The use of pre- or postoperative antibiotics in surgery for appendicitis: A systematic review

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1 433SJS / Use of pre- or postoperative antibiotics for appendicitis K. Daskalakis, et al. SYSTEMATIC REVIEW Scandinavian Journal of Surgery 103: 14 20, 2013 The use of pre- or postoperative antibiotics in surgery for appendicitis: A systematic review K. Daskalakis, C. Juhlin and L. Påhlman Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden Abstract Background and Aim: The aim of this study was to review the literature regarding the use of pre- and/or postoperative antibiotics in the management of appendicitis, using data obtained from PubMed and the Cochrane Library. Material and Methods: A literature search was conducted using the terms appendicitis combined with antibiotics. Studies were selected based on relevance for the evidence on prophylactic and postoperative treatment with regard to the route and duration of drug administration and the findings of surgery. Results: Patients with acute appendicitis should receive preoperative, broad-spectrum antibiotics. The use of postoperative antibiotics is only recommended in cases of perforation, and treatment should then be given intravenously, for a minimum period of 3 5 days for adult patients, until clinical signs such as fever resolve and laboratory parameters such as C-reactive protein curve and white blood cell (WBC) start to decline. Conclusion: Preoperative antibiotic prophylaxis is recommended in all patients with acute appendicitis, whereas postoperative antibiotics only in cases of perforation. Key words: Acute appendicitis; perforated appendicitis; appendectomy; antibiotic prophylaxis; antibiotic treatment; oral antibiotics; intravenous antibiotics Introduction Appendicitis is the most common cause of acute abdominal pain requiring surgical intervention. The incidence of appendicitis is generally reported in 100 out of 100,000 inhabitants annually, and the Correspondence: Kosmas Daskalakis, M.D. Department of Surgical Science Uppsala University University Hospital Geijersgatan 18b Uppsala Sweden kosmas.daskalakis@akademiska.se accumulative life risk is 7% (1). The result of appendectomy after clinically suspected appendicitis has historically shown a correct diagnosis in 70% 75% of cases, and the frequency of appendicitis with perforation has been 15% 30% (1). More recently, introduction of diagnostic imaging aids, specifically computed tomography (CT), has allowed more accurate diagnosis of appendicitis (2). The rates of finding a normal appendix at surgery, in studies where CT was part of the diagnostic process, were 3.3% 7.2%, compared to rates of 3.2% 15% for the patients who were immediately referred for appendectomy. At the same time, the liberal use of CT scanning and laparoscopy has led to an increase in the number of cases with detected appendicitis, with a subsequent higher appendectomy rate, implying that the disease may heal by itself (3). Although antibiotics may be used as primary

2 Use of pre- or postoperative antibiotics for appendicitis 15 Titles identi ied through database searching n=633 Abstracts screened n=61 Full-text artiles assesed for eligibility n=36 Studies eligible for inclusion in the review n=13 (twelve RCTs and one Cochrane Database review). Fig. 1. Flowchart. RCTs: randomized controlled trials. Titles excluded n=572 Abstracts excluded n=25 Full text articles exluded (Pediatric RCTs and trials on intra-abdominal infections) n=23 definitive treatment for selected patients with suspected uncomplicated appendicitis, appendectomy is still the gold standard therapy (4). Appendiceal abscess or phlegmon is found in 3.8% of patients with appendicitis. These patients are treated conservatively as immediate surgery is associated with higher morbidity (5). Moreover, the development of CT and ultrasound (US) has improved the diagnosis of enclosed inflammation and made drainage of intra-abdominal abscesses easier. The risk of recurrence with nonsurgical