Antibiotics-first approach in uncomplicated acute appendicitis Good morning senior and colleagues. My topic for presentation is antibiotics first approach for uncomplicated acute appendicitis. JOINT HOSPITAL SURGICAL GRAND ROUND WONG YIM PING TUEN MUN HOSPITAL 23rd April, 2016

Outline Background and introduction Definition Literature review and appraisal Summary

Acute appendicitis One of the commonest cause of acute abdomen Lifetime incidence 7% in the US population [1] In Hong Kong 2492 appendicectomies were performed in year 2014-2015 [2] [1] Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol. 1990;132:910–25. [2] SOMIP reprt July 2014 –June 2015

Conventional teaching Appendicectomy for uncomplicated appendicitis Prevent progression to perforation and other complications Appendicectomy is a surgery of low morbidity and mortality

Is antibiotic therapy as useful as surgery?

Antibiotics first approach Antibiotic therapy Supportive care Careful observation +/- appendicectomy

Uncomplicated acute appendicitis No universal consensus = Simple acute appendicitis

Sallinen, V. , Akl, E. A. , You, J. J. , Agarwal, A. , Shoucair, S Sallinen, V., Akl, E. A., You, J. J., Agarwal, A., Shoucair, S., Vandvik, P. O., Agoritsas, T., Heels-Ansdell, D., Guyatt, G. H. and Tikkinen, K. A. O. (2016), Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis. Br J Surg, 103: 656–667. doi: 10.1002/bjs.10147

Key points Five studies included, total 1116 adult patients Single-center or multicenter randomized trials All were conducted in the Europe Participant: patients with suspected uncomplicated acute appendicitis ( clinical +/- radiological)

Key points Intervention : 3rd generation cephalosporin IV  fluoroquinolone and tinidazole PO Carbopenem IV  fluoroquinolone + metronidazole PO Amoxicillin plus clavunalic acid IV or PO Duration of treatment 8-15 days No pre-specified cross over criteria in most studies

Key points Control: open or laparoscopic appendicectomy Outcomes measure: Appendicectomy rate within index admission Success of treatment Post intervention complications Recurrence Length of stay Length of sick leave Pain( VAS or medications use)

Outcome measures Rate of appendicectomy within 1 month Major complications Minor complications Recurrence of appendicitis Length of hospital stay Length of sick leave

Rate of appendicectomy within 1 month Antibiotic group Appendicectomy group 47/550 (8.5) 561/ 562 (99.8) Open 434/561 (77.4) Laparoscopic 127/561 (22.6)

Major complications Clavien- Dindo complications grade III or above Appendiceal perforation Deep infections Incisional hernias Adhesive bowel obstruction not requiring intervention Clavien- Dindo complications grade III or above ( conditions requiring endoscopic, radiological or surgical intervention, or causing organ dysfunction or death), such as appendiceal perforation, deep infections, incisional hernias,adhesive bowel obstruction not requiring

Major complications 25/510 (4.9) 41/489 (8.4) Appendiceal perforation (23) Appendiceal perforation (32) Adhesive bowel obstruction (1) Deep infection (5) Death (1) Incisional hernia (2) Laparoscopic adhesiolysis (1)

Major complications

Rate of perforation First author Antibiotic group Appendicectomy group Eriksson (n=40) 1/20 (5) Styrud (n=252) 7/128 (5) 6/124 (5) Salminen (n=530) 5/257 (2) 2/273 (<1)

Minor complications Superficial wound infections Diarrhea Abdominal discomfort

Minor complications 11/510 (2.2) 61/489 (12.5) Superficial wound infections (3) Superficial wound infection (38) Abdominal or incisional discomfort (4) Abdominal or incisional discomfort (22) Not stated in detail (4) Diarrhea (1) All author fail to report complications of antibiotic such as diarrhoea and allergic reaction, and most failed to report appendicectomy complications in details in patients who initially received antibiotics, but who went on to have appendicectomy for recurrent appendicitis

Minor complications

Recurrence of appendicitis Confirmed or suspected recurrence of appendicitis between 1 month and 1 year Antibiotic group Appendicectomy group 114/510 (22.6) 0/489 (0)

Length of hospital stay

Length of sick leave

Pain measure Not included as inconsistent measurement of pain First author Antibiotic group Appendicectomy group Eriksson (n=40) 6 >10 Hansson (n=369) 9 Vons (n=239) 1.63 1.7

Conclusion Length of hospital stay is shorter in the appendicectomy group (p<0.001)

Limitation of current evidence Poor study design Low enrollment rate, ? Selection bias Difficulty in establishment of diagnosis Poor generalizability High crossover rate

Cross over rate during index hospitalisation First author Crossover during index hospitalization Eriksson (n=40) 1/20 (5) Styrud (n=252) 15/128 (12) Hansson (n=369) 96/202 (53) Salminen (n=530) 15/257 (6)

Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg 2009; 96: 473–481.

