World J Surg (2010) 34:199209 DOI 10.

1007/s00268-009-0343-5

ORIGINAL SCIENTIFIC REPORTS AND REVIEWS

Antibiotic Therapy Versus Appendectomy for Acute Appendicitis: A Meta-Analysis

Krishna K. Varadhan David J. Humes Keith R. Neal Dileep N. Lobo

Published online: 30 December 2009 te Internationale de Chirurgie 2009 Socie

Abstract Background Antibiotic treatment has been shown to be effective in treating selected patients with acute appendicitis, and three randomized controlled trials (RCTs) have compared the efcacy of antibiotic therapy alone with that of surgery for acute appendicitis. The purpose of this metaanalysis of RCTs was to assess the outcomes with these two therapeutic modalities. Methods All RCTs comparing antibiotic therapy alone with surgery in patients over 18 years of age with suspected acute appendicitis were included. Patients with suspected perforated appendix or peritonitis, and those with an allergy to antibiotics had been excluded in the RCTs. The outcome measures studied were complications, length of hospital stay, and readmissions. Results Meta-analysis of RCTs of antibiotic therapy versus surgery showed a trend toward a reduced risk of complications in the antibiotic-treated group [RR (95%CI): 0.43 (0.16, 1.18) p = 0.10], without prolonging the length of hospital stay [mean difference (inverse variance, random, 95% CI): 0.11 (-0.22, 0.43) p = 0.53]. Of the 350

patients randomized to the antibiotic group, 238 (68%) were treated successfully with antibiotics alone and 38 (15%) were readmitted. The remaining 112 (32%) patients randomized to antibiotic therapy crossed over to surgery for a variety of reasons. At 1 year, 200 patients in the antibiotic group remained asymptomatic. Conclusions This meta-analysis suggests that although antibiotics may be used as primary treatment for selected patients with suspected uncomplicated appendicitis, this is unlikely to supersede appendectomy at present. Selection bias and crossover to surgery in the RCTs suggest that appendectomy is still the gold standard therapy for acute appendicitis.

Introduction Acute appendicitis is one of the commonest of surgical emergencies, and appendectomy has become established as the gold standard of therapy. However, as the diagnosis of appendicitis in most countries is mainly a clinical one, based on history and examination, diagnostic uncertainty in patients with suspected appendicitis may lead to a delay in treatment or negative surgical explorations, adding to the morbidity associated with the condition [1]. Traditionally, patients with no overt diagnostic signs such as right iliac fossa guarding or peritonism are monitored for changes in clinical signs with or without having been started on antibiotic therapy [2]. While antibiotics are indicated in patients with signs of peritonism, their role in the routine treatment of acute non-perforated appendicitis is still debatable [3, 4]. Some studies have reported that antibiotic therapy reduces wound and intra-abdominal septic complications following surgery [5, 6]. Although antibiotic therapy has been shown to be effective in treating

This article was presented at the Annual Conference of the Society for Academic and Research Surgery, London, January 2010. K. K. Varadhan D. J. Humes D. N. Lobo (&) Division of Gastrointestinal Surgery, Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom e-mail: dileep.lobo@nottingham.ac.uk K. R. Neal Department of Epidemiology and Public Health, and Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham University Hospitals, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom

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selected patients with suspected acute appendicitis, their role in the primary treatment of the disease has not yet been established clearly. Over the past two decades three randomized clinical trials (RCTs) [79] have compared the efcacy of antibiotic therapy alone with that of surgery for acute appendicitis. The purpose of the present study was to perform a meta-analysis of RCTs in order to assess the outcomes with the two therapeutic modalities.

Manager Version 5 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) [10] for analysis. Statistical methods The Review Manager Version 5 software was used to assess the heterogeneity between studies by considering the I-squared method alongside the chi-square p value. A random-effects model was used to analyze the differences in outcome measures between the two groups, as this model allows more exibility in detecting between-patient differences (as some patients respond differently from others) and reduces false positivity when compared with a xed-effects model [11]. Risk ratio was preferred to odds ratio, as the latter is more appropriate for casecontrol studies [12].