treatment is 7.4%, and a malignant disease is detected in 1.2% of patients during follow-up (5). Interval appendectomy is not recommended as a routine, and it should be done only for special indications such as persisting complaints that suggest appendicitis. With respect to antibiotic therapy, there is considerable variability in the choice, duration, and route of administration in acute appendicitis treated operatively. Moreover, there is an escalating problem with antibiotic resistance among bowel pathogens (6, 7), with an increased rate of antibiotic resistant bacteria. Even after short course of antibiotic therapy, extendedspectrum beta-lactamase (ESBL) resistance has been found with increased costs, prolonged hospitalization, and increased mortality (8). Since antimicrobial use proceeds to the emergence of antimicrobial resistance, optimized use of antibiotics is required. The purpose of this review is to provide an overview of studies on antibiotics for acute appendicitis treated operatively and to see whether evidence-based recommendation can be suggested. Material and Methods A search was made using PubMed and the Cochrane Library database. Appendicitis and antibiotics were selected as search terms. All studies, published in English, with a publication date ranging from 1994 to December 2011 were included. The selection was based on relevance for the following questions: 1a. Should preoperative antibiotics be used for patients with suspicious acute appendicitis prior to surgery? 1b. What preoperative antibiotics should then be used? 2a. Is there any benefit in treating patients postoperative with antibiotics in case of phlegmonous, gangrenous, or perforated appendicitis, respectively? 2b. What postoperative antibiotics should then be used, what route, and for how long? A total of 633 study titles were identified by the initial search strategy, and of these, 572 were excluded after title searching, based on the relevance for the questions mentioned above. A total of 61 potential articles were selected. In the next stage, abstracts were reviewed and 36 articles were selected for further review of full text publications. 79 study titles, reporting patients with periappendicular abscess not operated upon, are excluded from this review. All potentially eligible studies were randomized controlled trials (RCTs). Of these, 17 trials addressing to intra-abdominal infections were identified, but not included as they did not provide data on acute appendicitis alone. Six pediatric RCTs were excluded as adolescents are not directly comparable with adults, especially regarding the clinical course of acute appendicitis. Finally, 12 trials, plus one Cochrane Database meta-analysis addressing acute appendicitis, were included in this analysis (Fig. 1). Of these 12 trials, 8 had two treatment arms and 4 had three or more arms. Age of the included patients ranged from 4 to 80 years. Eleven studies reported the male/female ratio. Five of the studies classified the appendicitis either as simple or uncomplicated and advanced or complicated. Ten studies reported wound infection, six studies reported intra-abdominal abscess and eight studies reported length of stay in hospital. The classification into phlegmonous, gangrenous, and perforated appendicitis was used for the purposes of this review. In several studies, the terms simple/ uncomplicated and complicated/advanced were encountered, applying for phlegmonous and gangrenous/perforated appendicitis, respectively. In three trials, the specimens were sent to pathology for the final diagnosis, whereas in the others, the classification was based on the macroscopic appearance of the appendix peroperatively. In none of the studies, preoperative standardized radiological assessment was performed. Seven studies reported an open McBurney incision as the standardized method of surgery, whereas in none of the studies was laparoscopy standardized. Results 1a. Should preoperative antibiotics be used for patients with suspicious acute appendicitis prior to surgery?

