Accepted Manuscript

The efficacy of antibiotic treatment versus surgical treatment of uncomplicated acute

appendicitis: Systematic review and network meta-analysis of randomized controlled
trial

Napaphat Poprom, Pawin Numthavaj, Chumpon Wilasrusmee, Sasivimol Rattanasiri,

John Attia, Mark McEvoy, Ammarin Thakkinstian
PII: S0002-9610(18)30954-1
DOI: 10.1016/j.amjsurg.2018.10.009
Reference: AJS 13051

To appear in: The American Journal of Surgery

Received Date: 4 July 2018

Revised Date: 14 September 2018
Accepted Date: 5 October 2018

Please cite this article as: Poprom N, Numthavaj P, Wilasrusmee C, Rattanasiri S, Attia J, McEvoy
M, Thakkinstian A, The Efficacy of Antibiotic Treatment versus Surgical Treatment of Uncomplicated
Acute Appendicitis: Systematic review and Network Meta-analysis of Randomized Controlled Trial., The
American Journal of Surgery (2018), doi: https://doi.org/10.1016/j.amjsurg.2018.10.009.

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 ACCEPTED MANUSCRIPT

Abstract

Background: The efficacy of antibiotics in appendicitis remains controversial, and physicians

are not confident in prescribing antibiotics as the first line treatment. This network meta-analysis

was conducted to assess the efficacy and safety of individual antibiotics in uncomplicated

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appendicitis.

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Methods: Randomized controlled trials (RCTs) were identified from MEDLINE and SCOPUS

databases since inception to July, 2017. Studies. Network meta-analysis was applied to estimate

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treatment effects and safety. Probability of being the best treatment was estimated using surface

under the cumulative ranking curve (SUCRA).

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Results: Among 9 RCTs meeting our inclusion criteria. A network meta-analysis indicated that
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those receiving antibiotics had about 12-32% lower chance of treatment success and lower risk

of complication about 23-86%, especially Beta-lactamase than appendectomy. The overall

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appendicitis recurrence rate in the antibiotic group was about 18.2%. The SUCRA indicated that
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appendectomy was ranked first for treatment success and least complications, followed by Beta-
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lactamase.

Conclusions: Appendectomy is still the most effective treatment in uncomplicated appendicitis

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but it carries complications. Beta-lactamase, might be an alternative treatment if there are any

contraindications for operation.

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The Efficacy of Antibiotic Treatment versus Surgical Treatment of Uncomplicated Acute

Appendicitis :Systematic review and Network Meta-analysis of Randomized Controlled

Trial.

Napaphat Poprom1,2, M.Ph., Pawin Numthavaj1 M.D .Ph.D., Chumpon Wilasrusmee2, MD.,

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Sasivimol Rattanasiri1, Ph.D., John Attia, MD, FRCPC, PhD3, Mark McEvoy, PhD3,

Ammarin Thakkinstian1, Ph.D.

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1
Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi

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Hospital, Mahidol University, Thailand.
2
Department of Surgery, Faculty of Medicine, Ramathibodi Hospital, Mahidol University,

Thailand.
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3
School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW,
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Australia.

Corresponding author :Pawin Numthavaj, M.D .Ph.D.,

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Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi

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Hospital, Mahidol University, Thailand.

270 Rama VI Road, Rachatevi, Bangkok 10400, Thailand.

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Email :pawin.num@mahidol.ac.th
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Key word: Antibiotics treatment, uncomplicated appendicitis, network meta-analysis.

Author contributions:

Napaphat Poprom: Conceived the study, designed the study, data collection, analyzed the

data, drafted the manuscript.

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Pawin Numthavaj and Ammarin Thakkinstian: Supervised the conduct of the study, designed

the study, data collection.

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Chumpon Wilasrusmee: Designed the study, data collection.

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Sasivimol Rattanasiri: Managed the data, including quality control.

Ammarin Thakkinstian, John Attia, and Mark McEvoy: Provided statistical advice on study

design and analyzed the data.

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All authors contributed substantially to its revision.
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Acknowledgement
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This study did not have any potential conflict of interest.

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Introduction

Appendicitis is the most common urgent condition in general surgical practice with an

incidence ~100/100,000/year, and higher prevalence in men than women (8.6% versus 6.7%).1,2

Standard treatment is appendectomy (i.e., open and laparoscopic appendectomy). About

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310,000 appendectomies are performed/year in the United States, of which 250,000 have

definite appendicitis3, giving a negative appendectomy rate of about 15% to 30%4.

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Appendectomy itself is associated with intra and post-operative morbidities including

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vascular injuries, urinary tract complications, hematomas, colonic fistulas, surgical site

infections, adhesions, bowel obstructions, and significant length of hospital stay4-6. The post-

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operative complication rate ranges from 2% to 23% and more than 3% of patients are readmitted
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with intestinal obstruction and post-operative adhesion7-9.
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Conservative treatment with antibiotics is an alternative choice for appendicitis;

although the risk of failure is about 13% higher, but the risk of complications is lower. For
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instance, the odds of overall complications, bowel obstruction, and reoperation were 0.24

(95%CI: 0.13 to 0.44), 0.35 (95%CI: 0.17 to 0.71), and 0.17 (95%CI: 0.04 to 0.75) respectively,
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when compared to appendectomy 10. In addition, management might be more cost-effective

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with antibiotics than appendectomy11.

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Conservative treatment with antibiotics for uncomplicated appendicitis is a topical

issue in general surgery and there are 312-14, 1315-27, and 110 systematic reviews in children,

adults and mixed populations (children and adults) respectively. Among 13 systematic reviews

in adults, 10 reviews considered only randomized controlled trials (RCT) published during

1995 to 2015 with the number of included RCTs ranging from 3 to 6. Among them, all except

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one review16 pooled efficacy and complications between antibiotics and appendectomy

applying meta-analysis. Although various antibiotics (i.e. 3rd generation of cephalosporin,

metronidazole, penicillin, and beta-lactamase) had been used, they were collapsed into one

category when compared with appendectomy. We therefore conducted a systematic review

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and network meta-analysis to assess both the efficacy and safety between individual

antibiotics and appendectomy. Probabilities of being the best treatment option, i.e., high

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efficacy and safety, were estimated and ranked.

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Material and Methods

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The systematic review and network meta-analysis was conducted following the
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Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines
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extension for network meta-analysis28, and was registered at PROSPERO (NO.

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CRD42017072585).
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Literature and search strategy.

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Studies were identified from MEDLINE and SCOPUS databases since inception to

July, 2017. The search terms were constructed based on components of Patient, Intervention,
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Comparator, and Outcome (PICO) as described in supplementary table s1a and s1b.

Study selection.

RCTs published in English were selected if they met all the following criteria:

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• Studies in children or adult patients who were diagnosed as uncomplicated

appendicitis,

• Compared effects of any pair of intervention including antibiotics (e.g., 3rd

Cephalosporin, Beta-lactamase, Penicillin, and Metronidazole/Tinidazole),

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open appendectomy, and laparoscopic appendectomy,

• Reported at least 1 of following outcomes of interest including initial

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successful of treatment, overall complications, recurrence, and length of stay

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(LOS).

Two reviewers (NP and CW) independently selected studies by screening titles and abstracts.

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If a decision could be not made, the full texts were retrieved and reviewed. Any disagreement
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was resolved by consensus, with adjudication by a third author (AT).
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Interventions
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Any antibiotic administered intravenously as the first-line treatment for 24- 48 hours
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was considered. Antibiotics were categorized by class as follows: 3rd generation cephalosporin
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plus metronidazole/tinidazole (Cep+Met), beta-lactamase plus metronidazole/tinidazole (Beta-

lac+Met), beta-lactamase plus penicillin (Beta-lac+Pen), beta-lactamase inhibitor (Beta-lac), and

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penicillin (Pen). The standard comparator was surgery (Surg), which could be either open or
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laparoscopic appendectomy. Details of antibiotic dosage are described in supplementary table

s2.

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Outcome of interests
The primary outcomes of interest were initial treatment success, recurrence and

overall complications, which were defined according to the original studies. Briefly, the initial

treatment success was defined as therapeutic efficacy at initial hospitalization, which was

pathologically confirmed appendicitis after surgery for appendectomy but this was variously

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defined in antibiotic uses including improvement with subsequent hospital discharge in that

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admission, dischargeable without recurrence or need for surgery within 1 to 3 months or even

1 year of follow up. Overall complications included any of the following: clinical wound

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infection occurring within 30 days after the appendectomy which was diagnosed by a

surgeon with/without a positive bacteria culture2,29-31, wound rupture/dehiscence30-32, wound

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hernia2,7, peritonitis31, abscess7,32, re-operation31,32, small bowel obstruction2,7,32, venous
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thromboembolism (VTE)31, postoperative cardiac problems31,32, and ileocecal resection31
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(Supplementary Table s3). Recurrence was considered and compared only among antibiotic
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uses, which was defined as recurrence of appendicitis within 1 month to 1 year.