Methods All RCTs in which patients over 18 years of age with suspected acute appendicitis were randomized to antibiotic therapy alone or surgery (appendectomy) at initial presentation were included. Patients with suspected perforated appendix or peritonitis, and those with allergy to antibiotics used in the protocols had been excluded in the RCTs. The primary outcome measure of this meta-analysis was complications, as described in the individual RCTs [79] (major complications such as reoperation, abscess, small bowel obstruction, wound rupture, wound hernia, deep vein thrombosis, pulmonary embolism, postoperative cardiac problems, and need for ileocecal resection, as well as minor complications such as prolonged postoperative course, bladder dysfunction, anesthesia-related complications, diarrhea, Clostridium difcile infection, fungal infection, and wound infection among others). Secondary outcome measures included length of hospital stay and readmission rates. Search strategy The Medline, Embase and Cochrane Library databases were searched for RCTs comparing antibiotic therapy with surgery for suspected acute appendicitis, published between January 1966 and June 2009. The MESH terms, antibiotics, surgery, appendicectomy, appendectomy, randomized controlled trial, controlled clinical trial, randomized, placebo, drug therapy, randomly, trial, and groups were used in combination with the Boolean operators AND, OR, and NOT. The related article function was used to identify other eligible studies for inclusion in the meta-analysis. The search included publications in all languages. Data collection and analysis Two review authors (K.K.V. and K.R.N.) inspected the citations identied from the search, and the retrieved articles were assessed according to the previously dened criteria for inclusion in the meta-analysis. The data were extracted from the included RCTs by the authors (K.K.V. and K.R.N.) independently and integrated into the Review

Results Characteristics of the studies included Three RCTs [79] with a total of 661 patients were eligible for inclusion in the meta-analysis (Fig. 1). The characteristics of the studies, as shown in Table 1, were similar. The studies included showed a moderate heterogeneity, and the mean Jadad score [13] was 2.7. The methodological quality of the studies is summarized in Table 2. Diagnosis of appendicitis All patients were admitted with a history and clinical signs of acute appendicitis with positive laboratory tests. Along with raised inammatory markers, positive ndings at ultrasonography formed part of the inclusion criteria in one study where the patients had repeat ultrasound examinations at days 10 and 30 during follow-up [9]. Computed tomography and ultrasound scans were performed only in some patients in the study by Hansson et al. [7], whereas, imaging investigations were not mentioned in the study by Styrud et al. [8]. The outcome measures commonly identied in the three studies were treatment efcacy, diagnosis at operation, complications, length of hospital stay, and readmission. Time off work and patient experience of abdominal pain in the rst post-treatment year were also reported in these studies. Antibiotic group The patients in the antibiotic group were treated with intravenous antibiotics cefotaxime and metronidazole [7], cefotaxime and tinidazole [8, 9], for a minimum of

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World J Surg (2010) 34:199209 Fig. 1 Selection of studies

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12 days, followed by oral antibiotics consisting of ciprooxacin and metronidazole [7], ooxacin and tinidazole [8, 9], for 810 days. In one study [7], antibiotic treatment was continued beyond the initial course if there was no clinical improvement. Patients with increasing abdominal pain despite antibiotic therapy, or those who had signs of perforation or peritonitis underwent surgery according to protocol. For the purpose of this meta-analysis, patients were analyzed as being part of the antibiotic group when initial randomization placed them in the antibiotic group and they went onto have surgery, either for worsening symptoms and signs during their primary admission or when they were readmitted with suspicious signs of appendicitis. Surgery group In the study by Hansson et al. [7], after initial randomization 96 patients were transferred from the antibiotic group to the surgery group, and 10 were transferred from the surgery group to the antibiotic group. The histological data were not listed separately for this group of patients in

this study, and subsequent analysis for outcome measures such as complications and length of stay was performed both as intention to treat and per protocol. Therefore, the diagnostic accuracy based on intention-to-treat analysis cannot be ascertained. Moreover, we felt that, because of inappropriate randomization, 32 patients who wanted other therapy and those who withdrew from the study should not have been included for further analysis. For purpose of studying the outcome of antibiotic therapy, the data are presented with or without these patients (Figs. 2 and 3). However, we were unable to separate these patients for meta-analysis of complication rates and length of stay. In the other two studies [8, 9], crossover to surgery only happened after failed antibiotic therapy per protocol. These patients (n = 16) were included for both intention to treat and per protocol analysis, as illustrated in Fig. 4. Patients randomized to surgery underwent either open or laparoscopic appendectomy. Except for 3 patients who were successfully treated with a second course of antibiotics, all patients who were readmitted with suspected recurrent appendicitis following initial successful treatment with antibiotics, underwent appendectomy.

