risk |Moderate Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low Risk |Low or Moderate Risk |

RCT=Randomized Controlled Trial. q-RCT=Quasi-Randomized Controlled Trial. RCS=Retrospective Cohort Study. PCS=Prospective Cohort Study.

Supplemental Digital Content. Table_3. Summary of Outcomes_1 (laparoscopic appendectomy, index admission antibiotic treatment failure, recurrence at 1-year follow-up, total costs, all appendicitis-related care costs).

Supplemental Digital Content. Table_3. Summary of Outcomes_1 (laparoscopic appendectomy, index admission antibiotic treatment failure, recurrence at 1-year follow-up, total costs, all appendicitis-related care costs).

|Study |Laparoscopic appendectomy. |Index admission antibiotic |Recurrence at 1-year follow-up. |Total costs. |All appendicitis-related care costs |

| |N (%)* |treatment failure. N (%) |N (%) |Mean ± SD in USD & |Mean ± SD in USD & |

| |A |S |A |S |A |S |A# |S |A^ |S |

|Eriksson S. 1995 |- |- |- |NA |7 (35) |NA |NR |NR |NR |NR |

|Styrud J. 2006 |NR |8 (6.5) |15 (12) |NA |16 (12.5) |NA |NR |NR |NR |NR |

|Hansson J. 2009 |NR |NR |11 (9.2) |NA |15 (12.6) |NA |2.045 ± 124 |4.193 ± 261 |NR |NR |

|Turhan AN. 2009 |NR |33 (18) |11 (10.3) |NA |9 (8.4) |NA |120,7 |155,8 |NR |NR |

|Vons C. 2011 |9 (64.3) |78 (65) |13 (10.8) |NA |44 (36.9) |NA |NR |NR |NR |NR |

|Armstrong J. 2014|4 (100) |12 (100) |2 (16.7) |NA |2 (16.7) |NA |NR |NR |NR |NR |

|Koike Y. 2014 |NR |NR |5 (3.7) |NA |24 (19.2) |NA |729 ± 51,3 |1.137 ± 152,9 |NR |NR |

|Park HC. 2014 |NR |NR |NR |NA |23 (19.3) |NA |1.140 ± 226 |2.207 ± 357 |NR |NR |

|Minneci PC. 2015 |9 (100) |65 (100) |2 (5.4) |NA |7 (18.9) |NA |3.641 ± 506 |4.960 ± 226 |4.219 ± 1.524 |5.029 ± 255 |

|Salminen P. 2015 |NR |15 (5.5) |15 (5.8) |NA |55 (21.4) |NA |NR |NR |NR |NR |

|Svensson JF. 2015|2 (100) |26 (100) |1 (4.1) |NA |5 (20.8) |NA |3.499 ± 1.475 |5.216 ± 2.025 |3.930 ± 4.189 |5.205 ± 2.125 |

|Hartwich J. 2016 |NR |NR |3 (12.5) |NA |2 (9.5) |NA |1.365 ± 247 |4.130 ± 909 |NR |NR |

|Mahida JB. 2016 |NR |NR |2 (40) |NA |1 (20) |NA |NR |NR |NR |NR |

|Tanaka Y. 2016 |NR |86 (100) |1 (1.3) |NA |22 (28.2) |NA |NR |NR |NR |NR |

|Allievi N. 2017 |NR |103 (94.5) |5 (1.7) |NA |47 (16.5) |NA |NR |NR |NR |NR |

|Gorter RR. 2017 |NR |NR |1 (4) |NA |3 (12) |NA |NR |NR |NR |NR |

|Lee SL. 2017 |24 (100) |32 (100) |16 (31) |NA |9 (26) |NA |9.384 |10.637 |NR |NR |

|Mudri M. 2017 |9 (100) |26 (100) |- |NA |9 (34.6) |NA |2.698,99 |3.708,68 |6.365,36 |8.236,25 |

|Poillucci G. 2017|45 (80.3) |157 (85.6) |34 (20.9) |NA |33 (20.3) |NA |NR |NR |NR |NR |

|Talan DA. 2017 |NR |9 (64.3) |- |NA |2 (12.5) |NA |5.145 ± 9.945 |12.447 ± 9.931 |NR |NR |