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The secondary outcomes were recurrence and LOS. The recurrence was defined as

diagnosis of appendectomy again after initial treatment; LOS was defined as number of days
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of primary admission.
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Data Extraction.

The data extraction was performed by two independent authors. The characteristics

of studies and patients were extracted and included study design, follow up period, type of

subjects, type of antibiotics, type of surgical treatment, type of outcome reported, number of

subjects, mean age, sex, body mass index (BMI, kg/m2), duration of symptoms, body

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temperature, C-reactive protein (CRP, mg/L), WBC, (×109/L), and neutrophils (×109/L).

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Risk of Bias Assessments.

The Cochrane risk of bias tool 33 assessed 6 domains including selection bias,

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performance bias, attrition bias, detection bias, reporting bias; in case of disagreement,
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consensus including a third party was sought.
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Statistical Analysis.
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Direct meta-analysis
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For each study, risk ratio (RR) and mean difference (MD) along with their variances

were estimated for dichotomous outcomes (i.e., efficacy/treatment successful, overall

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complications, and recurrence) and continuous outcomes (i.e., pain, and LOS), respectively.
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These RRs and MDs were then pooled across studies.

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Heterogeneity was checked using the Cochrane’s Q test and I2 statistic. If

heterogeneity was present (p-value of Q test < 0.1 and I2 < 25%), a random-effects model was

used; otherwise a fixed-effects model was used. Sources of heterogeneity were explored by

fitting each covariate (i.e., gender, age, duration of symptom, body temperature, BMI, CRP,

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WBC count, and neutrophil) in a meta-regression model if data were available. If adding that

variable decreased the I2, that variable was considered a source of heterogeneity, and sub-

group analysis was performed accordingly.

Publication bias was assessed using a funnel plot and Egger test. If the funnel was

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asymmetrical, a contour enhanced funnel plot was constructed to distinguish whether

heterogeneity or publication bias was the cause of asymmetry.

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Network meta-analysis (NMA).

A two-stage NMA was applied to assess relative treatment effects (e.g., ln(RR) or MD)

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as follows34,35: First, a binary or linear regression was used to estimate relative treatment
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effects and the variance-covariance for each individual study using open appendectomy as the
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reference. Second, a multivariate random-effect meta-analysis with consistency model was

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used to pool relative treatment effects (e.g., ln(RR), MD) across the studies. Mixed relative
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treatment comparisons were then estimated.

Transitivity (also called similarity or exchangeability) was checked by exploring

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distributions of co-variables or effect modifiers (e.g., gender, age, BMI) between each pair of
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interventions and studies. Consistency, agreement between direct and indirect comparisons,
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was assessed using a design-treatment interaction inconsistency model. A global Chi-square

test was used to test inconsistency. If inconsistency was present, the characteristics of studies

were explored. The probability of being the best treatment was estimated and ranked using

surface under the cumulative ranking curve (SUCRA). Publication bias was assessed using an

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adjusted funnel plot. All analyses were performed using STATA 14.2. P value less than 0.05

was the threshold for statistical significance, except for heterogeneity where P <0.1 was used.

Results

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A total of 3,498 studies were identified from PUBMED and SCOPUS databases, and

2,545 articles remained after deleting duplicates, consisting of 17 systematic reviews

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with/without meta-analyses (SR/MA) and 2528 individual studies. Among 17 SRs/MAs, there

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were 52 included studies but only 9 RCTs 2,7,29-32,36-38 met our inclusion criteria, see Figure 1 .

Among 2528 individual studies, the same 9 RCTs 2,7,29-32,36-38 were identified.

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Characteristics information of eligible studies.

The characteristics of the 9 RCTs 2,7,29-32,36-38 are described in Table 1. Among 9

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RCTs, 2 30,36 and 6 2,7,29,31,32,37,38 RCTs studied children and adults respectively, while the
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remaining RCT(37) included a mixed population (although the majority of patients were
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adults). This RCT was therefore combined with adult studies in further analyses. Among the 2
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Pediatric RCTs 30,36, the interventions were Cep+Met (N=1)36, and Beta-lac+Met (N=1)30, which

were compared with laparoscopic appendectomy for treatment success 30,36, LOS 30,36,
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recurrence 30, and complications 30. The mean age of children ranged from 9.5 to 11 years and
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WBC count ranged from 14.00×109/L to 17.20×109/L.

Among the 7 adult RCTs2,7,29,31,32,37,38, interventions and comparators were as

follows: Cep+Met versus appendectomy (N=3)29,32,37, Beta-lac versus appendectomy (N=2)2,31,

Beta-lac+Pen versus appendectomy (N=1)38, and Pen versus appendectomy (N=1)7.

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All 7 RCTs 2,7,29,31,32,37,38 in adults reported treatment success and LOS, whereas

overall complications and recurrence were reported in 6 RCTs 2,7,29,31,32,37 and 4 RCTs2,7,29,37

respectively . The follow-up period of all included studies were 12 months with a percent lost

follow-up of between 1% and 10 %, see Table 1. Mean age ranged from 18.5 to 38 years. Most

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RCTs reported mean CRP and WBC count, which ranged from 35 to 80.5 mg/L and 11.9 to

14.4×109/L, respectively. Further quantitative analyses were focused on adult RCTs only.

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Risk of bias assessment

Risk of bias assessments were performed, see supplementary table s4. Among the 7

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adult RCTs, all studies were considered at low risk of bias for blinding of outcome
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assessment (detection bias), and selective reporting (reporting bias). About 70% of RCTs were

at low risk of bias for random sequence generation, allocation concealment (selection bias),
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and incomplete outcome data (attrition bias). All RCTs were at high risk of bias for blinding
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of participants but this was because those who received operations could be not blinded.
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Direct meta-analysis (DMA)

DMA was performed by pooling effects of Cep+Met vs Surg on treatment success (n=3),
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complication (n = 3), and LOS (n = 3). , see supplementary table s6a-6c. The pooled RRs for
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treatment success and overall complications were 0.70 (0.49, 1.01) and 0.39 (95%CI: 0.22, 0.70),

respectively. LOSs were not much different between Cep+Met vs Surg with a pooled MD of

0.17 (-0.23, 0.56), see supplementary table s6c.

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Network meta-analysis

Treatment success

Network meta-analysis was performed using data from 7 RCTs 2,7,29,31,32,37,38 with 2,017

patients, see Figure 2a and supplementary Table s6a. Relative treatment comparisons were

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pooled indicating all antibiotic regimens had lower treatment success compared with

appendectomy, with pooled RRs between 0.68 and 0.88, although none of them was

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statistically significant, see Table 2. Among antibiotics, Beta-lac+Pen and Beta-lac inhibitor

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seemed to be better than Cep+Met with pooled RRs of 1.24 (0.73, 2.10) and 1.16 (0.75, 1.78),

respectively although these were not significant. In addition, both regimens were also better

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than Pen alone with corresponding pooled RRs of 1.30 (0.68, 2.47) and 1.21 (0.69, 2.13)

respectively. However, none of these were statistically significant. The probability of being
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the best treatment was Surg, followed by Beta-lac+Pen and Beta-lac inhibitor with SUCRAs
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of 89.9, 61.9, and 50, respectively (see Table 2). The adjusted funnel plot showed little
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asymmetry (see Figure 3a).

A sensitivity analysis was perform considering percentage of complicated appendicitis

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finding after operation, which ranged from 2.7% to 35% and 1.5% to 60% in antibiotics and
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appendectomy, respectively. Excluding one study with highest complicated appendicitis in

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antibiotic group (i.e., 35%) from the overall analysis did not change much results. Beta-

lac+Pen and Beta-lac inhibitor were still better than Cep+Met with the pooled RRs of 1.21

(0.63, 2.31) and 1.13 (0.66, 1.94), respectively, although these were not significant. Likewise,

the two regimens were also better than Pen with corresponding pooled RRs of 1.30 (0.61,

2.75) and 1.21 (0.63, 2.34).