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Table 1 Characteristics of studies in the meta-analysis

Study of Hansson et al. [7]

Methods

Randomized controlled trial. Three hospitals included for the study; one hospital used only as a reference cohort for comparison with study and control groups at the other two hospitals. Allocation by date of birth (odd numberantibiotics group, even numbersurgery group). Questionnaire was sent to all patients after 1 and 12 months. Telephoned if no response

Participants

369 patients with positive history, clinical signs, laboratory tests, and in some cases, ultrasonography, computed tomography, and gynecological examination

Interventions Antibiotics: intravenous (IV) cefotaxime 1 g twice daily and metronidazole for at least 24 h. Patients when improved were discharged 24 h later with oral ciprooxacin 500 mg twice a day and metronidazole 400 mg three times a day for 10 days. If no improvement, IV treatment was prolonged

Surgery: Appendectomy was performed according to the authors usual practice: single- dose antibiotic prophylaxis, open or laparoscopic technique, and postoperative antibiotic treatment when the appendix was gangrenous or perforated

All specimens were sent for histological examination

Outcomes

Treatment efcacy, complications, recurrences, and reoperations, length of antibiotic therapy, abdominal pain after discharge from hospital, length of hospital stay, and sick leave. The total costs for the primary hospital stay were analyzed for each patient

Study of Styrud et al. [8]

Methods

Patients were asked to participate if appendectomy was planned, and those who agreed were subsequently randomized either to surgery or antibiotic therapy. Patients were monitored at the end of 1 week, 6 weeks, and 1 year

Participants

Male patients, 1850 years of age, admitted to six different hospitals between 1996 and 1999. No women were enrolled by decision of the local ethics committee. Patients with suspected appendicitis with a C-reactive protein (CRP) level [ 10 mg/l in whom perforation was not suspected were asked to participate in the study

Interventions Antibiotics: Intravenous cefotaxime 2 g 12 hourly and tinidazole 800 mg daily for 2 days. Discharged after 2 days with oral ooxacin 200 mg twice daily and tinidazole 500 mg twice daily for 10 days. If symptoms had not improved within rst 24 h, appendectomy was performed. All conservatively treated patients with a suspected recurrence of appendicitis underwent surgery Surgery: Patients randomized to surgery were operated open or laparoscopically at the surgeons discretion. All removed appendixes were sent for histology

Outcomes

Hospital stay, sick leave, diagnosis at operation, recurrences, complications

Study of Eriksson et al. [9]

Methods

Randomization of patients admitted with history and clinical signs of acute appendicitis. Ultrasonography and laboratory testsWBC, CRPto identify patients with a high probability of acute appendicitis

Participants

Patients with typical history and clinical signs, positive ndings at ultrasound (US), and either increased WBC and CRP values or high CRP or WBC levels on two occasions within a 4-h interval. Initial randomization of 20 patients in each group, but one patient from the antibiotic group developed increased abdominal pain and generalized peritonitis, and underwent surgery; subsequent data were discounted

Interventions Conservative: Cefotaxime 2 g 12 hourly and tinidazole for 2 days. Discharged after 2 days with oral ooxacin 200 mg twice daily and tinidazole 500 mg twice daily for 8 days. Pain was registered every 6 h on a visual analogue scale (VAS), and oral temperature was measured twice daily. Patients were excluded from the study in the event of increased abdominal pain and generalized peritonitis leading to surgery

Surgery: Treated with antibiotics only in the event of perforation or for 24 h in cases of abdominal spillage. Discharged when conditions were satisfactory and when patients wished to return home. Pain was recorded on VAS every 6 h and oral temperature was measured twice daily. All specimens were sent for histology

Follow-up: All patients were seen 6, 10, and 30 days after admission, and blood tests for WBC and CRP were taken; pain scores (VAS) and body temperature were recorded. Abdominal and rectal examination on days 6 and 10. Stools examined for Clostridium difcile toxin at day 30; US performed on days 10 and 30

World J Surg (2010) 34:199209

Outcomes

Pain scores, morphine consumption, WBC, and body temperature, positive diagnosis at surgery, hospital stay, wound infection, recurrent appendicitis

