Post-operative antibiosis for uncomplicated appendicitis Though the idea of this presentation is supposed to be case based - I have not quite done so as there have been 6 or more cases where we have deviated from the non-perforated appendectomy protocol. This mainly occurs when operations are performed in the night and the 18 hrs it takes to get three doses of cefoxitin do not pass before discharge. I have reviewed the literature on post-operative antibiosis in uncomplicated appendicitis, particularly as it relates to surgical site infections and intra-abdominal abscesses. Barclay Stewart General Surgery Intern University of Washington

Comparison of 30-day outcomes after laparoscopic versus open appendectomy at ACS NSQIP hospitals (2005–2008) Outcomes Open (n = 7,714; 23.6%) Lap (n = 24,969; 76.4%) Total (n = 32,683) P value SSI 513 (6.65) 814 (3.26) 1,327 (4.06) <.0001 Superficial SSI 300 (3.89) 314 (1.26) 614 (1.88) Deep SSI 76 (0.99) 60 (0.24) 136 (0.42) Organ space SSI 133 (1.72) 448 (1.79) 581 (1.78) 0.68 UTI 28 (0.36) 92 (0.37) 120 (0.37) 0.94 Septic shock 167 (2.16) 288 (1.15) 455 (1.39) The incidence of surgical site infections and intra-abdominal abscesses in the US are best described by the NSQIP data. Around 3.3% of lap appy’s have post-operative surgical site infections. These are further broken down into relatively equal numbers of wound infections (1.5%) and intra-abdominal abscesses (1.8%). These data do not separate uncomplicated and complicated appendectomies - therefore, for the purposes of this talk - intra-abdominal abscesses are likely significantly less common than more superficial infections. To decrease these numbers, we give post-operative antibiotics. Ingraham, AM, et al. “Comparison of outcomes after laparoscopic versus open appendectomy for acute appendicitis at 222 ACS NSQIP hospitals” CSA 2010 Meeting, Chicago Illinois.

Meta-analysis of all relevant RCTs through 2005 Systematic review and meta-analysis of all RCTs and CCTs in which ANY antibiotic regimen was compared to placebo in patients of ANY age who underwent appendectomy (laparoscopic or open). Meta-analyses divided into: Single vs multiple antibiotic(s) Single vs multiple dose(s) Normal vs simple appendicitis(‘acutely inflamed,’ ‘phlegmonous,’ ‘suppurative,’ ‘early,’ ‘uncomplicated’) vs complicated appendicitis (‘gangrenous,’ ‘perforated,’ ‘generalized peritonitis,’ ‘abscess’) The data through 2005 is conveniently summarized in a Cochrane Review and Meta-analysis which examined RCTs in which ANY antibiotic regimen was compared to placebo in patients of ANY age who underwent appendectomy. Further analyses compared single and multiple antibiotics and single and multiple doses. All of these were stratified by normal, simple and complicated appendicitis. Anderson, BR et al. “Antibiotics vs placebo for prevention of post-operative infection after appendectomy” The Cochrane Library, 2009, Issue I

Meta-analysis Included 45 studies of 9,576 patients Age 3 months to 94 years 7 trials exclusively in children (<15yrs) totaling 776 kids The study included 45 manuscripts totaling 9,576 patients age 3 months to 94 years. They also analyzed 776 children from 7 trials.

Any systemic antibiosis vs placebo for wound infection, all comers The primary outcome of the study is described here. The top half of the table and forest plot reflect the same data - the odds of developing a post-operative wound infection if given ANY systemic antibiosis compared to receiving no antibiosis. Clearly there is strong evidence to show that the odds of developing a wound infection after an uncomplicated appendectomy when given antibiotics are lower than in those who received placebo - around 0.3. Though not the focus of this discussion, these odds did not differ significantly for the outcome of wound infection in appendicitis, simple appendectomy or complicated appendectomy. The forest plot illustrates these findings. Outcome No. of studies No. of participants Effect size Wound infection 47 8812 0.33 [0.29, 0.38] Appendicitis 21 2343 0.31 [0.24, 0.42] Simple appy 26 5317 0.37 [0.30, 0.46] Complicated appy 24 1152 0.28 [0.21, 0.38] Intra-abd abscess 16 4468 0.43 [0.25, 0.73] 8 1033 0.35 [0.13, 0.91] 2968 0.46 [0.23, 0.94] 4 467 0.54 [0.12, 2.43] Length of stay 1200 -1.69 [-1.78, -1.61]

