Optimizing the Antibiotic Treatment of Uncomplicated Acute Appendicitis
Optimizing the Antibiotic Treatment of Uncomplicated Acute Appendicitis
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 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.

 The aim of this randomized prospective study is to optimize antibiotic therapy for
 uncomplicated acute appendicitis by comparing different antibiotic regimens; intravenous
 antibiotic (ertapenem) followed by per oral antibiotic (levofloxacin and metronidazole) with
 only per oral antibiotics (moxifloxacin). Before randomization, the diagnosis of acute
 uncomplicated appendicitis is confirmed with a CT scan.

 The hypothesis is that broad-spectrum intravenous antibiotics requiring additional hospital
 resources are not necessary for the treatment of uncomplicated acute appendicitis and that
 per oral mono therapy is non-inferior to the combination of intravenous and per oral
 antibiotic therapy.
Acute appendicitis is the most common cause of abdominal pain in emergency departments and
 appendectomy is the most common emergency abdominal surgery. The lifetime risk of acute
 appendicitis in males is 8.6% and 6.7% in females. In Finland according to Stakes data there
 were 6 377 appendectomies (3242 in males, 3135 in females, median age 35 years) performed in
 2010. The total number of days in hospital care was 16 111 days and the mean length of
 hospital stay was three days.

 Although acute appendicitis is the most common reason for surgical emergency department
 visit, its diagnosis still remains challenging. The clinical diagnosis has previously been
 based on patient history, physical examination and laboratory findings as well as the
 clinical surgical diagnosis. Several scoring systems have been created to aid in the
 diagnosis of acute appendicitis18-20, but the accuracy of clinical diagnosis without
 preoperative imaging is about 76 - 80 % for combined patient groups of males and females.

 As acute appendicitis has historically been thought to always progress to perforation
 requiring emergency appendectomy, high negative appendectomy rates even up to 40 % in some
 patient populations have been previously accepted as good surgical practice. For the last two
 decades, the use of dedicated imaging in acute abdomen in general and also in acute
 appendicitis has led to improved diagnostic accuracy.

 Based on large epidemiological studies, it is now known that complicated (perforated) and
 uncomplicated (non-perforated) appendicitis have followed different epidemiological trends.
 These unassociated epidemiologic trends suggest different pathophysiology for the two form of
 appendicitis. The differential diagnosis is essential as patients with an uncomplicated acute
 appendicitis may not require surgical intervention and might experience even spontaneous
 resolution without perforation. The majority (approximately 80 %) of acute appendicitis cases
 are of uncomplicated nature.

 Complicated acute appendicitis defined as a finding of a perforation, appendicolith, abscess
 or a suspicion of a tumor, requires emergency appendectomy with the exception of cases with
 abscess as they are often managed conservatively.

 Appendicolith is a calcified fecal concretion in the appendix resulting in internal luminal
 obstruction and it is the most common form of complicated acute appendicitis. In the first
 randomized study by Vons et al. comparing operative treatment and antibiotic therapy using CT
 as a diagnostic inclusion criterion, the presence of an appendicolith in preoperative CT scan
 was the only factor that significantly increased the risk of complicated appendicitis and it
 was also the only factor associated with the failure of antibiotic therapy for acute
 appendicitis. Indeed, if Vons et al had excluded the patients with an appendicolith from
 their analysis, no significant difference in the incidence of post-intervention peritonitis
 between the treatment groups would have been noticed in their study.

 CT imaging is the primary imaging modality and the golden standard in the diagnosis of acute
 appendicitis as it establishes the diagnosis with almost perfect diagnostic accuracy. The
 advantages of CT imaging are high accuracy, availability, ease of performance and
 interpretation, and that it is rarely affected by bowel gas, severe abdominal pain or extreme
 body habitus. The main disadvantage of CT is exposure to radiation.