World J Surg (2010) 34:199209 Jadad score

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Summary of outcomes
3 2 3

Description of dropouts and withdrawals

Table 3 illustrates the main outcome measures listed for the two groups. All patients included in the studies had a minimum follow-up for 1 year.
Yes No Yes

Antibiotic group There were 350 patients randomized to the antibiotic group, of whom 238 (65%) were treated successfully with antibiotics alone. Among those 238 patients, there were 38 (15%) recurrences reported. Of the patients with recurrence, 3 were retreated successfully with antibiotics; the remaining 35 had appendicitis (25 phlegmonous, 9 perforated, and 1 gangrenous on histology after appendicectomy). Of the 112 patients who crossed over from the antibiotic group to the surgery group, histological diagnosis was available for 26. In the crossover group, 23 of the 26 patients had histologically proven appendicitis (10 phlegmonous, 10 perforated, and 3 gangrenous). The diagnoses in the remaining 3 patients were reported as normal, terminal ileitis, or other. More signicantly, 200 patients in the antibiotic group remained asymptomatic at 1 year (Fig. 2). Surgery group

Not blinded

Method of randomization described & appropriate

Blinding

Not blinded Yes No Yes 1

Allocation concealment

Yes

Consecutive series of patients

No

Median follow-up (years)

Yes

Yes

No

Yes

Not blinded

Table 2 Quality assessment and study design

There was no crossover from the surgery group to the antibiotic group in trials by Styrud et al. [8] and Eriksson et al. [9] In the study by Hansson et al. [7] 10 patients changed from their assigned groups: 7 patients wanted other therapy, 2 were allocation faults, and 1 patient was too ill for an operation, as described in the article. Of the 394 patients randomized to surgery, 357 were treated successfully for histologically conrmed appendicitis (249 phlegmonous, 57 perforated, and 51 gangrenous). Of the remaining patients, 23 had other diagnoses and 14 had normal appendices, as illustrated in Fig. 4. Complications noted in the two groups are summarized in Fig. 5. Meta-analysis of RCTs showed a trend for a reduced risk of complications for antibiotic therapy [RR (95%CI): 0.43 (0.16, 1.18) P = 0.10] and no difference between antibiotic therapy and surgery for length of hospital stay [mean difference (inverse variance, random, 95% CI): 0.11 (-0.22, 0.43) P = 0.53]. The results for complication rates and length of hospital stay are summarized in the Forest plots in Figs. 6 and 7, respectively.

38 (1) Range 1850; mean not reported 38 (1) Range 1850; mean not reported 124 128 Styrud et al. [8]

Mean (standard error of mean)

Mean (range) Mean (range) Eriksson et al. [9] 20 20

Age groups

Mean (standard error of mean)

Surgery

No. of patients

Antibiotic therapy

Hansson et al. [7]

202

167

27 (1853)

Antibiotic therapy

35 (1975)

Surgery

Discussion The results from this meta-analysis suggest that although antibiotics may be used as primary treatment for selected

RCT

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Fig. 2 Outcome data for antibiotic therapy (intention to treat)

Fig. 3 Outcome data for antibiotic therapy (excluding inappropriate randomization)

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World J Surg (2010) 34:199209 Fig. 4 Outcome data for patients undergoing appendectomy

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patients with suspected uncomplicated appendicitis, on current evidence, this therapeutic approach is unlikely to supersede appedectomy. Treatment with antibiotics resulted in a trend toward reduced risk of complications [RR (95%CI): 0.43 (0.16, 1.18) P = 0.10] without prolonging the length of hospital stay [mean difference (inverse variance, random, 95%CI): 0.11 (-0.22, 0.43) P = 0.53], when compared with appendectomy. However, only 68% patients were treated successfully with antibiotics in their primary admission, with a 15% readmission rate. Antibiotic therapy was not associated with increased morbidity through readmissions, as reected by similar histological results in these patients to those who had surgery during their primary admission. It should be emphasized that 42% of patients initially treated with antibiotics required surgical intervention either at initial admission or at readmission. Therefore, these results have to be interpreted more carefully in the clinical context, as the conclusions of this meta-analysis are limited by the study design, relatively high cross-over rate from the antibiotic to the surgery group, methodological quality, and denitions of primary endpoints such as treatment efcacy, recurrence, and complication rates in the included RCTs. Paucity of specic data for patients who crossed over to surgery further limits the validity of the conclusions. The diagnosis of acute appendicitis in the included RCTs was largely based on history, clinical examination, and laboratory ndings, combined with some imaging tests where necessary. As there was no common standardized protocol for diagnosing appendicitis in these studies, some patients treated in the antibiotic group may not have had appendicitis, and therefore the classication does not necessarily reect the true treatment efcacy of antibiotic