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Overall complications

Seven RCTs 2,7,29,31,32,37,38 with 2,017 patients compared overall complications between

antibiotics and appendectomy (see Figure 2b), which consisted of Cep+Met versus Surg (N=3,

n= 661)29,32,37, Beta-lac+Pen versus Surg (N =1, n= 553)38, Beta-lac versus Surg (N =2, n=

560)2,31, and Pen versus Surg (N=1, n=243)7. Data for these comparisons are described in

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Supplementary table s6b. Compared to appendectomy, Beta-lac and Cep+Met had

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significantly lower risk of complications (RR 0.14 (0.05, 0.37) and 0.35 (0.16, 0.75) respectively)

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whereas Pen had about 3 fold (RR 2.98 (0.29, 30.36) higher risk but this was not statistically

significant (see Table 3). Comparing among antibiotics, Pen had significantly higher risk of

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developing complications than Beta-lac and Cep+Met, with a pooled RRs of 21.06 (1.70,

260.77) and 8.52 (0.74, 98.01), although the latter was not statistically significant. In addition,
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adding Pen to Beta-lac significantly increased the risk of complication when compared to
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beta-lac alone, with a pooled RR of 5.43 (1.44, 20.42) (see Table 3).
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The lowest risk of complications was in the Beta-lac group followed by Cep+Met, with

SUCRAs of 97.5 and 72.6, respectively (see Table 3). The adjusted funnel showed no evidence
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of inconsistency (see Figure 3b).

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Recurrence
Data from 5 RCTs 3 2,31,38 with 1,725 patients were used to compare relative treatment

effects including Cep+Met vs Surg (N=1, n= 369)32, Beta-lact+Pen vs Surg (N=1, n=553)38, Beta-

lac vs Surg (N=2, n=560)2,31, Pen vs Surg (N=1, n=243)7, (see Supplementary table s6c). The

pooled incidence of recurrence across antibiotic groups was 18.3% (95% CI: 8.5%, 27.9%). All

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treatments were mapped (see Supplementary figure s1a) and mixed treatment comparisons

indicated a highly significant risk of recurrence for all antibiotics compared to appendectomy,

with pooled RRs ranging from about 12 to 87, see Supplementary table s7a. Compared to

other antibiotics, Pen had higher risk of recurrence, with pooled RRs of about 3 to 7, although

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these were not statistically significant. Surgery had the lowest risk of recurrence, followed by

Cep+Met regimen. An adjusted funnel plot showed no evidence of bias or inconsistency (see

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Supplementary figure s2a).

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LOS

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All 7 RCTs with 2,017 patients compared mean differences of LOS between
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intervention groups, see Supplementary table s6d. A network map was constructed (see

Supplementary figure s1b) and mixed treatment comparisons were estimated (see
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Supplementary table s7b) indicating Beta-lac+Pen had about 0.6 (-1.05,-0.15) days significantly
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shorter LOS than Surg whereas the rest had about 0.16 to 0.92 days longer but none was
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statistically significant. Among antibiotics, Beta-lac+Pen had about -0.76 (-1.41,-0.11) and -1.52
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(-2.62,-0.42) significantly shorter LOS than Cep+Met and Pen, respectively. Beta-lac+Pen

(SUCRA 98.9), was ranked as shortest LOS followed by Surg (SUCRA = 55.5), see
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Supplementary table s7b. Additionally, the adjusted funnel plot showed no evidence of

inconsistency or study size effect (see Supplementary figure s2b).

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Discussion

We conducted a systematic review and network meta-analysis to compare important

clinical outcomes (i.e., treatment success, overall complications, and recurrence) between

antibiotics and surgical treatment of uncomplicated appendicitis in adults. Six intervention

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regimens were considered including Surg (either open or laparoscopic appendectomy), Pen,

Beta-lac, Beta-lac+Pen, and Cep+Met. Surg ranked best for treatment success and recurrence,

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but ranked second worst for overall complications. Among antibiotics, beta-lac with/without

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Pen emerged as the best treatment in successful with lower complications and recurrence

rates compared with other antibiotic regimens.

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Although Beta-lac had about 18% lower treatment success than Surg, it had much
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lower risk for complication occurrences whereas LOS was not different. These findings were

consistent with previous studies in which antibiotic treatments had fewer complications15,16,21-
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, but stand in contrast to other studies which found shorter LOS 12,23,25,26. However, post-
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operation complications were very rare which could occur early or late after operation. For
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instance, infections occurred within 30 days with a range of 2% to 13 % 2,7,32,38 whereas late

and major complications were obstruction/adhesion, intra-abdominal abscess, and re-

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operation with the rates of 4%2 , 4% 32, and 2%38, respectively. In addition, wound rupture,

wound hernia, and lesion of bladder after operation were reported about 0% to 5% 2,32,38.
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Although these complications were common in surgery than antibiotic treatments, they were
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mostly treatable.

Our finding of low recurrence in the surgical group was similar to previous findings
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, undoubtedly because the appendix was removed after surgery. Therefore, the risk of

recurrence should be compared among antibiotic groups only; this indicated that Cep+Met

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had about 36%, 54%, and 86% lower risk of recurrence than Beta-lac+Pen, Beta-lac, and Pen

respectively. In addition, consideration of antibiotic choices should take into account both risk

and benefit. For instance, Beta-lac was better than Cep+Met in treatment efficacy and lower

complications, although it had about 50% higher chance of disease recurrence. As a result,

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Beta-lactamase with/without penicillin might be recommended as a first-line antibiotic

treatment of uncomplicated appendicitis where surgery is not possible.

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The recurrence rate across all antibiotics was about 18.2%, which is higher than a recent

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RCT (~13.3%)31 but lower than the previous meta-analysis (~27.4%)17. If all of these recurrent

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patients have to go to appendectomy as the second line treatment, this is still a small number
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compared to the conventional approach that all appendicitis patients go to surgery. In

addition, 42,7,32,37 out of 9 studies reported that disability and time away from work were
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shorter in antibiotic treatments than appendectomy with a range of 5 to 9 days and 6 to 19

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days, respectively. However, we could not apply NMA because of insufficient data. To
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answer whether antibiotics will be more benefit than risk when compare to appendectomy

should be further evaluated by well conducted RCT alongside with cost-effectiveness/utility

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analysis, that should consider longer time horizon (say at least 1 year) and also allow to

adjust for factors may affect on disease recurrence in an antibiotics such as type of
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appendicitis (complicated versus uncomplicated appendicitis), use of drainage, underlying

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disease (e.g., obesity, diabetes), etc.

Although a standard of care for both of uncomplicated and complicated appendicitis

was surgical management as for a clinical practice guideline39, a conservative treatment by

antibiotics might be another choice of care for uncomplicated acute appendicitis depending

on clinician’s and patient’s judgment and discussion39 with the results from imaging before

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treatment including ultrasonography or computer tomography to confirm uncomplicated

acute appendicitis. However, ultrasound and/or compute tomography might face with false

negative results, in which complicated appendicitis finding after appendectomy was varied

from 2.7% to 35% in the antibiotic group. Although a sensitivity analysis by excluding the

study with highest complicated appendicitis did not change the outcome of successful, this is

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still needs to proof if antibiotics work as good as appendectomy by considering only

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uncomplicated appendicitis. Doing this is required individual patient data to adjust for this

factor.

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Another issue that should be considered is the development of hospital-acquired

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Clostridium difficile colitis and the change in intestinal flora among antibiotic users40. Among
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broad-spectrum antibiotics, cephalosporins have a higher risk of development of C. difficile
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infection compared to penicillin combinations41. As trials in this review followed patients for
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a maximum of one year, long term changes in antibiotics resistance, particularly among
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different types of antibiotics, remain unknown and rates of C. difficile diarrhea were not

systematically collected.
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Our study had some strengths. To our knowledge, this is the first meta-analysis that
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has assessed both risks and benefits of treatments for uncomplicated appendicitis by
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comparing individual antibiotics with appendectomy; the NMA covers the broad range of

treatment options that are relevant clinically. We also aimed to assess not only antibiotics as a

group but also which individual/combination antibiotics were best compared with

appendectomy. To achieve this aim, we had to keep individual antibiotics without lumping

them all to one group as previous meta-analyses did10,12-27. Although this gives more

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clinically useful information, it also means that only a few RCTs were included for each

comparison, resulting in an imprecise estimation of relative treatment effects. This review

should be updated as new RCTs are published. However, few limitations could be not

avoided. First, definition of outcomes (i.e., successful, complication, recurrence) had been

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defined differently across studies in which they could not be re-defined based on

summary/aggregated data and thus might affect on clinical efficacy and generalizability.

