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SURGICAL INFECTIONS Volume 14, Number 1, 2013 Mary Ann Liebert, Inc. DOI: 10.1089/sur.2011.

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Post-Operative Antibiotics after Appendectomy and Post-Operative Abscess Development: A Retrospective Analysis
Michael J. Hughes, Ewen Harrison, and Simon Paterson-Brown

Abstract

Background: Appendectomy is one of the most common emergency operations. Prophylaxis against infective complications involves post-operative antibiotics. There is no consensus as to the optimum antibiotic regimen. This study aimed to assess the relation between the duration of the post-operative antibiotic administration and intra-abdominal infections (IAIs). Patients and Methods: All patients who underwent appendectomy between September 1, 2009, and August 31, 2010, were identied. The appearance of the appendix at operation, post-operative antibiotics, white blood cell count, and temperature at the time of conversion of intravenous (IV) to oral antibiotics were compiled. IAIs were assessed as the nal outcome. Results: Two hundred sixty six patients underwent appendectomy188 for simple appendicitis and 78 for complicated appendicitis. There were 18 IAIs (6.8%) overall, 10 (12.8%) after complicated appendicitis and eight (4.2%) after simple appendicitis. Prolonging antibiotics beyond the operation in the simple appendicitis group did not alter the incidence of IAI. Similarly, in the complicated appendicitis group, prolonging antibiotics beyond ve days did not alter the incidence of IAI. Furthermore, in patients with complicated appendicitis, the presence of leukocytosis, fever, or both when IV antibiotics were converted to oral drugs was associated with the development of IAI (p = 0.013). Conclusion: In simple appendicitis, post-operative antibiotics may not be benecial at all. In complicated appendicitis, prolonging the course of antibiotics was not associated with a reduced IAI rate. However, cessation of IV antibiotics when fever or leukocytosis was present was associated with IAI development.

ppendectomy is the most common emergency operation undertaken in general surgery [1], with good evidence showing little difference in complication rates between the open and laparoscopic techniques [2]. However, postoperative morbidity remains a concern [3], in particular the development of intra-abdominal infections (IAIs). Various post-operative antibiotic regimens have been recommended in an effort to prevent post-operative infections, although there is no consensus as to the optimum length of treatment or the timing of cessation of intravenous (IV) antibiotics [4]. Long-term broad-spectrum antibiotic treatment is associated with morbidity, including Clostridium difcile infection, bacterial resistance, and a prolonged hospital stay [5]. It therefore would be benecial to reduce the length of IV antibiotic administration and complete the drug course orally, outside the hospital.

This study evaluated the relation between the length of the post-operative antibiotic course and IAI. Also examined was whether conversion from IV to oral antibiotics in the presence of fever or leukocytosis has any bearing on subsequent infective complications. Patients and Methods Clinical details on all patients admitted to the Royal Inrmary of Edinburgh are collected prospectively using the Lothian Surgical Audit System (LSAS). Electronic and case records for all patients undergoing emergency laparoscopic or open appendectomy between September 1, 2009, and August 31, 2010, were retrieved and reviewed for demographic data; pre-operative details, including the administration of antibiotics; and operative ndings, along with the post-operative

Department of General Surgery, Royal Inrmary of Edinburgh, Edinburgh, United Kingdom.

2 antibiotic regimen. Pre-operative antibiotics were given either at induction of anesthesia or before arrival in the operating theater. The presence of fever (pyrexia 38C) or leukocytosis (white blood cell [WBC] count > 11,000 106/L) was recorded when the antibiotics were converted from IV to oral administration. In patients who did not receive postoperative IV antibiotics, temperature and WBC count were recorded when they were discharged from the hospital, regardless of whether they were taking oral antibiotics at that time. This was done in an effort to reect the clinical decision-making process. Patient outcome and the development of any post-operative complications after discharge were ascertained by reviewing follow-up data from both the LSAS and the patients case records. The patients were categorized according to the appearance of the peritoneal cavity and the appendix at the time of operation, as documented in the operation note. Pus and feces mentioned in the operation note were considered contamination and not just free uid. The cohort was divided into Group A: Simple appendicitis (at the time of the operation, the appendix appeared normal or inamed without any perforation or intra-peritoneal contamination); or Group B: Complicated appendicitis (evidence of a perforated or gangrenous appendix with intra-peritoneal contamination). The Surgical Infection Society (SIS) Guidelines [4] advise that the post-operative antibiotic regimen be adjusted according to the appearance of the appendix at operation. For perforated and gangrenous/inamed appendicitis with intraperitoneal contamination, as many as ve days of antibiotics is recommended. For gangrenous/inamed appendicitis with no evidence of intra-peritoneal contamination, no more than one day of antibiotics is recommended. For simple inamed appendicitis and normal appendices, no antibiotics should be administered after surgery. The main outcome measure was the development of an IAI, as demonstrated either by ultrasound scan or by computed tomography (CT) in the presence of at least one of the following within 30 d of the operation: Increased WBC count, C-reactive protein > 5 units/L, or pyrexia. Statistical analysis of the data was performed to establish associations with IAI. The w2 or Fisher exact test was used in the univariable analysis.