therapy. Furthermore the crossover of patients to the surgery group following their initial randomization to antibiotic therapy would result in unidentied bias in reporting complication rates in the surgery group. Moreover, although the readmissions following antibiotic therapy were presumed to be due to recurrent appendicitis and were treated by appendectomy, the reported readmissions in the surgery group were mainly for surgery-related reasons. Therefore a direct comparison of recurrence rates or morbidity between the groups has to be interpreted with caution. A negative appendectomy rate as high as 1525% has been reported in the literature with the inherent risk of increased complications and morbidity [14, 15]. However, a retrospective study of 199 patients in our institution showed no statistically signicant difference in the complication rates following surgery, between inamed and non-inamed appendicitis, although it showed increased septic complications in the inamed group [1]. Reported recurrence rates following conservative treatment of acute appendicitis range between 3 and 25%, and the complication rate following interval appendectomy varies from 8 to 23% [16]. However, a retrospective study of 60 patients who were initially treated conservatively for appendicitis conrmed on the basis of ultrasound ndings obtained at admission and follow-up, showed a recurrence rate of 38% [17], whereas the results of the present metaanalysis show a readmission rate of 15% following antibiotic therapy. The treatment of acute appendicitis with antibiotics may result in failure to diagnose neuroimmune appendicitis [18, 19]. Failure to treat these patients with an appendectomy may lead to development of chronic right iliac fossa pain, but it should be emphasised that this was not an apparent problem in any of the RCTs.

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Treatment efcacy n (%) Surgery 142 (85) 51 55 15 0 3 (0.1) 3 (0.2) Antibiotics Surgery Antibiotics Surgery Antibiotics Surgery Antibiotics 21 (9 ? 12) 9 in primary admission: 3 phlegmonous; 3 gangrenous, 3 perforated 12 of 15 recurrences had appendectomy; 8 phlegmonous, 1 gangrenous, 3 perforated. (3 treated with antibiotics) 113 (88) 120 (96) 4 17 16 0 3.0 (1.4) 2.6 (1.2) 31 (15 primary ? 16 readmissions; 1 primary had terminal ileitis) 0 38 0 3.1 (0.3) 3.4 (1.9) 8 (1 primary ? 7 readmissions) 60/63 120 Complications n Recurrences n Length of stay (days) Mean (SD) Positive diagnosis at operation Surgery 220 (128 phlegmonous, 42 gangrenous, 50 perforated) (3 other surgically treatable causes) 97 (48) 19 (95) 240 360 29 104 17 (85) 0 2 7 17 357/394

Table 3 Summary of outcomes

Study

No. of patients

Antibiotics Surgery Antibiotics

Hansson et al. [7] 202

167

Styrud et al. [8]

128

124

Eriksson et al. [9]

20

20

Total

350

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World J Surg (2010) 34:199209 Fig. 5 Complications

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Fig. 6 Forest plot of comparison: complications (M-H = Mantel-Haenszel test)

Fig. 7 Forest plot of comparison: length of stay (IV = inverse variance)

Another risk of antibiotic therapy in women of childbearing age is tubal infertility, which has been reported between 3.2 and 4.8% [2022]. In addition, other diagnoses may be missed, especially in the elderly. Although the routine use of imaging modalities including ultrasound or CT in patients with suspected acute

appendicitis is not recommended [23, 24], many studies support selective use of imaging techniques by body imaging radiologists with improved diagnostic criteria [2527]. In this context, the diagnostic value of laparoscopy with its advantages of reduced risk of postoperative ileus and wound infection in this group of