Any systemic antibiosis vs placebo for intra-abdominal abscess, all comers The story is the same for the outcome of intra-abdominal abscess in uncomplicated appendectomy. Again, out of the scope of this talk, there is not enough evidence to say that antibiotics reduce intra-abdominal abscess in complicated appendectomy.

Any systemic antibiosis vs placebo for length of hospital stay, all comers Antibiotics also reduce hospital stay by around 1.7 days. This figure is a bit misleading, however - the studies that examined this were mostly pre-laparoscopic era and stays were significantly longer and may have varied greatly by institution.

Pre-op abx vs placebo for wound infection (SA, SD), all comers Focusing on the topic at hand - these plots depict single dose pre-operative antibiotics vs placebo AND both pre- and post-operative antibiotics vs placebo. For uncomplicated appendectomy, there is no difference between the groups - meaning, no to only moderate benefit to SINGLE DOSE post-operative antibiotics. Pre- and post-op abx vs placebo for wound infection (SA, SD), all comers

Pre- and post-op abx vs placebo for wound infection (SA, SD), all comers In patients that received more than a single dose of post-operative antibiotics, wound infections were more common. Pre- and post-op abx vs placebo for wound infection (SA, MD), all comers

Any systemic antibiosis vs placebo for wound infection, children In children specifically, there seemed to be no benefit to the use of ANY antibiotics for uncomplicated appendicitis. This was not the case for complicated appendicitis. These data are limited by their relative few numbers of wound infections, however.

Any systemic antibiosis vs placebo for intra-abdominal abscess, children The benefit of antibiosis in the prevention of intra-abdominal abscess is less clear. However, it seems that there is evidence to support antibiosis use in uncomplicated appendicitis. The benefit in complicated appendectomy was not shown by this study.

The bottom line... Antibiosis better than none, in adults Timing made little to no difference in outcomes pre- vs pre- and post-operative abx So, the bottom line to this largely inclusive meta-analysis is that some antibiotics are better than none in adults - not as clear in children. In addition, wether individuals received pre OR pre- and post-op antibiosis did not greatly impact their outcomes of wound infection or intra-abdominal abscess.

Pre- or pre- and post-operative cefoxitin? RCT of 179 adults with clinical appendicitis Group 1: pre-operative cefoxitin Group II: pre-operative cefotetan Group III: pre- and 3 doses of cefoxitin post- operatively Infection rates Group 1: 11.1% Group II: 0% Group III: 1.9% I found this article from 1995 that I thought was interesting given our protocol. Liberman performed a RCT of 179 adults with appendicitis. These adults were randomized to pre-op cefoxitin, pre-op cefotetan and pre- and 3-dose post-operative cefoxitin. These data show two things. One - cefotetan was clearly superior to cefoxitin in the single dose regimen. Two - post-operative cefoxitin, when compared to itself, greatly decreased SSIs. Liberman MA, Greason KL, Frame S, Ragland JJ: Single-dose cefotetan or cefoxitin versus multiple-dose cefoxitin as prophylaxis in patients undergoing appendectomy for acute nonperforated appendicitis. J Am Coll Surg 1995, 180:77–80.

Pre-operative vs pre- and 3 dose post-operative vs pre- and 5 day post-operative antibiotic prophylaxis 269 individuals between 15-70 years with non-perforated appendicitis, open appendectomy with cefuroxime and metronidazole This Mui study was not included in the meta-analysis previously presented. 269 adults with non-perforated appendectomy were treated with single pre-op dose, a pre-op dose and 3 post op doses or a pre-op dose and 5 day course - - all with cefuroxime and flagyl. There was no difference in wound infections between the groups. There was evidence for an INCREASE in UTIs and C diff in longer courses of antibiotics.   Pre-op abx + 3 dose abx + 5-day abx Wound infection 6 (6.5%) 6 (6.4%) 3 (3.6%)  P-value 0.97 0.5  OR (95% CI) 1 1.01 (0.34–3.26) 0.89 (0.46–7.79) UTI and C diff 0 (0%) 1 (1.1%) 4 (4.8%) 1.0 0.048†  OR (95%CI) 1.01 (0.99–1.03) 1.05 (1.001–1.1) Mui, LM et al. “Optimum duration of prophylactic antibiotics in acute non-perforated appendicitis” ANZ Journal of surgery 2005 75(6)