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Second, studied patients were different across studies, i.e., 1 study36 included only

complicated appendicitis, 2 studies29,32 mentioned to include acute appendicitis which might

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mix complicated and uncomplicated appendicitis, whereas the rest 6 studies2,7,30,31,37,38

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included only uncomplicated appendicitis. Among 8 later studies, complicated appendicitis
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was found in operations which ranged from 2.7% to 35% and 1.5% to 60% in antibiotic and

surgery groups, respectively. Contamination of complicated appendicitis might result in

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lowering successful and increasing recurrence rates among antibiotic groups. A sensitivity

analysis by excluding one study with highest complicated appendicitis did not change the
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results comparing with overall pooling. However, proper adjusting for this effect should be
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better analysis but this is required raw data.

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Conclusion
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Our evidence suggests that the use of antibiotics for treating uncomplicated
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appendicitis would result in about 12% to 32% lower treatment success at 1 year than

appendectomy but about 23% to 86% fewer complications. Penicillin was inferior to surgery

and other antibiotics with respect to all outcomes. Appendectomy was ranked first followed

by Beta-lac with/without Pen for treatment success whereas Beta-lac and Cep+Met were

ranked first and second in lowest complications. Evidences about benefits and risks for taking

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antibiotics or appendectomy should be provided to patients to properly choose their optimal

course of actions with physicians. Further large scale RCTs should be conducted alongside

economic evaluations.

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Reference

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25. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with

appendicectomy for treatment of uncomplicated acute appendicitis: Meta-analysis of

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31. Talan DA, Saltzman DJ, Mower WR, et al. Antibiotics-First Versus Surgery for
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32. Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized

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33. Higgins JPT., Green S. Cochrane Handbook for Systematic Reviews of Interventions

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35. White IR. Network meta-analysis. Stata Journal. 2015;15(4):951-985.

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36. St. Peter SD, Aguayo P, Fraser JD, et al. Initial laparoscopic appendectomy versus

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37. Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic treatment in

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38. Hansson J, Körner U, Ludwigs K, Johnsson E, Jönsson C, Lundholm K. Antibiotics

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40. Huston JM, Kao LS, Chang PK, et al. Antibiotics vs. Appendectomy for Acute
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Directions. Surg Infect (Larchmt). 2017;18(5):527-535.

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infection: update of systematic review and meta-analysis. The Journal of

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Legends of tables

Table 1. Characteristics of included RCTs

Table 2. Mixed treatment comparisons for treatment successful

Table 3. Mixed treatment comparisons for overall complications

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Legends of figures

Figure 1. Flow diagram of selection of studies

Figure 2. Network of eligible treatment comparison mapping by outcomes

a) Treatment successful

b) Overall complications

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Figure 3. Adjusted funnel plot

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a) Treatment successful

b) Overall complications

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Supplementary Material

The Efficacy of Antibiotic Treatment versus Surgical Treatment of Uncomplicated Acute

Appendicitis: Systematic review and Network Meta-analysis of Randomized Controlled

Trial.

Napaphat Poprom, M.Ph., Chumpon Wilasrusmee, MD., Sasivimol Rattanasiri, Ph.D.,

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Ammarin Thakkinstian, Ph.D.

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Supplementary table s1. Search Term and Search Strategy

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Supplementary table s1a. The search results from PUBMED

Supplementary table s1b. The search results from SCOPUS

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Supplementary table s2. Interventions, comparators, and dosage of antibiotics
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Supplementary table s3. Definition of inclusion criteria and outcome
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Supplementary table s4. Risk of bias assessments

Supplementary table s5. Direct meta-analysis

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Supplementary table s5a. Treatment successful of antibiotics treatment in UAA

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patients

Supplementary table s5b. Complications of antibiotics treatment in UAA patients

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Supplementary table s5c. Length of hospital stay of antibiotics treatment in UAA

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patients
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Supplementary table s6. Data used for Network Meta-analysis

Supplementary table s6a Treatment successful

Supplementary table s6b Overall complications

Supplementary table s6c Recurrence

Supplementary table s6d Length of hospital stay

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Supplementary figure s1. Network Meta-analysis

Supplementary figure s1a Network of eligible treatment comparison mapping by

recurrence

Supplementary figure s1b Network of eligible treatment comparison mapping by

length of hospital stay

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Supplementary table s7. Network Meta-analysis

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Supplementary table s7a Mixed treatment comparisons of recurrence

Supplementary table s7b Mixed treatment comparisons of length of hospital stay

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Supplementary figure s2. Adjusted funnel plots

Supplementary figure s2a Recurrence

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Supplementary figure s2b Length of hospital stay
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Supplementary table s1a. The search results from PUBMED

Search Term Results

P/patient
#1 Appendicitis 22,014
I/intervention
#2 (general term) antibiotics 718,023
#3 cephalosporin[MeSH Terms] 39,179
#4 (Second generation) cefaclor or cefuroxime axetil or 10,305

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cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime
#5 (combine second cephalosporin[MeSH Terms] or 43,287

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generation) cefaclor or cefuroxime or cefprozil or
loracarbef or cefotetan or cefoxitin or
cefuroxime

SC
#6 (Third generation) Cefixime or Cefpodoxime or Cefdinir 29,731
or Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone

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#7 (combine third cephalosporin[MeSH Terms] or 50,661
AN
generation) Cefixime or Cefpodoxime or Cefdinir
or Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone
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#8 (combine cephalosporin cephalosporin[MeSH Terms] or 53,185

group) cefaclor or cefuroxime or cefprozil or
loracarbef or cefotetan or cefoxitin or
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cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or
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Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone
#9 (Amebicides) Tinidazole or Tindamax or 18,375
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metronidazole or metrolex
#10 (Beta-lactam) Carbapenem 13,295
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AC

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Supplementary table s1a. The search results from PUBMED (Cont.)

Search Term Results

I/intervention (cont.)
#11 ertapenem or invanz or meropenem or 5,876
mapenem
#12 (combine Beta-lactam Carbapenem or ertapenem or invanz 15,624
group) or meropenem or mapenem
#13 (Penicillin group) amoxicillin or augmentin or 50,067

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ampicillin or cloxacillin or
tazobactam or tazocin or piptazo or
clavulanic acid

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#14 (combine all cephalosporin[MeSH Terms] or 115,642
antibiotics) cefaclor or cefuroxime or cefprozil or
loracarbef or cefotetan or cefoxitin or

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cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or
Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or

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Ceftizoxime or Ceftriaxone or
Tinidazole or Tindamax or
AN
metronidazole or metrolex or
Carbapenem or ertapenem or invanz
or meropenem or mapenem or
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amoxicillin or augmentin or
ampicillin or cloxacillin or
tazobactam or tazocin or piptazo or
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clavulanic acid
C/comparative
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#15 appendectomy 12,748

#16 appendicectomy 13,410
#17 "surgical treatment" 129,484
#18 surgery 4,083,001
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#19 (combine all Appendectomy or appendicectomy or 4,101,998

comparators) "surgical treatment" or surgery
O/outcome
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#20 (clinical outcome) Efficacy or recurrence or "initial 1,037,691

successful"
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#21 (Complications) Complications 2,712,682

#22 (major complications) "major complications" or reoperation 678,885
or abscess or "small bowel
obstruction" or "wound rupture" or
dehiscence or "wound hernia" or
"venous thromboembolism" or "post-
operative cardiac problems" or
"ileocecal resection" or safety

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Supplementary table s1a. The search results from PUBMED (Cont.)