HUGHES ET AL. Table 1. Baseline Characteristics Simple appendicitis (n = 188) 31 98/90 16 4 4 5 11 12.5 37.2 43.1 39.1 Complicated appendicitis (n = 78) 29 50/28 10 4 7 2 8 14.6 95.1 37.2 57.2

Characteristic Mean age (years) Male/female Co-morbidities Asthma Diabetes mellitus Hypertension Urologic Other Pre-operative details Mean WBC count ( 109/L) Mean CRP (units/L) Mean duration of symptoms (h) Mean post-operative length of stay (h)

CRP = C-reactive protein; WBC = white blood cell.

percutaneous drainage (n = 4), or non-operative measures (n = 5). In Group A, the IAIs were managed with percutaneous drainage (n = 4) or non-operative measures (n = 4) Five patients with surgical site infections did not require hospital admission and were treated with antibiotics only. All except one appendectomy were commenced laparoscopically, and 11 required conversion to open operation because of severe intra-peritoneal contamination. Pelvic drain insertion and the performance of peritoneal lavage were not associated signicantly with the prevention of IAI development (Table 3). Length of post-operative antibiotic course Table 4 illustrates the post-operative antibiotic course lengths, including IV and total (including oral) courses. A tendency to prolong antibiotic use was observed in both complicated and simple appendicitis compared with the SIS guidelines. The incidence of IAIs observed within each sub-group of course lengths is illustrated. An increase in antibiotic course length did not result in fewer IAIs. This was true for both IV and total (IV + oral) antibiotic course lengths in both Group A and Group B (see Tables 4 and 5). In the univariable analysis, the w2 test for trend was used to assess the incidence of IAIs observed among the three lengths of total post-operative antibiotic course (0d, > 05d, and > 5d). No signicant difference in IAI incidence was observed in Group A (p = 0.63) or Group B (p = 0.34). Also, pre-operative Table 2. Complications of Appendectomy Simple appendicitis (%) (n = 188) 8 (4.2) 5 (2.7) 13 (6.9) Complicated appendicitis (%) (n = 78) 10 (12.8) 2 ( 2.5) 12 (15.3)

Results Baseline characteristics The series consisted of 266 patients, of whom 78 had complicated appendicitis (Group B) and 188 had simple appendicitis (Group A) (Table 1). Among them, 158 received post-operative IV antibiotics, and 92 of these patients subsequently received oral antibiotics. A total of 107 patients (67.7%) received IV piperacillin-tazobactam, and 66 patients (71.7%) received oral amoxicillin/clavulanic acid. The local protocol advises this combination of antibiotics. Deviations from this regimen were the result of individual surgeon preference. A total of 25 patients (9.4%) had some form of infective post-operative complication (Table 2), with 8/188 (4.2%) in Group A and 10/78 (12.8%) in Group B developing IAIs. The IAIs in Group B were managed by laparotomy (n = 1),

Complication Intra-abdominal infection Incisional infection Total

POST-APPENDECTOMY ANTIBIOTICS AND IAI Table 3. Operative Techniques and Intra-Abdominal Infection (IAI) Developmenta Simple appendicitis (n = 188) (%) 184 (97.9) 1 ( 0.5) 3 ( 1.6) 59 (31.4) 131 (69.7) Site infection (n = 5) 5 0 0 1 5 Complicated appendicitis (n = 78) (%) 70 (89.7) 0 ( 0) 8 (10.3) 50 (64.1) 72 (92.3)

Operative technique Laparoscopic Open Laparoscopic converted to open Drain inserted Washout performed
a

IAI (n = 8) 7 1 0 2 (p = 1.00) 5 (p = 0.70)