A=Antibiotic group. S= Surgery group. NR=Not Reported. NA=Not Applicable. *In the antibiotic group, after failure of the primary treatment and subsequent surgery. #For successful antibiotic treatment. ^All appendicitis-related care (conservative treatment success or failure Vs surgery without complications or surgery with complications). & Currency conversion from original value to USD (United States Dollar) made on 15/08/2018.

Supplemental Digital Content. Table_4. Summary of Outcomes_2 (wound infections, bowel obstruction, incisional hernia, abscess formation, length of primary hospital stay, total length of stay per patient, duration of pain, length of sick leave, length of time off work).

Supplemental Digital Content. Table_4. Summary of Outcomes_2 ( wound infections, bowel obstruction, incisional hernia, abscess formation, length of primary hospital stay, total length of stay per patient, duration of pain, length of sick leave, length of time off work).

|Study |Wound infections. |Bowel obstruction. |Incisional hernia. |Abscess |Length of primary |Total length of stay |Duration of pain |Length of sick leave|Length of time off |

| |N (%)* |N (%)* |N (%)* |formation. |hospital stay (Days). |per patient: |(Days). |(Days). |work (Days). |

| | | | |N (%)* |Mean ± SD |primary+readmissions |Mean ± SD |Mean ± SD |Mean ± SD |

| | | | | | |(Days). Mean ± SD | | | |

|A |S |A |S |A |S |A |S |A |S |A |S |A |S |A |S |A |S | |Eriksson S. 1995 |- |1 |NR |NR |NR |NR |- |- |3.1 ± 0.3 |3.4 ± 1.9 |NR |NR |NR |NR |NR |NR |NR |NR | |Styrud J. 2006 |NR |17 |NR |- |NR |- |NR |- |3.0 ± 1.4 |2.6 ± 1.2 |NR |NR |NR |NR |5.3 ± 4.1 |6.0 ± 4.4 |8.0 ± 8.0 |10.1 ± 7.6 | |Hansson J. 2009 |1 |19 |- |4 |- |1 |1 |9 |2.0 ± 0.1 |3.0 ± 0.2 |NR |NR |5 ± 1 |8 ± 1 |5 ± 1 |10 ± 1 |NR |NR | |Turhan AN. 2009 |5 |6 |- |- |- |- |- |1 |3.1 ± 0.1 |2.4 ± 0.1 |NR |NR |NR |NR |NR |NR |NR |NR | |Vons C. 2011 |2 |1 |1 |- |- |- |- |- |3.9 ± 4.8 |3.0 ± 1.5 |NR |NR |1.6 ± 1.3 |1.7 ± 1.0 |NR |NR |9.8 ± 10.5 |10.4 ± 8.2 | |Armstrong J. 2014 |- |1 |- |- |- |- |1 |1 |1.5 ± 1.0 |1.3 ± 0.5 |1.8 ± 1.1 |1.7 ± 0.9 |NR |NR |NR |NR |NR |NR | |Koike Y. 2014 |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |4.4 ± 2.8 |6.7 ± 2.7 |NR |NR |NR |NR |NR |NR | |Park HC. 2014 |1 |9 |- |5 |- |- |- |2 |3.4 ± 1.3 |6.4 ± 1.7 |NR |NR |- |- |- |- |- |- | |Minneci PC. 2015 |NR |NR |NR |NR |NR |NR |NR |NR |0.8 ± 0.1 |1.5 ± 0.1 |NR |NR |NR |NR |8 ± 3.7 |21 ± 2.8 |NA |NA | |Salminen P. 2015 |1 |23 |4 |23 |- |2 |- |1 |3 ± 0.2 |3.0 ± 0.1 |NR |NR |NR |NR |19 ± 2 |7 ± 1.4 |NR |NR | |Svensson JF. 2015 |- |- |- |- |- |- |- |- |2.1 ± 0.6 |1.4 ± 0.9 |NR |NR |- |- |- |- |- |- | |Hartwich J. 2016 |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR | |Mahida JB. 2016 |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR | |Tanaka Y. 2016 |NR |NR |- |2 |NR |NR |NR |NR |6.6 ± 2.6 |6.5 ± 2.4 |NR |NR |NR |NR |NR |NR |NR |NR | |Allievi N. 2017 |NR |18 |NR |5 |NR |- |NR |2 |3.1 ± 1.4 |4.1 ± 1.6 |3.6 ± 1.9 |4.8 ± 7.2 |NR |NR |NR |NR |6.0 ± 5.2 |14.6 ± 10.2 | |Gorter RR. 2017 |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR | |Lee SL. 2017 |- |1 |1 |2 |- |- |- |1 |NR |NR |2.0 ± 0.6 |2.0 ± 0.9 |3 ± 0.9 |5 ± 1.4 |5 ± 1.4 |6 ± 2 |NA |NA | |Mudri M. 2017 |- |- |- |- |- |- |- |2 |NR |NR |NR |NR |NR |NR |1.4 |1.0 |NR |NR | |Poillucci G. 2017 |1 |6 |NR |NR |NR |NR |- |4 |3.3 ± 1.8 |4.8 ± 2.6 |NR |NR |NR |NR |NR |NR |NR |NR | |Talan DA. 2017 |- |- |- |- |- |- |- |1 |NR |NR |NR |NR |NR |NR |NR |NR |NR |NR | |