Search Term Results

#23 (combine all Complications or "major complications" or 3,212,582
outcoms) reoperation or abscess or "small bowel
obstruction" or "wound rupture" or
dehiscence or "wound hernia" or "venous
thromboembolism" or "post-operative cardiac
problems" or "ileocecal resection" or safety

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Combine P & I & C & O
#24 (with outcomes) appendicitis and cephalosporin[MeSH 151
Terms] or cefaclor or cefuroxime or cefprozil

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or loracarbef or cefotetan or cefoxitin or
cefuroxime or Cefixime or Cefpodoxime or
Cefdinir or Ceftibuten or Cefoperazone or

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Cefotaxime or Ceftazidime or Ceftizoxime or
Ceftriaxone or Tinidazole or Tindamax or
metronidazole or metrolex or Carbapenem or
ertapenem or invanz or meropenem or

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mapenem or amoxicillin or augmentin or
ampicillin or cloxacillin or tazobactam or
AN
tazocin or piptazo or clavulanic acid and
appendectomy or appendicectomy or
"surgical treatment" and Complications or
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"major complications” or reoperation or

abscess or “small bowel obstruction” or
“wound rupture” or dehiscence or “wound
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hernia” or “venous thromboembolism” or

“post-operative cardiac problems” or
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“ileocecal resection” or safety

#25 (open outcomes) appendicitis and cephalosporin[MeSH 1,376
Terms] or cefaclor or cefuroxime or cefprozil
or loracarbef or cefotetan or cefoxitin or
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cefuroxime or Cefixime or Cefpodoxime or

Cefdinir or Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or Ceftizoxime or
C

Ceftriaxone or Tinidazole or Tindamax or

metronidazole or metrolex or Carbapenem or
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ertapenem or invanz or meropenem or

mapenem or amoxicillin or augmentin or
ampicillin or cloxacillin or tazobactam or
tazocin or piptazo or clavulanic acid or
antibiotic and appendectomy or
appendicectomy or "surgical treatment" or
surgery

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Supplementary table s1a. The search results from PUBMED (Cont.)

Search Term Results

Limited types of study design
#26 meta-analysis 124,965
#27 "systematic review" 92,037
#28 (combine systematic "systematic review" or meta-analysis 179,793
review and meta-analysis)
#29 "randomized controlled trial" or "clinical 846,298

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trial" or "randomized trial"
#30 (limited to systematic appendicitis and cephalosporin[MeSH 37
review and meta-analysis) Terms] or cefaclor or cefuroxime or

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cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or Ceftibuten or

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Cefoperazone or Cefotaxime or Ceftazidime
or Ceftizoxime or Ceftriaxone or Tinidazole
or Tindamax or metronidazole or metrolex
or Carbapenem or ertapenem or invanz or

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meropenem or mapenem or amoxicillin or
augmentin or ampicillin or cloxacillin or
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tazobactam or tazocin or piptazo or
clavulanic acid or antibiotic and
appendectomy or appendicectomy or
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"surgical treatment" or surgery and

"systematic review" or meta-analysis
#31 (limited to RCTs study) appendicitis and cephalosporin[MeSH 243
D

Terms] or cefaclor or cefuroxime or

cefprozil or loracarbef or cefotetan or
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cefoxitin or cefuroxime or Cefixime or

Cefpodoxime or Cefdinir or Ceftibuten or
Cefoperazone or Cefotaxime or Ceftazidime
or Ceftizoxime or Ceftriaxone or Tinidazole
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or Tindamax or metronidazole or metrolex

or Carbapenem or ertapenem or invanz or
meropenem or mapenem or amoxicillin or
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augmentin or ampicillin or cloxacillin or

tazobactam or tazocin or piptazo or
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clavulanic acid or antibiotic and

appendectomy or appendicectomy or
"surgical treatment" or surgery and
"randomized controlled trial" or "clinical
trial"

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Supplementary table s1a. The search results from PUBMED (Cont.)

Search Term Results

Limited types of study design
#32 (limited to systematic appendicitis and cephalosporin[MeSH 3
review and meta-analysis Terms] or cefaclor or cefuroxime or
of RCT study) cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or Ceftibuten or

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Cefoperazone or Cefotaxime or
Ceftazidime or Ceftizoxime or Ceftriaxone
or Tinidazole or Tindamax or

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metronidazole or metrolex or Carbapenem
or ertapenem or invanz or meropenem or
mapenem or amoxicillin or augmentin or

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ampicillin or cloxacillin or tazobactam or
tazocin or piptazo or clavulanic acid or
antibiotic and appendectomy or
appendicectomy or "surgical treatment" or

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surgery and "systematic review" or meta-
analysis))) and "randomized controlled
AN
trial" or "clinical trial" or "randomized
trial"
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Supplementary table s1b. The search results from SCOPUS

Search Term Results

P/patient
#1 Appendicitis 29,663
I/intervention
#2 (general term) antibiotics 697,144
#3 cephalosporin[MeSH Terms] 51,381
#4 (Second generation) cefaclor or cefuroxime axetil or 42,564

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cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime
#5 (combine second cephalosporin[MeSH Terms] or 84,500

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generation) cefaclor or cefuroxime or cefprozil or
loracarbef or cefotetan or cefoxitin or
cefuroxime

SC
#6 (Third generation) Cefixime or Cefpodoxime or Cefdinir 99,461
or Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone

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#7 (combine third cephalosporin[MeSH Terms] or 132,941
AN
generation) Cefixime or Cefpodoxime or Cefdinir
or Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone
M

#8 (combine cephalosporin cephalosporin[MeSH Terms] or 151,651

group) cefaclor or cefuroxime or cefprozil or
loracarbef or cefotetan or cefoxitin or
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cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or
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Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone
#9 (Amebicides) Tinidazole or Tindamax or 58,764
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metronidazole or metrolex
#10 (Beta-lactam) Carbapenem or ertapenem or invanz 31,863
or meropenem or mapenem
C
AC

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Supplementary table s1b. The search results from SCOPUS (Cont.)

Search Term Results

I/intervention (cont.)
#11 (Penicillin group) amoxicillin or augmentin or ampicillin 63,158
or cloxacillin or tazobactam or tazocin
or piptazo or clavulanic acid
#12 (combine all cephalosporin[MeSH Terms] or 151,684
antibiotics) cefaclor or cefuroxime or cefprozil or

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loracarbef or cefotetan or cefoxitin or
cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or

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Ceftibuten or Cefoperazone or
Cefotaxime or Ceftazidime or
Ceftizoxime or Ceftriaxone or

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Tinidazole or Tindamax or
metronidazole or metrolex or
Carbapenem or ertapenem or invanz
or meropenem or mapenem or

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amoxicillin or augmentin or ampicillin
or cloxacillin or tazobactam or tazocin
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or piptazo or clavulanic acid
C/comparative
#13 (combine all Appendectomy or appendicectomy or 2,010,603
M

comparators) "surgical treatment" or surgery

O/outcome
#14 (clinical outcome) Efficacy or recurrence or "initial 3,563,568
D

successful"
#15 (Complications) Complications 1,571,706
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#16 (major complications) "major complications" or reoperation 1,456,569

or abscess or "small bowel
obstruction" or "wound rupture" or
dehiscence or "wound hernia" or
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"venous thromboembolism" or "post-

operative cardiac problems" or
"ileocecal resection" or safety
C

#17 (combine all Complications or "major 2,808,284

outcomes) complications" or reoperation or
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abscess or "small bowel obstruction"

or "wound rupture" or dehiscence or
"wound hernia" or "venous
thromboembolism" or "post-operative
cardiac problems" or "ileocecal
resection" or safety

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Supplementary table s1b. The search results from SCOPUS (Cont.)

Search Term Results

#18 (open outcomes)
Combine P & I & C & O
appendicitis and cephalosporin[MeSH 2,122
Terms] or cefaclor or cefuroxime or
cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or Ceftibuten

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or Cefoperazone or Cefotaxime or
Ceftazidime or Ceftizoxime or
Ceftriaxone or Tinidazole or Tindamax

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or metronidazole or metrolex or
Carbapenem or ertapenem or invanz or
meropenem or mapenem or amoxicillin

SC
or augmentin or ampicillin or
cloxacillin or tazobactam or tazocin or
piptazo or clavulanic acid or antibiotic
and appendectomy or appendicectomy

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or "surgical treatment" or surgery
Limited types of study
AN
#19 (combine systematic "systematic review" or meta-analysis 2,478,951
review and meta-analysis)
#20 "randomized controlled trial" or 3,048,038
M

"clinical trial" or "randomized trial"

#21 (limited to systematic appendicitis and cephalosporin[MeSH 85
review and meta-analysis) Terms] or cefaclor or cefuroxime or
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cefprozil or loracarbef or cefotetan or

cefoxitin or cefuroxime or Cefixime or
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Cefpodoxime or Cefdinir or Ceftibuten

or Cefoperazone or Cefotaxime or
Ceftazidime or Ceftizoxime or
Ceftriaxone or Tinidazole or Tindamax
EP

or metronidazole or metrolex or
Carbapenem or ertapenem or invanz or
meropenem or mapenem or amoxicillin
C

or augmentin or ampicillin or
cloxacillin or tazobactam or tazocin or
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piptazo or clavulanic acid or antibiotic

and appendectomy or appendicectomy
or "surgical treatment" or surgery and
"systematic review" or meta-analysis

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Supplementary table s1b. The search results from SCOPUS (Cont.)