IAI (n = 10) 7 0 3 7 (p = 0.74) 10 (p = 1.00)

Site infection (n = 2) 0 0 2 2 2

Fisher exact test performed to assess signicance of association between operative techniques and IAI development.

antibiotics were not protective against IAI development in either group (Table 5). Fever and leukocytosis In Group A, 3/8 patients (37.5%) with IAIs exhibited leukocytosis, fever, or both when IV antibiotics had been converted to oral drugs or, if they had not received antibiotics, when they were discharged from the hospital (Table 6). This gure was not statistically signicant (p = 0.70). The mean time to discharge post-operatively in Group A was 39 h. However, in Group B, 8/10 patients suffered IAIs if IV antibiotics had been converted to oral or stopped when leukocytosis or fever was still present. In the univariable analysis shown in Table 6, this was statistically signicant (p = 0.013). Organism sensitivity Peritoneal cultures were not routine. Post hoc analysis of samples that were taken and the sensitivities are shown in Tables 7 and 8. There were no positive post-operative blood cultures. Of the positive peritoneal samples, the majority yielded coliforms and anaerobes, all of which were sensitive to the broad-spectrum antibiotics that had been prescribed. Among the patients who developed IAIs, again, no positive blood cultures were obtained. Two negative peritoneal samples and two positive samples were found. On both occasions, Table 4. Length of Post-Operative Antibiotic Course and Associated Intra-Abdominal Infection (IAI) Rate Simple appendicitis (n = 188) N IAIs (%) N Complicated appendicitis (n = 78) IAIs (%) 0 1 6 2 1

the organism cultured was sensitive to the antibiotic received by the patient (Table 9). Discussion This study has demonstrated that a longer antibiotic course does not mean a reduction in IAI development after appendectomy for either simple or complicated appendicitis. Recent research into simple appendicitis has shown similar results. In a randomized controlled trial of 263 patients undergoing open appendectomy for simple appendicitis, no difference was observed in the incidence of post-operative IAI in groups receiving a single dose, three doses, or ve days of antibiotics [6]. These ndings were conrmed by a further study [7] demonstrating no difference in post-operative infection rates between groups receiving post-operative antibiotics and those who received none. Our study therefore adds further evidence that post-operative antibiotics for simple appendicitis may not be necessary at all. Table 5. Antibiotic Course Length and Intra-Abdominal Infection (IAI) Development IAI developed in simple appendicitis (%) No Post-operative antibiotic course None 102 (96.2) 5 d 50 (96.2) >5 d 28 (93.3) Pre-operative antibiotics given Yes 164 (95.9) No 16 (94.1) Yes 4 (3.8) 2 (3.8) 2 (6.7) (p = 0.63) 7 (4.1) 1 (5.9) (p = 0.38) Total 106 52 30 171 17

IAI developed in complicated appendicitis (%) No Yes Total 2 32 44 70 8

Duration of intravenous antibiotic administration None given 104 4 ( 3.8) 4 1 dose1 d 50 0 19 > 13 d 29 3 (10.3) 38 > 35 d 4 0 15 >5 d 1 1 (100) 2 Total duration of antibiotic administration (intravenous or oral) None given 106 4 ( 3.8) 2 1 dose1 d 29 1 ( 3.4) 9 > 13 d 13 1 ( 7.7) 6 > 35 d 10 0 18 >5 d 30 2 ( 6.7) 43

( 5.3) (15.8) (13.3) (50)

0 0 1 (16.7) 2 (11.1) 7 (16.2)

Post-operative antibiotic course None 2 (100) 0 5 d 29 ( 90.6) 3 (9.4) >5 d 37 ( 84.1) 7 (15.9) (p = 0.34) Pre-operative antibiotics given Yes 61 ( 87.1) 9 (12.9) No 7 ( 87.5) 1 (12.5) (p = 0.41)

Chi-square test for trend analysis showed no signicant difference between post-operative course lengths and IAI development. Fisher exact test showed no signicant difference in IAI development in those who received pre-operative antibiotics versus those who did not.