3 16 K. Daskalakis, et al. Table 1 Summary of Cochrane Database review regarding use of antibiotics for appendicitis. Systemic antibiotics versus placebo. Outcome No. of studies No. of participants Statistical method Effect size 1. Wound infection Peto odds ratio (Peto, fixed, 95% CI) 2. Postoperative intraabdominal Peto odds ratio (Peto, abscess fixed, 95% CI) 3. Length of stay in Mean, difference (IV, hospital fixed, 95% CI) 0.33 (0.29, 0.38) 0.43 (0.25, 0.73) 1.69 ( 1.78, 1.61) CI: confidence interval. Table 2 Data in studies on different regimens of antibiotic prophylaxis in acute appendicitis (11 14) and duration of IV antibiotics in cases of non-perforated appendicitis (14, 15). Studies Regimens n Wound infection Hospital stay Ravari et al. (11) PO metronidazole 102 6% 2.3 ± 0.8 IV metronidazole 102 4% 2.7 ± 1.1 Kumarakrishnan et al. (12) IV metronidazole and gentamycin 60 n = (not infected) 7.5 IV metronidazole and ciprofloxacin 60 n = (not infected) 10.5 IV metronidazole and cefotaxime 60 n = (not infected) 9 Salam et al. (13) IV cefoxitin % (n = 3) 4 8 (not infected); IV piperacillin 126 4% (n = 5) 4 8 (not infected); Liberman et al. IV cefotetan 37 0 No data (14) IV cefoxitin % (n = 5) No data Three-dose (1-day) IV cefoxitin % (n = 1 patient No data with abscess) Mui et al. (15) Single-dose, preoperative IV % (n = 6) 4.3 cefuroxime and metronidazole Three-dose (1-day) IV cefuroxime % (n = 6) 4.6 and metronidazole 5-day course of IV cefuroxime and metronidazole % (n = 3) 4.8 PO: oral; IV: intravenous. The Cochrane Database review supports that broadspectrum antibiotics given preoperatively are effective in decreasing wound infection and abscesses (9; Table 1). This meta-analysis includes 45 studies and confirms an overall effect of antibiotics on reduction of infectious complications, regardless of whether administered prophylactically (a single-dose administration in case of normal removed appendix or phlegmonous appendicitis) or as repetitive treatment in case of complicated appendicitis. Regarding the timing of antibiotic treatment, Almqvist et al. (10) conducted a prospective randomized trial on patients with gangrenous appendicitis and showed that antibiotic treatment started during the operation is not significantly less effective, at preventing infectious complications, than started prior to surgery. 1b. What preoperative antibiotics should then be used? In Andersen et al. Cochrane meta-analysis (9), the most common antibiotics used were cephalosporin and imidazole derivatives. Four RCTs (Table 2; 11 14) have compared different antibiotic regimens as prophylaxis for nonperforated appendicitis. Ravari et al. (11) showed that single dose of oral metronidazole prior to operation can provide a sufficient prophylaxis for non-perforated appendicitis, when compared to single dose of intravenous (IV) metronidazole before surgery. Kumarakrishnan et al. (12) showed that the combination of cefotaxime metronidazole had the lowest wound infection rate compared to metronidazole gentamycin and metronidazole ciprofloxacin. Salam et al. (13) showed that prophylactic cefoxitin or piperacillin were similarly effective in minimizing the rate of wound infections. A single-dose cefotetan was equally effective as multiple-dose cefoxitin according to the study by Liberman et al. (14).

4 Use of pre- or postoperative antibiotics for appendicitis 17 Table 3 Data in studies on IV regimens (16 18) and IV versus PO regimens (19, 20) in perforated appendicitis. Group n Age IV days PO days Complications Allo et al. (16) IV ticarcillin clavulanate (3.1%) IV imipenem cilastatin (4.1%) Hopkins et al. IV cefotetan ± (17) IV clindamycin amikacin ± Berne et al. IV meropenem ± (18) IV tobramycin clindamycin ± Banani and IV ceftizoxime (no pus) or IV ceftizoxime (14.16%) Talei (19) preoperatively and penicillin, chloramphenicol, and gentamycin postoperatively (pus) PO metronidazole (15.78%) Taylor et al. (20) IV: intravenous; PO: oral. IV ampicillin sulbactam PO placebo ± (27.3%) IV ampicillin sulbactam PO amoxicillin ± (26.1%) clavulanic (<18 years) or levofloxacin (>18 years) There were no RCTs found comparing different regimens of antibiotic prophylaxis specifically regarding perforated appendicitis. 