Search Term Results

Limited types of study
#22 (limited to RCTs study) appendicitis and cephalosporin[MeSH 329
Terms] or cefaclor or cefuroxime or
cefprozil or loracarbef or cefotetan or
cefoxitin or cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or Ceftibuten

PT
or Cefoperazone or Cefotaxime or
Ceftazidime or Ceftizoxime or
Ceftriaxone or Tinidazole or Tindamax

RI
or metronidazole or metrolex or
Carbapenem or ertapenem or invanz or
meropenem or mapenem or amoxicillin

SC
or augmentin or ampicillin or
cloxacillin or tazobactam or tazocin or
piptazo or clavulanic acid or antibiotic
and appendectomy or appendicectomy

#23 (limited to systematic
review and meta-analysis of
U
or "surgical treatment" or surgery and
"randomized controlled trial" or
AN
"clinical trial"
appendicitis and cephalosporin[MeSH 54
Terms] or cefaclor or cefuroxime or
M

RCT study) cefprozil or loracarbef or cefotetan or

cefoxitin or cefuroxime or Cefixime or
Cefpodoxime or Cefdinir or Ceftibuten
D

or Cefoperazone or Cefotaxime or
Ceftazidime or Ceftizoxime or
TE

Ceftriaxone or Tinidazole or Tindamax

or metronidazole or metrolex or
Carbapenem or ertapenem or invanz or
meropenem or mapenem or amoxicillin
EP

or augmentin or ampicillin or
cloxacillin or tazobactam or tazocin or
piptazo or clavulanic acid or antibiotic
C

and appendectomy or appendicectomy

or "surgical treatment" or surgery and
AC

"systematic review" or meta-

analysis))) and "randomized
controlled trial" or "clinical trial" or
"randomized trial"

36

Supplementary table s2. Interventions, comparators, and dosage of antibiotics
Intervention regimens
Surgery:
Open/laparoscopic
appendectomy.
3rd generation of
cephalosporin plus
metronidazole/tinidazole
Beta-lactamase plus
metronidazole/tinidazole
Beta-lactamase plus
penicillin
Beta-lactamase inhibitor
Penicillin
*intravenous administration
C EP
AC
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Dosage of IV* Regimens of oral Dosage of oral antibiotics
antibiotics antibiotics
- - -
- Cefotaxim 2 g plus Fluoroquinolone plus - Ofloxacin 200 mg plus
Tinidazol 800 mg, metronidazole/tinidazole Tinidazole 500 mg
PT
- Cefotaxim 1 g plus - Ciprofloxacin 500 mg plus
Metronidazole 1.5 g, Metronidazole 400 mg
- Ceftriaxone 50 mg - Levofloxacin 500 mg plus
RI
plus Metronidazole 30 Metronidazole 500 mg
mg
- Meropenem 10 mg 3rd generation of - Cefdinir 300 mg plus
plus Metronidazole 20 cephalosporin plus Metronidazole 500 mg
SC
mg metronidazole/tinidazole
- Piperacillin plus Penicillin - Amoxicillin plus
Tazobactam 4 g, Clavulanic acid 3 g
- Ertapenem 1 g
U - -
AN
- Amoxicillin plus
- -
Clavulanic acid 3 g
M
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Supplement Table s3. Describe inclusion criteria and definition of outcomes

Author, Interventions Inclusion criteria for % Complicated Outcomes Definitions

year patients appendicitis*
Antibiotics: Improvement and subsequent hospital discharge without recurrence

PT
Open/laparoscopic Successful or need for surgery within 1 year.
Acute appendicitis diagnosed
appendectomy 60 Surgery: Improvement by histopathology.
by ultrasonography and
Eriksson,
laboratory results (C-reactive Complications NR
199529

RI
protein, and white blood cell
count) Recurrence NR
Cefotaxim +tinidazol 35
LOS NR

SC
Antibiotics: Symptom improves within the first 2 days.
Open/laparoscopic Uncomplicated acute Successful
4.8 Surgery: Improvement by satisfactory condition and histopathology.
appendectomy appendicitis diagnosed by
Styrud, Complication Major complications without defining
Laboratory results including
200637

U
C-reactive protein and white Recurrence The occurrence of appendicitis within 1 year.
Cefotaxim +tinidazol. blood cell count 5.5
LOS The number of days of sick leaves.

AN
Antibiotics: Improvement without the need for surgery within 1 year.
Successful
Open/laparoscopic Surgery: Confirmed appendicitis at operation and result of histopathology.
Acute appendicitis by 25.7
Hansson**, appendectomy Major complications including re-operation, abscess, bowel obstruction, wound
diagnosed computer Complication
200932 rupture or hernia, and cardiac problem.

M
tomography
Cefotaxim + LOS
16.8 Length of hospital stay and sick leave.
metronidazole
Antibiotics: Successful when tolerating the diet and drain was removable

D
Laparoscopic
Complicated acute 100 Successful Surgery: Improvement appendicitis at operation and by leukocyte was normal,
St.Peter, appendectomy
appendicitis diagnosed by patient was afebrile, and tolerating regular diet.
201036

TE
Ceftriaxone + computer tomography LOS
100 Total length of hospital days.
metronidazole
Antibiotics: The occurrence of appendicitis or peritonitis was not occurred
Successful within 30 days
Open/laparoscopic
EP
17.6 Surgery: Clinical improvement and histopathology confirmed appendicitis.
appendectomy Uncomplicated acute
Vons, Complications within 1 year including wound abscess, wound hernia, and
appendicitis diagnosed by Complication
20117 occlusion.
computer tomography Recurrence of appendicitis after antibiotic treatment between 30 days to 1 year
C

Amoxicillin + Clavulanic Recurrence

7.5 of follow-up
acid LOS Total days including any additional hospital stay.
AC

*Complicated appendicitis finding in operation; **reported percutaneous drainage 0.5% to 1.5%

LOS, length of stay; NR, not report

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Supplement Table s3. Describe inclusion criteria and definition of outcomes (cont.)

Author, year Interventions Inclusion criteria for subjects % Complicated Outcomes Definitions
appendicitis*
Antibiotics: Recovery without the need for surgery for primary hospital stay and 1

PT
Open/laparoscopic year follow-up without recurrence.
Uncomplicated acute 34.2 Successful
Hansson, appendectomy Surgery: based on positive finding at exploration (appendicitis or other surgical
appendicitis diagnosed by diagnosis).
201238
computer tomography

RI
Piperacillin + Complications Major complications without defined.
4.9
tazobactam LOS Total days including any additional hospital stay.
Antibiotics: Resolution of acute appendicitis, resulting in discharge from the hospital

SC
without need fir surgical intervention and no recurrence appendicitis during a
Successful minimum follow-up of 1 year.
Open/laparoscopic
Uncomplicated acute 1.5 Surgery: patient successfully undergoing an appendectomy and confirmed by
Saliminen, appendectomy
appendicitis diagnosed by histopathology.
20152

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computer tomography Major complications including surgical site infection within 30 days, incisional
Complication
hernia, bowel obstruction.

AN
Recurrence The diagnosed on a clinical basis as recurrence acute appendicitis when???
Ertapenem 2.7
LOS Total days including any additional hospital stay.
Antibiotics: Resolution without any significant complications within 48 hours or
without recurrence within 3 months.
Laparoscopic Successful

M
Uncomplicated acute 26.9 Surgery: Improvement by histopathology, adequate pain relief, tolerating a light diet,
Svensson, appendectomy
appendicitis diagnosed by and afebrile for 24 hour.
201530
computer tomography Complication Major complications including wound infection, wound dehiscence, and diarrhea.
Meropenem + Recurrence Recurrence of appendicitis within 1 year.

D
20.8
Metronidazole LOS NR
Antibiotics: patient successfully with met criteria including systolic blood pressure

TE
greater than 90 mmHg, pulse rate less than 100 beats/min, temperature less than 38.5
°C, pain controlled with oral analgesics according to physician judgment, and
tolerated oral fluids and medication within admission.
Successful
Open/laparoscopic Surgery: patient successfully with met criteria including without diffuse abdominal
Uncomplicated acute 21.4
EP
31 appendectomy tenderness consistent with peritonitis, without severe sepsis/septic shock,
Talan, 2017 appendicitis diagnosed by
improvement in abdominal pain, temperature less than 38.5°C, WBC less than
computer tomography
15,000/µL, and confirmed by pathology.
Major complications within 1 month including wound infection, wound dehiscence,
C

Complication
pneumonia, venous thromboembolism, urinary tract infection, and cardiac problem.
Ertapenem 12.5 LOS Total number of days from admission in emergency department to discharge day.
AC

*Complicated appendicitis finding in operation

LOS, length of stay; NR, not report

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Supplementary table s4. Risk of bias assessments

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Supplementary table s4. Risk of bias assessments (cont.)