4 Table 6. Difference in Incidence of Intra-Abdominal Infection (IAI) in Patients Who Did and Did Not Have Signs of Sepsis When Intravenous Antibiotics Were Stopped Signs of sepsis when intravenous antibiotics were converted to oral (or stopped)a Yes No
a

HUGHES ET AL. IV antibiotics to oral when leukocytosis or fever was present was associated signicantly with IAI development in the univariable analysis (p = 0.013). The reason for this nding is unclear. In the circumstances of complicated appendicitis, it may represent a developing infective process and subsequent inevitable IAI development despite IV antibiotics. However, recent work investigating early conversion of IV to oral antibiotics [1821] has found little difference in outcome. However, again, these studies, which include randomized controlled trials, have assessed intra-abdominal sepsis in general rather than appendicitis specically. They also do not assess exclusively the conversion of IV to oral antibiotics when signs of sepsis are still present. There is a growing body of evidence in the pediatric population advocating early cessation or conversion of IV to oral antibiotics and early discharge regardless of whether signs of sepsis are present [2224]. The advantage of this practice is possible early discharge and less IV antibiotic administration. The results of our study are slightly at odds with these studies in children, as converting IV to oral antibiotics in the presence of sepsis was associated with IAI. This may reect an inability to generalize the results of the pediatric literature to an adult population. To date, no other study has addressed this issue specically in adults with appendicitis. The results of our study reect a high rate of IAIs. The largest review on appendectomy outcomes, the American College of Surgeons: National Surgical Quality Improvement Program (ACS/NSQIP) shows overall IAI rates of 1.8% for all appendectomies [25] and 6.7% for complicated appendicitis [26]. Similarly, the Cochrane review [27] presented an overall IAI rate of 1.4% after open or laparoscopic appendectomies. However, it is difcult to compare our results with those of these large studies. The Cochrane review does not differentiate between complicated and uncomplicated appendicitis, which are now considered as two separate diseases. Also, the authors of the Cochrane review acknowledge that the quality of the evidence they had available is mediocre to poor and that the denition of IAI was inconsistent, with moderate heterogeneity between studies. The ACS/NSQIP data were retrieved retrospectively from a national database collected from participating hospitals. This represents a high standard of audit and surgical practice. However, the results should be reviewed with a degree of caution, as the reporting of postoperative complications and the degree of peritoneal contamination is reliant on the coding in the database rather than on direct review of the individual cases. We acknowledge that our results represent high IAI rates, but comparison with the large bodies of evidence is not straightforward. Furthermore, there is a high degree of variability of reported IAI rates in the literature, and our results are not unprecedented. When examining individual studies of similarly described cohorts, our IAI rates are similar, with 16.3% [28] and 9.3% [29] following complicated appendicitis and 5.1% following simple appendicitis [30]. Our regular performance of peritoneal lavage and placement of pelvic drains for the rst 24 h after laparoscopic appendectomy is to remove any residual washout uid in order to reduce IAI. However, the evidence for or against these practices is equivocal. Allemann et al. [31] found no signicant difference in the IAI rate between those with and without prophylactic drain placement, and a meta-analysis from 2004 [32] conrmed no difference in IAI rate regardless of peritoneal

Simple appendicitis No IAI 56 124 IAI (%) 3 (5.1) 5 (3.9) (p = 0.70)

Complicated appendicitis No IAI 24 44 IAI (%) 8 (25) 2 (4.5) (p = 0.013)b

If no post-operative intravenous antibiotics were given, signs of sepsis were assessed at the point of discharge. b Fisher exact test.

A Cochrane review published in 2005 [8] concluded that antibiotics resulted in fewer post-operative intra-abdominal abscesses following appendicitis compared with placebo. However, the analysis did not illustrate any superiority for pre-, peri-, or post-operative administration of prophylactic antibiotics. In our study, most patients received pre-operative antibiotics, and therefore, it might follow that a single pre- or peri-operative prophylactic dose is all that is required for simple appendicitis. In Group A, irrespective of whether patients were given post-operative antibiotics, and whether they had signs of sepsis (leukocytosis, fever, or both) at the time of discharge, there was no association with subsequent development of IAI. This may be because the mean discharge time was 39 h post-operatively, and these signs of sepsis within this period normally would be attributable to the post-operative inammatory response and not an indication for continued observation or antibiotic administration. In Group B, the length of the antibiotic course likewise was not associated with signicantly different incidences of IAIs. Several studies in the literature have reported that prolonging antibiotics post-operatively for a variety of intra-abdominal septic conditions does not affect IAI incidence [913]. Our study concurs with this nding. The SIS recommendation, based on four studies [1417], is to continue antibiotics until leukocytosis or fever has resolved but no longer than ve days, after which an alternative source of sepsis should be sought. However, three of these studies are now 30 years old, and not all patients had appendicitis. With the length of antibiotic course not being predictive of the development of IAI, the timing of conversion of IV to oral antibiotics or the cessation of IV antibiotics needs to be addressed. In our study, in complicated appendicitis, converting Table 7. Number and Site of Cultures and Growth Complicated appendicitis (n = 45/78) Site Blood (n = 25) Peritoneal uid (n = 20) Growth/no growth 0/25 9/11 Simple appendicitis (n = 47/188) Site Blood (n = 28) Peritoneal uid (n = 19) Growth/no growth 0/28 4/15