Post-operative antibiosis Retrospective review of 763 non- perforated appy’s, mean age 32, all with appropriate pre-operative antibiosis Compared those with post-operative antibiosis to those without a post- operative dose There are two recent large, retrospective reviews that I will go over. The first is of 763 non-perforated appys with a mean age of 32. Patients who received post-operative antibiosis were compared to those without a post-operative dose. Le D, et al. “Post-operative antibiotic use in non-perforated appendicitis” American Journal of Surgery, 2009 198(6)

Characteristics of study population Variable Post-op abx No post-op abx Number 321 186 Mean age 32 31 Open vs lap 39 vs 61% 31 vs 69% Temp 37 WBC 14.3 14.0 Immune supp. 6% 5% Duration of OR (min) 60 54 Nml appendix 2% Acute appy 94% 90% Gangrenous Perforation 3% Mean f/u time (d) 16.8 16.1 Despite the retrospective nature of the study, the demographics and clinical proxies are all strikingly similar. Le D, et al. “Post-operative antibiotic use in non-perforated appendicitis” American Journal of Surgery, 2009 198(6)

Observed complications Postoperative Antibiotics No Postoperative Antibiotics P Total 10% 9.0% 0.64 Superficial SSI 9.3% 5.4% 0.13 Deep SSI 0.3% 0.5% 1.0 Organ space SSI 2.8% 2.7% 0.78 Postoperative diarrhea 2.5% 1.1% 0.34 Urinary tract infection 0.6% Post-operative antibiotics did not change the incidence of SSIs or post-opp diarrhe or UTI. Le D, et al. “Post-operative antibiotic use in non-perforated appendicitis” American Journal of Surgery, 2009 198(6)

A recent retrospective review... 1000 pts from 2005 to 2010 at Mt Sinai MC No significant difference in: demographics, ASA score, co- morbidities, temperature, pre-op abx, OR time, EBL, appendiceal diameter, WBC Lastly, from this past month in JACS, 1000 patients with appendectomy were examined in retrospect to determine the odds of SSI with antibiotics in comparison to no post-op abx. Coakley BA, et. al. “Postoperative antibiotics correlate with worse outcomes after appendectomy for nonperforated appendicitis.” Journal of the American College of Surgeons. 20011, 213(6))

Infectious complications Variable Post-operative abx (n = 334) No post-op abx (n = 394) P value Total infections 11.1 6.1 0.02 UTI 2.4 0.5 0.05 Diarrhea 8.1 1.5 < 0.01 Superficial SSI 8.4 5.6 0.14 Deep SSI 1.2 0.3 0.19 Organ-space SSI 0.09 Clostridium difficile 0.0 Wound dehiscence 0.2 Ileus 2.7 1.3 Other 3.0 1.0 0.1 30-d reoperation 0.06 30-d readmission 3.3 Total infections, UTIs, diarrhea, C diff were more common in the post-operative dosing scheme. Coakley BA, et. al. “Postoperative antibiotics correlate with worse outcomes after appendectomy for nonperforated appendicitis.” Journal of the American College of Surgeons. 20011, 213(6))

Conclusions Pre-op prophylactic antibiotics are a must Post-operative antibiotics are likely not a must and may increase infectious complications, costs and length of stay So - pre-op abx are a must. The jury is still out on post-operative antibiosis, however, they do increase cost and length of stay - with potentially no benefit.

Questions Do these data hold true for children? Does single dose cefoxitin confer appropriate antibiosis? So, pre-operative antibiosis is a must. Whether or not they are important in children or if one regimen is superior to another after the operating room.