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Supplementary table s5. Direct meta-analysis

A. Treatment Antibiotics Surgery

Weight
successful No. of subjects No. of No. of subjects No. of RR (95%CI)
(%)
event event
Cep+Met vs Surg
Erikson S, 199529 20 13 20 20 0.65 (0.47, 0.91) 28.43
Styrud J, 200637 128 113 124 120 0.91 (0.85, 0.98) 36.71
Hansson J, 200932 202 97 167 142 0.57 (0.48, 0.66) 34.86
Pooled RR* 350 223 311 282 0.70 (0.49, 1.01) 100.00

PT
B. Overall Antibiotics Surgery
complications Weight
No. of subjects No. of No. of subjects No. of RR (95%CI)
(%)
event event
Cep+Met vs Surg

RI
Erikson S, 199529 20 0 20 1 0.33 (0.01, 7.71) 3.48
Styrud J, 200637 128 4 124 17 0.23 (0.08, 0.66) 30.53
Hansson J, 200932 202 11 167 18 0.51 (0.25, 1.04) 65.99
Pooled RR** 350 15 311 36 0.39 (0.22, 0.70) 100.00

SC
C. Length of hospital Antibiotics Surgery
Weight
stay No. of mean SD No. of mean SD WMD (95%CI)
(%)
subjects subjects

U
Cep+Met vs Surg
Erikson S, 199529 20 3.1 0.3 20 3.4 1.9 -0.30 (-1.14, 0.54) 17.39
Styrud J, 200637 128 3 1.4 124 2.6 1.2 0.40 (0.08, 0.72) 55.11
AN
Hansson J, 200932 202 3 1.4 167 3 3.8 0.00 (-0.62, 0.62) 27.50
Pooled WMD*** 350 18.2 3.1 311 9 6.9 0.17 (-0.23, 0.56) 100.00
*I2, 93.7%; χ2, <0.01; Egger’s test p, 0.07. **I2, 0%; χ2, 0.48; Egger’s test p, <0.01. ***I2, 35.4%; χ2, 0.21; Egger’s test p,
0.40.
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Supplementary table s6. Data used for Network Meta-analysis

Supplementary table s6a Treatment successful

No. of No. of treatment
Author, year Intervention patients successful

Styrud J, 200637 3rd cephalosporin + Metronidazole 128 113

Open/laparoscopic appendectomy 124 120
Hansson J, 200932 3rd cephalosporin + Metronidazole 202 97
Open/laparoscopic appendectomy 167 142

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Erikson S, 199529 3rd cephalosporin + Metronidazole 20 13
Open/laparoscopic appendectomy 20 20
Total 661 505

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Hansson J, 201238 Beta-lactam+Penicillin 442 342
Open/laparoscopic appendectomy 111 98
Total 553 440

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Salminen P, 20152 Beta-lactam 257 186
Open/laparoscopic appendectomy 273 272
Talan DA, 201731 Beta-lactam 16 14

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Open/laparoscopic appendectomy 14 14
Total 560 486
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Vons C, 20117 Penicillin 123 81
Open/laparoscopic appendectomy 120 117
Total 243 198
M

Overall 2,017 1,629

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Supplementary table s6b Overall complications

No. of No. of overall

Author, year Intervention patients complications

Styrud J, 200637 3rd cephalosporin + Metronidazole 128 4

Open/laparoscopic appendectomy 124 17
Hansson J, 200932 3rd cephalosporin + Metronidazole 202 11
Open/laparoscopic appendectomy 167 18
Erikson S, 199529 3rd cephalosporin + Metronidazole 20 0

PT
Open/laparoscopic appendectomy 20 1
Total 661 51

Hansson J, 201238

RI
Beta-lactam+Penicillin 442 28
Open/laparoscopic appendectomy 111 9
Total 553 37

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Salminen P, 20152 Beta-lactam 257 6
Open/laparoscopic appendectomy 273 45
Talan DA, 201731 Beta-lactam 16 1
Open/laparoscopic appendectomy 14 2

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Total 560 54
AN
Vons C, 20117 Penicillin 123 3
Open/laparoscopic appendectomy 120 1
Total 243 4
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Overall 2,017 146

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Supplementary table s6c Recurrence

No. of
Author, year Intervention patients No. of recurrence

Hansson J, 200932 3rd cephalosporin + Metronidazole 202 15

Open/laparoscopic appendectomy 167 1
Total 369 16

Hansson J, 201238 Beta-lactam+Penicillin 442 38

PT
Open/laparoscopic appendectomy 111 0
Total 553 38

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Salminen P, 20152 Beta-lactam 257 70
Open/laparoscopic appendectomy 273 0
Talan DA, 201731 Beta-lactam 16 2
Open/laparoscopic appendectomy 14 0

SC
Total 560 72

Vons C, 20117 Penicillin 123 44

Open/laparoscopic appendectomy 120 0

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Total 243 44
AN
Overall 1,725 170
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Supplementary table s6d Length of hospital stay

No. of Mean of LOS* SD of LOS

Author, year Intervention patients

Styrud J, 200637 3rd cephalosporin + Metronidazole 128 3.0 1.4

Open/laparoscopic appendectomy 124 2.6 1.2
Hansson J, 200932 3rd cephalosporin + Metronidazole 202 3.0 1.4
Open/laparoscopic appendectomy 167 3.0 3.8
Erikson S, 199529 3rd cephalosporin + Metronidazole 20 3.1 0.3

PT
Open/laparoscopic appendectomy 20 3.4 1.9
Total 661 18.1 10.0

Hansson J, 201238

RI
Beta-lactam+Penicillin 442 2.3 0.1
Open/laparoscopic appendectomy 111 2.9 0.3
Total 553 5.2 0.4

SC
Salminen P, 20152 Beta-lactam 257 3.50 0.32
Open/laparoscopic appendectomy 273 3.50 0.31
Talan DA, 201731 Beta-lactam 16 37.53 835.6
Open/laparoscopic appendectomy 14 60.3 736.2

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Total 560 104.83 1,572.43
AN
Vons C, 20117 Penicillin 123 3.96 4.87
Open/laparoscopic appendectomy 120 3.04 1.50
Total 243 7 6.37
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Overall 2,017 135.13 1,589.2

*LOS; length of hospital stay
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Supplementary figure s1 Network of eligible treatment comparison mapping by outcomes

PT
RI
SC
The node refers to intervention, its size corresponds to the number of individual studies. The edge refers to direct comparison

U
between interventions and its thickness corresponds to the number of studies for that comparison. Numbers above the edge
refer to number of included studies along with numbers of patients in the round brackets.
Cep, cephalosporin; Met, metronidazole; Beta, beta-lactamase; Pen, penicillin.
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Supplementary table s7. Mixed treatment comparisons

Supplementary table s7a Recurrence

PT
Interventions Surg Cep+Met Beta-lac+Pen Beta-lac Pen

RI
Surg [92.6; 72.2] 12.40 (0.15,1048.99) 19.47 (0.15,2450.01) 26.70 (0.84,845.14) 86.85 (0.69,10892.44)

SC
Cep+Met 0.08 (0.00,6.82) [50.9; 12.6] 1.57 (0.00,1112.01) 2.15 (0.01,596.41) 7.00 (0.01,4948.31)

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Beta-lac+Pen 0.05 (0.00,6.46) 0.64 (0.00,451.24) [43.0; 10.1] 1.37 (0.00,522.42) 4.46 (0.00,4150.01)

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Beta-lac 0.04 (0.00,1.19) 0.46 (0.00,128.67) 0.73 (0.00,277.76) [37.6; 2.1] 3.25 (0.01,1235.67)

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Pen 0.01 (0.00,1.44) 0.14 (0.00,100.89) 0.22 (0.00,208.52) 0.31 (0.00,116.78) [25.9; 3.0]

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Value are risk ratio with 95% confidence intervals in round parentheses, of recurrence with use of antibiotics treatment and laparoscopic appendectomy (in column heading) compared with open
appendectomy (reference treatment). The values <1.00 show benefit of less recurrence compared with reference treatment. Values in square brackets are surface under the cumulative ranking