 The increased use of preoperative CT imaging has been evaluated thoroughly by evaluating its
 impact on the negative appendectomy rate reducing the number of unnecessary appendectomies.
 In 2010, a mandatory imaging guideline for suspected acute appendicitis was implemented in
 the Netherlands. After implementation the negative appendectomy rate dropped significantly
 from 23 % to 6 % (p<0.001) reducing the surgical complication rate from 20% to 14 % and
 resulting in average cost-per-patient decrease by 594€.

 The favorable diagnostic performance of CT imaging has encouraged optimization of the
 protocol to minimize exposure to radiation through the development of low-dose CT protocols.
 Low-dose protocols balance with as low as reasonably achievable-principle while maintaining
 diagnostic accuracy. However, low-dose protocols with intravenous contrast are still not
 implemented in routine clinical practice. These protocols require more advanced optimization
 and validation because of the wider need for contrast enhanced assessment. Kim et al showed
 that contrast enhanced low-dose CT (median radiation dose 116mmGy in dose-length product) was
 not inferior to standard-dose contrast enhanced CT (median radiation dose 521 mmGy), with
 negative appendectomy rates of 3.5% and 3.2% respectively and no statistical significance in
 appendiceal perforation rates or patients requiring additional imaging.

 The investigators have performed a prospective observational study (OPTICAP trial,
 NCT02533869, Ethical committee of Turku University Hospital approval) in order to optimize a
 low-dose CT scan for both diagnosing acute appendicitis and to differentiate uncomplicated
 acute appendicitis from a complicated acute appendicitis. In this study, phantom imaging with
 15 different imaging protocols were performed aiming to minimize radiation with optimal
 diagnostic accuracy. The phantom protocols were assessed by blinded evaluation of two
 gastrointestinal radiologists and the two best performing protocols were chosen for the
 clinical phase. The clinical evaluation included performing both of these imaging protocols
 for patients with suspected uncomplicated acute appendicitis evaluated by a senior digestive
 surgeon. All of the enrolled patients underwent laparoscopic appendectomy to evaluate the
 sensitivity and specificity of the imaging protocols. The most optimal imaging protocols were
 selected for use in the APPAC II trial; one low-dose CT protocol for patients with BMI under
 30 and one optimised standard CT protocol for patients with BMI exceeding 30.

 For over a century appendectomy has been the standard treatment for all patients with acute
 appendicitis. However, the results of our APPAC trial have now shown that the majority (73%)
 of patients with uncomplicated acute appendicitis were successfully treated with antibiotics
 alone. We also showed that none of the patients treated initially with antibiotics and later
 undergoing appendectomy had major complications or increased morbidity defining antibiotic
 therapy as a safe first-line treatment. Patients with a complicated acute appendicitis
 require emergency appendectomy and early identification of these patients is of vital
 importance. Laparoscopic appendectomy has become the golden standard for appendectomy
 providing lower morbidity and faster recovery compared with open appendectomy. For patients
 with uncomplicated acute appendicitis, the time has come to evaluate abandoning routine
 appendectomy and evaluating the optimal use of antibiotic therapy.

 The aim of study is to optimize the antibiotic therapy for uncomplicated acute appendicitis
 by evaluating the success of treatment in both study groups and by comparing intravenous
 antibiotic therapy followed by per oral antibiotics with per oral antibiotic monotherapy. The
 study hypothesis is that broad-spectrum intravenous antibiotics requiring additional hospital
 resources are not necessary for the treatment of uncomplicated acute appendicitis and that
 per oral monotherapy is non-inferior to the combination of intravenous and per oral
 antibiotic therapy. The secondary aim is to evaluate the results of the randomized APPAC
 trial in a prospective patient cohort by implementing antibiotic therapy as the first-line
 treatment for uncomplicated acute appendicitis in clinical practice.
Inclusion Criteria:

 -  Age 18-60 years

 -  CT confirmed uncomplicated acute appendicitis

 -  Ability to give consent to participate in the study

 Exclusion Criteria:

 -  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)

 -  CT confirmed complicated acute appendicitis

 -  Inability to co-operate and give informed consent