A=Antibiotic group. S=Surgery group. NR=Not Reported. * In the antibiotic group, after failure of the primary treatment and subsequent surgery. SD=Standard Deviation.

Supplemental Digital Content. Fig.1. Funnel plots demonstrate asymmetry for Complication-free treatment success [A], Treatment efficacy based on 1-year follow-up [B], Post-intervention Complications [C], Surgical complications [D], Complicated appendicitis at the time of surgical operation [E], and Length of primary hospital stay [F], suggesting the possibility of publication bias. No points fall outside of the 95 % CI limits for any other outcome of interest, suggesting the absence of publication bias.

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Supplemental Digital Content. Fig. 2. Meta-analysis of Intra-operative finding of complicated appendicitis. Subgroup analyses: Adults Vs Children [A], and RCTs Vs n-RCTS [B].

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Supplemental Digital Content. Fig. 3. Meta-analysis of Post-intervention complications. Subgroup analyses: Adults Vs Children [A], and RCTs Vs n-RCTS [B].

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Supplemental Digital Content. Fig. 4. Meta-analysis of Post-operative complications. Subgroup analyses: Adults Vs Children [A], and RCTs Vs n-RCTS [B].

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Supplemental Digital Content. Fig. 5. Meta-analysis of surgical complications. Wound infections [A], Bowel obstruction [B], Incisional hernia [C], Abscess formation [D]. Subgroup analyses: Adults Vs Children [A], [B], [D].

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Supplemental Digital Content. Fig. 6. Meta-analysis of Primary costs [A], and All appendicitis-related costs [B]. Subgroup analyses: Adults Vs Children [A].

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Supplemental Digital Content. Fig. 7. Meta-analysis of Length of primary hospital stay: Subgroup analyses: Adults Vs Children [A], and RCTs Vs n-RCTS [B].

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Supplemental Digital Content. Fig. 8. Meta-analysis of Total length of stay per patient [A], Duration of pain [B], Length of sick leave [C], and Length of time off work [D]. Subgroup analyses: Adults Vs Children [C].

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