TE
curve area; percentage probability of being best treatment.
C EP
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Supplementary table s7b Length of hospital stay

Interventions Surg Cep+Met Beta-lac+Pen Beta-lac Pen

PT
Surg [55.5; 0.2] 0.16 (-0.31,0.63) -0.60 (-1.05,-0.15) -0.00 (-0.45,0.45) 0.92 (-0.09,1.93)

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Cep+Met -0.16 (-0.63,0.31) [36.4; 0.8] -0.76 (-1.41,-0.11) -0.16 (-0.81,0.49) 0.76 (-0.35,1.87)

SC
Beta-lac+Pen 0.60 (0.15,1.05) 0.76 (0.11,1.41) [98.9; 96.3] 0.60 (-0.04,1.24) 1.52 (0.42,2.62)

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Beta-lac 0.00 (-0.45,0.45) 0.16 (-0.49,0.81) -0.60 (-1.24,0.04) [54.6; 2.5] 0.92 (-0.18,2.02)

AN
Pen -0.92 (-1.93,0.09) -0.76 (-1.87,0.35) -1.52 (-2.62,-0.42) -0.92 (-2.02,0.18) [4.5; 0.2]

Value are mean differences along with 95% confidence intervals in round parentheses of length of hospital stay for use of interventions in column compared with reference intervention in the

M
row. The values <0 show benefit of short length of hospital stay compared with reference treatment. Values in square brackets are surface under the cumulative ranking curve area; percentage
probability of being best treatment.

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PT
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ln [RR] ln [MD]
Favor antibiotics Favor surgery Favor antibiotics Favor surgery

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Supplementary figure s2. Adjusted funnel plots

A, 3rd generation of cephalosporin + metronidazole; C, beta-lactamase + penicillin; D, beta-lactamase; E, penicillin;

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F, open/laparoscopic appendectomy.
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Table 1 .Characteristics of included RCTs

Author, Type of Comparat Intervention Country Outcomes Follow- No .of Mean Mean Mean Mean Mean Mean time Second Appendix %comp Improv %lost
year patients or IV Oral up subjects age BMI CRP WBC neutrophil recurrence line diameter licated ement F/U

PT
Antibiotic Antibiotic )months )years( )kg/m2( )mg/L( )×109/L( )×109/L( )months( treatment (mm) AP* AP
(
Eriksson Adults Open/lapar Cefotaxim Ofloxacin Sweden Successful 12 40 36.00 NR 40.50 13.90 NR 7 Surgery >6 60 in US + NR
S, oscopic +tinidazol 200 mg + Complications surgery Lab

RI
199529 appendect tinidazole Recurrence
omy 500 mg LOS
Styrud Adults Open/lapar Cefotaxim Ofloxacin Sweden Successful 12 252 18-50 NR 54.50 12.50 NR 4 Surgery 0 5 Lab NR
J, oscopic +tinidazol . 200 mg + Complication

SC
200637 appendect tinidazole Recurrence
omy 500 mg LOS
Hansson Adults Open/lapar Cefotaxim Ciprofloxaci Sweden successful 12 369 38.00 NR 54.50 13.10 NR 5 Surgery 0 20 CT 10
J, oscopic + n 500 mg + Complication

U
200932 appendect metronidaz metronidazol LOS
omy ole e 400 mg

AN
St.Peter Children Laparosco Ceftriaxon NR Missouri successful 12 40 9.45 18.80 NR 17.20 NR NR NR 0 100 CT NR
SD, pic e + LOS
201036 appendect metronidaz
omy ole
Vons C, Adults Open/lapar Amoxicilli Amoxicillin + France Successful 12 239 32.50 23.50 NR NR 13.40 5 Surgery 6-15 12.6 CT 10

M
20117 oscopic n+ Clavulanic Complication
appendect Clavulanic acid 3 g Recurrence
omy acid LOS
Hansson Adults Open/lapar Piperacilli Ciprofloxaci Sweden successful 12 558 34.20 NR 56.80 12.80 10.40 NR NR 0 24.5 CT 1

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J, oscopic n + n 500 mg + LOS
201238 appendect tazobacta metronidazol

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omy m e 400 mg
Salimin Adults Open/lapar Ertapenem Levofloxacin Finland Successful 12 530 36.60 NR 34.90 11.90 NR 3 Surgery >6 2.1 CT 1
en P, oscopic 500 mg + Complication
20152 appendect metronidazol Recurrence
omy e 500 mg LOS
EP
Svensso Children Laparosco Meropene Ciprofloxaci Sweden Successful 12 50 11.04 NR 59.60 14.00 11.50 9 Surgery 9-10 24 CT NR
n JF, pic m + n 20 mg + Complication
201530 appendect Metronida metronidazol Recurrence
omy zole e 20 mg LOS
C

Talan Mixed Open/lapar Ertapenem Cefdinir 300 United Successful 12 30 37.90 NR 80.50 14.40 78.70 13 Surgery 7-18 17.2 CT NR
DA, children oscopic mg + State Complication
201731 and LOS
AC

appendect metronidazol
adults omy e 500 mg

*AP; appendicitis, CT; computer tomography, US; ultrasonography, Lab; laboratory results, NR; Not reported. ; included only complicated appendicitis.
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Table 2 .Mixed treatment comparisons for treatment successful

Interventions Surg Cep+Met Beta-lac+Pen Beta-lac Pen

Surg ]89.9; 60.4[ 0.71 )0.53,0.94( 0.88 )0.56,1.38( 0.82 )0.59,1.14( 0.68 )0.43,1.07(

PT
Cep+Met 1.41 )1.07,1.87( ]25.9; 0.6[ 1.24 )0.73,2.10( 1.16 )0.75,1.78( 0.95 )0.56,1.64(

RI
SC
Beta-lac+Pen 1.14 )0.73,1.79( 0.81 )0.48,1.37( ]61.9; 27.6[ 0.93 )0.53,1.63( 0.77 )0.40,1.47(

Beta-lac 1.22 )0.88,1.70( 0.86 )0.56,1.33( 1.07 )0.61,1.87( ]50; 8.3[ 0.83 )0.47,1.45(

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AN
Pen 1.48 )0.93,2.35( 1.05 )0.61,1.80( 1.30 )0.68,2.47( 1.21 )0.69,2.13( ]23.5; 3.1[

Value above off the diagonal cells are risk ratio with 95 %confidence intervals )in round parentheses (of treatment successful of antibiotics in the column heading compared with the reference in
the left row .The values >1.00 show benefit of treatment successful compared with reference treatment .Values in diagonal line in the square brackets are surface under the cumulative ranking

M
curve area; percentage probability of being best treatment.

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Table 3 .Mixed treatment comparisons for overall complications

Interventions Surg Cep+Met Beta-lac+Pen Beta-lac Pen

Surg ]27.7; 0.0[ 0.35 )0.16,0.75( 0.77 )0.31,1.90( 0.14 )0.05,0.37( 2.98 )0.29,30.36(

PT
Cep+Met 2.86 )1.34,6.11( ]72.6; 7.4[ 2.19 )0.67,7.14( 0.40 )0.11,1.48( 8.52 )0.74,98.01(

RI
Beta-lac+Pen 1.30 )0.53,3.23( 0.46 )0.14,1.48( ]41.9; 0.5[ 0.18 )0.05,0.69( 3.88 )0.32,46.96(

SC
Beta-lac 7.08 )2.69,18.63( 2.47 )0.68,9.03( 5.43 )1.44,20.42( ]97.5; 90.8[ 21.06 )1.70,260.77(

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Pen 0.34 )0.03,3.43( 0.12 )0.01,1.35( 0.26 )0.02,3.12( 0.05 )0.00,0.59( ]10.2; 1.3[

AN
Value above off the diagonal cells are risk ratio with 95 %confidence intervals )in round parentheses (of overall complications of antibiotics in the column heading compared with

the reference in the left row .The values <1.00 show benefit of less complications compared with reference treatment .Values in diagonal line in the square brackets are surface

M
under the cumulative ranking curve area; percentage probability of being best treatment

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Highlights

- A combination of beta-lactamase with or without penicillin is the best treatment option

compared to other antibiotics.

PT
- However, its treatment success was still about 18% lower than surgery.

- This meta-analysis covers the broad range of treatment options and aims to assess each

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individual antibiotic.

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- Beta-lactamase with or without penicillin might be considered as first line treatment for

patients with uncomplicated appendicitis.

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