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World J Surg (2010) 34:199209 primary treatment of acute appendicitis in unselected patients. Br J Surg 96:473481 Styrud J, Eriksson S, Nilsson I et al (2006) Appendectomy versus antibiotic treatment in acute appendicitis. A prospective multicenter randomized controlled trial. World J Surg 30:1033 1037 Eriksson S, Granstrom L (1995) Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg 82:166169 The Nordic Cochrane Centre (2008) Review Manager Version 5 Software. The Cochrane Collaboration, Copenhagen, Denmark. Available from http://www.cc-ims.net/revman. Accessed 1 July 2009 Cleophas TJ, Zwinderman AH (2008) Random effects models in clinical research. Int J Clin Pharmacol Ther 46:421427 The Cochrane Collaboration Open Learning Material (2002) Summary statistics for dichotomous outcome data. The Cochrane Collaboration, Copenhagen, Denmark. Available from http:// www.cochrane-net.org/openlearning/HTML/mod11-4.htm. Accessed 1 July 2009 Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:112 Flum DR, Koepsell T (2002) The clinical and economic correlates of misdiagnosed appendicitis: nationwide analysis. Arch Surg 137:799804 discussion 804 Humes DJ, Simpson J (2006) Acute appendicitis. BMJ 333:530 534 Coreld L (2007) Interval appendicectomy after appendiceal mass or abscess in adults: what is best practice? Surg Today 37:14 Cobben LP, de Van Otterloo AM, Puylaert JB (2000) Spontaneously resolving appendicitis: frequency and natural history in 60 patients. Radiology 215:349352 Franke C, Gerharz CD, Bohner H et al (2002) Neurogenic appendicopathy: a clinical disease entity? Int J Colorectal Dis 17:185191 Hoer H, Kasper M, Heitz PU (1983) The neuroendocrine system of normal human appendix, ileum and colon, and in neurogenic appendicopathy. Virchows Arch A Pathol Anat Histopathol 399:127140 Mueller BA, Daling JR, Moore DE et al (1986) Appendectomy and the risk of tubal infertility. N Engl J Med 315:15061508 Lopez PP, Cohn SM, Popkin CA et al (2007) The use of a computed tomography scan to rule out appendicitis in women of childbearing age is as accurate as clinical examination: a prospective randomized trial. Am Surg 73:12321236 Raman SS, Osuagwu FC, Kadell B et al (2008) Effect of CT on false positive diagnosis of appendicitis and perforation. N Engl J Med 358:972973 Franke C, Bohner H, Yang Q et al (1999) Ultrasonography for diagnosis of acute appendicitis: results of a prospective multicenter trial. Acute Abdominal Pain Study Group. World J Surg 23:141146 Lee CC, Golub R, Singer AJ et al (2007) Routine versus selective abdominal computed tomography scan in the evaluation of right lower quadrant pain: a randomized controlled trial. Acad Emerg Med 14:117122 Augustin T, Bhende S, Chavda K et al (2009) CT scans and acute appendicitis: a ve-year analysis from a rural teaching hospital. J Gastrointest Surg 13:13061312 Moteki T, Ohya N, Horikoshi H (2009) Prospective examination of patients suspected of having appendicitis using new computed tomography criteria including maximum depth of intraluminal appendiceal uid greater than 2.6 mm. J Comput Assist Tomogr 33:383389

patients has been proven to be more useful in some studies [2830]. It should, therefore, be considered in patients in whom the diagnosis is uncertain or in those who present with recurrent right iliac fossa pain.

8.

9.

Conclusions
10.

From this meta-analysis of RCTs, there is evidence to support the safe use of antibiotic therapy alone in selected patients presenting with acute appendicitis where perforation or peritonitis is not suspected. Antibiotic therapy is associated with a 68% success rate and a trend toward decreased risk of complications without prolonging hospital stay. However, the conclusions of this meta-analysis are limited by the study design, the high crossover rate from the antibiotic to the surgery group, methodological quality, and denitions of primary endpoints such as treatment efcacy, recurrence, and complication rates in the included RCTs. It should, therefore, be stressed that at present appendectomy remains the gold standard for the treatment of acute appendicitis. Before antibiotic therapy can replace surgery for uncomplicated appendicitis, further studies with clear inclusion and diagnostic criteria (e.g., randomization after appendicitis has been proven on CT scan) are needed to study the effects of antibiotic therapy as the rst-line treatment for uncomplicated appendicitis. Reporting of outcome should be on an intention-to-treat basis rather than a per-protocol basis in order to determine the true efcacy of the treatment.
Acknowledgments This work was supported in part by a Research Fellowship (K.K.V.) from the Nottingham Digestive Diseases Centre NIHR Biomedical Research Unit, Nottingham, UK.

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