2a. Is there any benefit in treating patients postoperative with antibiotics in case of phlegmonous, gangrenous, or perforated appendicitis, respectively? Only two RCTs were designed to evaluate the efficacy of postoperative antibiotics in addition to preoperative antibiotics in non-perforated appendicitis (Table 2; 14, 15). In the Liberman et al. study (14), patients with phlegmonous appendicitis were randomized to receive either preoperative cefotetan (n = 37), preoperative cefoxitin (n = 45), or preoperative cefoxitin followed by three postoperative doses of cefoxitin (n = 54). The single preoperative dose of cefoxitin had a significantly higher wound infection rate (11.1%) compared with the group that received both preoperative and postoperative cefoxitin (1.9%). However, a single dose of cefotetan was as efficacious as the combined course of preoperative and postoperative cefoxitin. Mui et al. (15) investigated wound infection rates in a three-armed RCT including patients with non-perforated (both phlegmonous and gangrenous) appendicitis. One group (n = 92) received one preoperative dose of cefuroxime and metronidazole, another group (n = 94) received an additional three postoperative doses, and a third group (n = 83) received postoperative antibiotics for an additional five consecutive days. No statistically significant difference was found in the wound infection rates between the three groups (6.5, 6.4, and 3.6, respectively). 2b. Which postoperative antibiotics should then be used, what route, and for how long? Postoperative antibiotic treatment is considered standard of care in cases of perforated appendicitis. Subsequently, in all reviewed RCTs (16 21), all patients received postoperative antibiotics. Three RCTs (16 18) could be found comparing postoperative IV antibiotic regimens on patients with perforated appendicitis (Table 3; 16 18). Allo et al. (16) showed that ticarcillin clavulanate is as effective and safe as imipenem cilastatin. Hopkins et al. (17) showed that monotherapy with a second generation, broad-spectrum cephalosporin, such as cefotetan, is an effective regimen, and aminoglycosides as well as other more potent antimicrobials should be reserved for resistant organisms or nosocomial infections. Berne et al. (18) showed that meropenem was more effective than tobramycin clindamycin. Antimicrobial therapy in studies mentioned above commonly includes broad-spectrum agents effective against aerobic gram-negative and anaerobic organisms. Two studies (Table 3; 19, 20) were found addressing to the treatment of acute perforated appendicitis with oral (PO) antibiotics. Banani and Talei (19) conducted a trial comparing PO metronidazole both preand postoperatively versus IV ceftizoxime if there was no pus in the abdomen or postoperative triple drug therapy with IV penicillin, chloramphenicol, and gentamycin if there was visible pus during surgery. The difference in complication rate was not statistically significant. In the study by Taylor et al. (20), patients received 2 5 days IV ampicillin sulbactam and were subsequently randomized to placebo or PO antibiotics consisting of amoxicillin clavulanate for patients above 18 years and levofloxacin for patients below 18 years. No statistically significant difference for infectious complications was found in the two groups. Studies (16 18) comparing different IV antibiotic regimens for perforated appendicitis demonstrate a variation in the duration of treatment. Allo et al. (16) used a protocol of 3 5 days, Hopkins et al. (17) a minimum of 5 days, and Berne et al. (18) 5 9 days. All the above-mentioned studies commonly used the white blood cell (WBC) normalization and a period of h without fever as criteria for the discontinuation of IV treatment.