Summary Large multicenter high quality randomized trials are needed before the antibiotics-first approach could be considered comparable to appendicectomy

Summary Appendicectomy remains the standard treatment for acute appendicitis Non operative management reserves to selected group of patients

The appendectomy remains the treatment of choice for acute appendicitis. Antibiotic therapy is a safe means of primary treatment for patients with uncomplicated acute appendicitis, but this conservative approach is less effective in the long-term due to significant recurrence rates. (Recommendation 1A).

Reference Sallinen, V., Akl, E. A., You, J. J., Agarwal, A., Shoucair, S., Vandvik, P. O., Agoritsas, T., Heels-Ansdell, D., Guyatt, G. H. and Tikkinen, K. A. O. (2016), Meta-analysis of antibiotics versus appendicectomy for non-perforated acute appendicitis. Br J Surg, 103: 656–667. doi: 10.1002/bjs.10147 Eriksson S, Granstrom L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg 1995; 82: 166–169. Salminen P, Paajanen H, Rautio T, Nordstrom P, Aarnio M, Rantanen T et al. Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis. JAMA 2015; 313: 2340–2349. Styrud J,Eriksson S,Nilsson I, Ahlberg G, Haapaniemi S, Neovius G et al. Appendectomy versus antibiotic treatment in acute appendicitis. A prospective multicenter randomized controlled trial. World J Surg 2006; 30: 1033–1037.

Reference Svensson JF, Patkova B, Almstrom M, Naji H, Hall NJ, Eaton S et al. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children. Ann Surg 2015; 261: 67–71. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet 2011; 377: 1573–1579. Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg 2009; 96: 473–481.

Defining uncomplicated appendicitis Simple appendicitis Complicated appendicitis ‘’Early ‘’in time course Mild periappendiceal inflammation Nonperforated ‘’Late’’ in time course Significant periappendiceal inflammation Perforation Mass Abscess

Antibiotic Common pathogens: Enteric gram- negative bacilli, anaerobes, enterococci Mono therapy with a beta- lactam/ beta- lactamase inhibitor, i.e. Ampicillin- sulbactam, Piperacillin- tazobactam, Ticarcillin- clavulanate Combination third generation cephalosporin plus metronidazole, i.e. Ceftriaxone plus metronidazole

Alternative empiric regimens Combination fluoroquinolone plus metronidazole, i.e. Ciprofloxacin or levofloxacin plus metronidazole Mono therapy with a carbapenem, i.e. Imipenem- cilastatin, meropenem, doripenem, ertapenem

Laparoscopic vs open Lap Open A lower rate of wound infection Surg: 9 Abx: 6 Laparoscopic vs open Lap Open A lower rate of wound infection A higher rate of an intra-abdominal abscess Less pain on postoperative day 1 by the VAS pain score A longer operative time Shorter duration of hospital stay Higher operative and in-hospital costs Shorter duration for return of bowel function

CT sensitivity For diagnosis For differentiating complicated vs uncomplicated

Complicated acute appendicitis Appendiceal maximal diameter (>10 mm), periappendiceal fat infiltration, and ascites on CT findings and CRP (>5 mg/dL) ---------Min BW. Change in the Diagnosis of Appendicitis by Using a Computed Tomography Scan and the Necessity for a New Scoring System to Determine the Severity of the Appendicitis. Annals of Coloproctology. 2015;31(5):174-175. doi:10.3393/ac.2015.31.5.174. Reference Min BW. Change in the Diagnosis of Appendicitis by Using a Computed Tomography Scan and the Necessity for a New Scoring System to Determine the Severity of the Appendicitis. Annals of Coloproctology. 2015;31(5):174-175. doi:10.3393/ac.2015.31.5.174.

Risks factors of recurrent appendicitis Male gender ------Lien WC1, Lee WC, Wang HP, Chen YC, Liu KL, Chen CJ. Male gender is a risk factor for recurrent appendicitis following nonoperative treatment. World J Surg. 2011 Jul;35(7):1636-42. doi: 10.1007/s00268-011-1132-5.