POST-APPENDECTOMY ANTIBIOTICS AND IAI Table 8. Pathogens Identied in Peritoneal Samples and Sensitivity Data Organism grown Complicated appendicitis Anaerobes Escherichia coli E. coli E. coli E. coli Coliforms E. coli E. coli E. coli Sensitive to (9 positive samples) Metronidazole Amoxicillin Amoxicillin Amoxicillin Amoxicillin Amoxicillin Amoxicillin Tazocin Amoxicillin/clavulanic acid Appropriate antibiotics given? Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes IAI developed?

No No No No (site infection) Yes No No No No No No No Yes

Simple appendicitis (4 positive samples) Klebsiella Amoxicillin/clavulanic acid E. coli Amoxicillin Bacteroides Metronidazole Anaerobes Metronidazole
IAI = intra-abdominal infection.

drain placement. Irrigation also is still a matter of debate. Our study showed no signicant difference in the IAI rate in the two groups. Data on this subject are limited; however, there is evidence showing no signicant difference in IAI rates retrospectively [33] or prospectively [34] (unpublished data), and it may be that these practices, although not protective against IAI development, can be avoided safely. Microbiologic analysis of the data is difcult because routine peritoneal sampling was not performed. However, this practice is not encouraged widely because of the high proportion of negative samples [35]. There also is acceptance of the idea that the organisms identied from peritoneal sampling are highly predictable and sensitive to routine antibiotic types [36]. Our limited analysis is in concert with these ndings, with the recovery mainly of coliforms sensitive to penicillins, which supports the local antimicrobial policy. Therefore, we do not envisage that either our antibiotic choice or a local variation in pathogenic organism contributed to the high IAI incidence. The retrospective nature of the data collection meant the ability to assess the signs of sepsis of a patient accurately when a decision was made regarding their antibiotic administration, and discharge was compromised. Blood tests were not performed routinely on the day of this decision, and leukocytosis was not assessed consistently at this point. Temperature measurement was more reliable, as it was performed regularly.

Table 9. Microbiology Findings in Patients Who Developed Intra-Abdominal Infections Negative blood culture No cultures taken Peritoneal sampleno growth Peritoneal samplegrowth 1 (Escherichia coli sensitive to piperacillintazobactam) 1 (Anaerobe sensitive to metronidazole)

Furthermore, different surgeons and clinicians were included in the study, allowing variation in practice to be introduced. The intra-operative classication of the appendices by different surgeons introduces the possibility of over-classication or under-classication of the degree of appendix pathology. Also, non-standardized post-operative practice could introduce bias in the antibiotic regimen selected. Moreover, only those patients who returned to the hospital were assessed for IAI. Thus, we cannot postulate a direct causal relationship. However, the following conclusions can be drawn. First, antibiotics administered after an appendectomy for simple appendicitis are not associated with a reduction in the IAI rate. Second, cessation of antibiotics when fever or leukocytosis is present is not associated with IAI development. Fever or leukocytosis in this instance might reect the inammatory response to surgery as opposed to an infective process, as these observations occurred within a mean of 39 h after surgery. Third, in complicated appendicitis, prolonging the course of antibiotics was not associated with a reduced IAI rate. However, cessation of IV antibiotics when fever or leukocytosis was present was associated with IAI development. This may reect the presence of a developing infective process despite antibiotic administration. If signs of sepsis persist beyond the ve-day antibiotic course, investigations to exclude an IAI (or another source of sepsis) should be instigated as opposed to prolonging the antibiotic course. A randomized controlled trial would be useful to conrm the exact duration of antibiotics required after complicated appendicitis. Author Disclosure Statement The authors declare that there are no conicts of interest. References
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Address correspondence to: Mr. Michael J. Hughes Department of General Surgery Royal Inrmary of Edinburgh Little France Edinburgh, United Kingdom EH16 4SA E-mail: michaelh@doctors.net.uk