5 18 K. Daskalakis, et al. In the study by Taylor et al. (21), a minimum IV 5-days antibiotic regimen versus no minimum IV regimen was studied in patients with complicated appendicitis and showed no statistically significant difference regarding infectious complications and average hospital stay. Clinical criteria for discontinuing IV antibiotics in both groups included resolution of fever, improved abdominal signs and symptoms, and return of bowel function, with some surgeons also using a decrease in leukocytosis. Discussion This review is focused on the use of antibiotics in surgically treated appendicitis. Although conservative antibiotic treatment of acute appendicitis has been investigated in several studies, appendectomy remains the standard treatment. This is supported by a Cochrane Database review by Wilms et al. (4). Nonoperative management of uncomplicated appendicitis with antibiotics was associated with significantly fewer complications, but antibiotics alone had lower efficacy compared to appendectomy. Moreover, the quality of RCTs on definitive antibiotic treatment of acute appendicitis was low to moderate. Based on this meta-analysis (4), antibiotic treatment might be used as an alternative treatment in a goodquality RCT or in specific patients or conditions where surgery is contraindicated, but this was not the scope of this report. Data strongly support that patients with acute appendicitis should receive preoperative, broadspectrum antibiotics. For non-perforated (phlegmonous or gangrenous) appendicitis, preoperative treatment is enough. If the appendicitis is perforated, postoperative, broad-spectrum antibiotics are recommended. The period is still not defined, but a period of 3 5 days for adult patients is recommended. Discontinuation of the IV treatment has been based on clinical and laboratory criteria in all studied series, but the present knowledge does not support the use of oral antibiotics after the initial IV treatment. One large RCT on oral versus IV antibiotic postoperative treatment and one large RCT on the duration of postoperative treatment in perforated appendicitis are necessary. However, there are several important limitations. The number of prospective RCTs on antibiotic treatment of patients with acute appendicitis is too small and subsequently underpowered. Furthermore, this review was neither addressing differences among antibiotic types nor differences in local antibiotic resistance. Another important limitation is that the classification of acute appendicitis into phlegmonous, gangrenous, and perforated is not followed by all the reviewed RCTs. Current pathology reporting terms lack the necessary specificity to differentiate cases of clinically significant inflammation from clinically unimportant mild inflammation in patients with phlegmonous appendicitis and incidentally removed appendix (22). In this meta-analysis, the majority of eligible RCTs used only a clinical classification based on the appearance of the appendix peroperatively. Since the diagnostic approach was similar in all the included RCTs, without CT scans or US scans in the preoperative assessment, the diagnostic procedure does not have any impact on the results. Open surgery was the standard procedure in seven trials, whereas laparoscopy in none. In all others, the method of surgery was not standardized. A Cochrane Database systematic review by Sauerland et al. (23) showed that diagnostic laparoscopy and laparoscopic appendectomy (either in combination or separately) seem to have various advantages over open surgery. Wound infections were less likely after laparoscopic than after open appendectomy, but the incidence of intra-abdominal abscesses increased. Diagnostic laparoscopy reduced the risk of a negative appendectomy, but this effect was stronger in fertile women as compared to unselected adults. Based on this Cochrane Database review by Sauerland et al. (23), the use of laparoscopy and laparoscopic appendectomy is generally recommended in patients with suspected uncomplicated appendicitis, especially in young female, obese, and employed patients. In cases of perforated appendicitis, intraabdominal abscesses are more likely to occur after laparoscopic surgery, and an open procedure or converting to open surgery after diagnostic laparoscopy should be considered. Implications for clinical practice on the use of antibiotics regarding the surgical technique cannot be made based on this meta-analysis and no RCTs on adult patients could be found on the subject, but the principles used in open surgery are still valid for laparoscopic appendectomy. A Cochrane Database meta-analysis (9) supports the use of broad-spectrum IV antibiotic prophylaxis in acute appendicitis. The positive overall effect of antibiotic prophylaxis on reduction of infectious complications was seen even in cases of removed normal appendix, which supports the use of IV preoperative antibiotic prophylaxis in all appendectomies (9). Moreover, the Cochrane Database meta-analysis results indicate that single doses have the same impact as multiple doses (9). In order to reduce cost, toxicity, and the risk of developing bacterial resistance, it is desirable to establish the shortest, effective prophylaxis for postoperative complications. Oral prophylaxis prior to surgery in cases of non-perforated appendicitis can be considered according to the study by Ravari et al. (11), but more RCTs on the subject are necessary. For gangrenous appendicitis, it is difficult to draw firm conclusions since several studies combine gangrenous and perforated appendicitis. Studies that separate simple or advanced/complicated appendicitis commonly include gangrenous appendicitis in the second group. On the contrary, the Mui et al. trial (15) pooled together phlegmonous and gangrenous appendicitis. There was no study providing data on duration of antibiotic treatment of gangrenous appendicitis alone. Based on the studies of Liberman et al. (14), Mui et al. (15), and Andersen et al. (9), single-dose preoperatively administrated antibiotic treatment for phlegmonous and gangrenous appendicitis is recommended.

6 Use of pre- or postoperative antibiotics for appendicitis 19 Table 4 Regimens that may be used for the treatment of perforated or abscessed appendicitis according to guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Regimen Single agent Combinations Mild-to-moderate severity: perforated or abscessed appendicitis Cefoxitin Ertapenem Moxifloxacin Tigecycline Ticarcillin clavulanic acid Cefazolin Cefuroxime Ceftriaxone Cefotaxime Ciprofloxacin Levofloxacin each in combination with metronidazole High risk or severity: severe physiologic disturbance, advanced age, or immunocompromised state Imipenem cilastatin Meropenem Doripenem Piperacillin tazobactam Cefepime Ceftazidime Ciprofloxacin Levofloxacin each in combination with metronidazole Regarding perforated appendicitis and the selection of antibiotic prophylaxis and antibiotic treatment in the postoperative course, broad-spectrum regimens effective against aerobic gram-negative organisms and anaerobic organisms are recommended according to guidelines by the Surgical Infection Society and the Infectious Diseases Society of America (24; Table 4). These guidelines apply even for cases of abscessed appendicitis treated conservatively. Regarding the length of IV antibiotic treatment in patients with perforated appendicitis, numerous studies on complicated intra-abdominal infections could be found comparing various antibiotic regimens, but they do not provide data for each intra-abdominal infection separately. Based on studies (16 20) on perforated appendicitis and postoperative antibiotics, a minimum 3- to 5-days treatment is recommended for adult patients. According to the study by Taylor et al. (21), the discontinuation of IV antibiotics based on resolution of clinical findings as compared to a required minimum postoperative IV antibiotic duration yielded similar outcome and saved antibiotic costs and potential hospital days. Discontinuation of IV therapy is arbitrary based on clinical criteria, such as absence of pyrexia, and supported by a decrease in leukocytosis and C-reactive protein (CRP). Regarding the importance of inflammatory response variables, only one prospective trial by Eriksson et al. (25) could be found investigating the kinetics of WBC, CRP, elastase, and interleukin-6 (IL- 6) after open appendectomy. This study concluded that it is important to understand the postoperative kinetics for each test in order to detect postoperative complications. Considering the limited number of RCTs (19, 20) on the treatment of perforated appendicitis with oral antibiotics, there is no sufficient evidence to support its use or the length of treatment. Moreover, both studies included patients with non-perforated appendicitis, who received antibiotics in the postoperative course, and in the study by Banani et al. (19), patients older than 50 years of age and cases with generalized peritonitis were excluded. Adding a course of outpatient PO antibiotics does not decrease postoperative infectious complications in appendicitis patients but increases the treatment cost (21). Therefore, oral antibiotics, alone or following IV regimens, for the treatment of perforated appendicitis cannot be recommended. Summary The evidence is strong supporting preoperative, broad-spectrum antibiotics to patients with acute appendicitis. In patients with non-perforated (phlegmonous or gangrenous) appendicitis, the use of postoperative antibiotic treatment is not recommended. In cases of perforated appendicitis, postoperative, broad-spectrum antibiotics are recommended for a minimum period of 3 5 days for adult patients. No good recommendations exist for how discontinuation of IV treatment should be done, since the majority of trials were done during an era with little focus on resistance to drugs. However, the present evidence does not support the use of oral antibiotics after the initial postoperative IV treatment in acute perforated appendicitis and further trials are awaited. References 1. Andersson RE: Appendicitis: Epidemiology and diagnosis. Doctoral Thesis, Linköpings universitet, Sweden, Rao PM, Rhea JT, Novelline RA et al: Effect of computed tomography of the appendix on treatment of patients and use of hospital resources. N Engl J Med 1998;338(3): Petrosyan M, Estrada J, Chan S et al: CT scan in patients with suspected appendicitis: Clinical implications for the acute care surgeon. Eur Surg Res 2008;40(2): Wilms IM, de Hoog DE, de Visser DC et al: Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane Database Syst Rev 2011;11:CD

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