t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2

Available online at www.sciencedirect.com

ScienceDirect
The Surgeon, Journal of the Royal Colleges
of Surgeons of Edinburgh and Ireland
www.thesurgeon.net

Antibiotics-first strategy for uncomplicated acute

appendicitis in adults is associated with increased
rates of peritonitis at surgery. A systematic review
with meta-analysis of randomized controlled trials
comparing appendectomy and non-operative
management with antibiotics*

Mauro Podda a,*, Nicola Cillara b, Salomone Di Saverio c, Antonio Lai a,

Francesco Feroci d, Gianluigi Luridiana e, Ferdinando Agresta f,
Nereo Vettoretto g, On behalf of the ACOI (Italian Society of Hospital
Surgeons) Study Group on Acute Appendicitis
a
General, Emergency and Minimally Invasive Surgery, San Francesco Hospital, Nuoro, Italy
b

Hospital, ASL8, Cagliari, Italy
General and Oncologic Surgery, Santissima Trinita
c
Emergency and Trauma Surgery, Maggiore Hospital, Bologna, Italy
d
General and Oncologic Surgery, Santo Stefano Hospital, Prato, Italy
e
Surgical Oncology, Businco Hospital, AOB, Cagliari, Italy
f
General Surgery Department, ULSS19 del Veneto, Rovigo, Italy
g
General Surgery, Montichiari Surgery, ASST Spedali Civili di Brescia, Brescia, Italy

article info abstract

Article history: Background: Acute appendicitis is the most common surgical diagnosis in young patients,
Received 15 September 2016 with lifetime prevalence of about 7%. Debate remains on whether uncomplicated AA
Received in revised form should be operated or not. Aim of this meta-analysis of randomized controlled trials was to
29 November 2016 assess current evidence on antibiotic treatment for uncomplicated AA compared to
Accepted 7 February 2017 standard surgical treatment.
Available online xxx Methods: Systematic literature search was performed using PubMed, EMBASE, Medline,
Google Scholar and Cochrane Central Register of Controlled Trials databases for random-
Keywords: ized controlled trials comparing antibiotic therapy (AT) and surgical therapy-appendec-
Acute appendicitis tomy (ST) for uncomplicated AA. Trials were reviewed for primary outcome measures:
Un-complicated appendicitis treatment efficacy based on 1 year follow-up, recurrence at 1 year follow-up, complicated
Antibiotic therapy appendicitis with peritonitis identified at the time of surgical operation and

List of abbreviations: AA, acute appendicitis; NOM, non-operative management; RCT, randomized controlled trial; AT, antibiotic
therapy; ST, surgical therapy; ED, emergency department; US, ultrasonography; CT, computed tomography; WBC, white blood cells; CRP,
C-reactive protein; LA, laparoscopic appendectomy; SILS, single-incision laparoscopic surgery.
*
Part of this study will be presented at the 2nd National Congress of the Joined Italian Surgical Societies, Rome, Italy, September 25e29,
2016.
* Corresponding author. General, Emergency and Minimally Invasive Surgery, San Francesco Hospital, Via Mannironi 1, 08100, Nuoro,
Italy.
E-mail address: mauropodda@ymail.com (M. Podda).
http://dx.doi.org/10.1016/j.surge.2017.02.001
1479-666X/© 2017 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.
Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
2 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2

Non-operative management post-intervention complications. Secondary outcomes were length of hospital stay and
Appendectomy period of sick leave.
Meta-analysis Results: Five RCTs comparing AT and ST qualified for inclusion in meta-analysis, with 1.351
Systematic review patients included: 632 in AT group and 719 in ST group. Higher rate of treatment efficacy
based on 1 year follow-up was found in ST group (98.3% vs 75.9%, P < 0.0001), recurrence at 1
year was reported in 22.5% of patients treated with antibiotics. Rate of complicated
appendicitis with peritonitis identified at time of surgical operation was higher in AT group
(19.9% vs 8.5%, P ¼ 0.02). No statistically significant differences were found when comparing
AT and ST groups for the outcomes of overall post-intervention complications (4.3% vs
10.9%, P ¼ 0.32), post-intervention complications based on the number of patients who
underwent appendectomy (15.8% vs 10.9%, P ¼ 0.35), length of hospital stay (3.24 ± 0.40 vs
2.88 ± 0.39, P ¼ 0.13) and period of sick leave (8.91 ± 1.28 vs 10.27 ± 0.24, P ¼ 0.06).
Conclusions: With significantly higher efficacy and low complication rates, appendectomy
remains the most effective treatment for patients with uncomplicated AA. The subgroups
of patients with uncomplicated AA where antibiotics can be more effective, should be
accurately identified.
© 2017 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and
Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

The aim of this systematic review and meta-analysis of

Introduction
Acute appendicitis (AA) is among the most common causes of
lower abdominal pain leading patients to emergency depart-
ment (ED) and the most common diagnosis made in young
patients admitted to hospital for acute abdominal pain, with a
lifetime prevalence of about 7%, and highest incidence in the
second decade of life.1,2
Significant debate remains on whether uncomplicated
(non-perforated) AA should be operated or not.
In 1886, Fitz reported that many autopsy specimens were
showing pathologic signs consistent with AA, therefore hy-
pothesizing that in some patients the disease could resolve
without any surgery.3 In 1953, Harrison reported 42 of 47 cases
of AA being successfully treated using antibiotics and Coldrey
in 1956 published the data on 471 patients with AA treated
conservatively, with low morbidity, mortality (0.2%), and
recurrence rates (14.4%).4,5
The renewed interest in the non-operative management
(NOM) of uncomplicated AA has been highlighted by the latest
guidelines for diagnosis and treatment of acute appendicitis,
published in 2016. Within the discussion on this topic, the
“Jerusalem guidelines” stated that the antibiotic therapy can
be successful in selected patients with uncomplicated
appendicitis who wish to avoid surgery, and accept the risk up
to 38% recurrence.6
Therefore the main question is whether it is possible to
treat patients having uncomplicated AA with antibiotic ther-
apy and how to distinguish during the patients’ assessment
those who might respond well to antibiotic treatment alone
from those who would require surgery. Moreover the com-
parison of conservative management and surgical
treatment needs to take into consideration the widespread
use of laparoscopic appendectomy (LA) which is considered,
in most cases, the gold standard surgical treatment.7,8
randomized controlled trials (RCTs) was the up-to-date reas-
sessment of the current available evidence on the antibiotic
approach to uncomplicated AA when compared to the stan-
dard surgical treatment, with particular focus on safety and
efficacy, and to discuss the limitations of published random-
ized trials, potentially limiting a more widespread diffusion of
the antibiotic-first treatment.
Materials and methods
Search methods for identification of randomized controlled
trials
A systematic literature search was performed using PubMed,
EMBASE, Medline, Google Scholar and The Cochrane Central
Register of Controlled Trials databases for studies comparing
Antibiotic Therapy (AT) and Surgical Therapy e Appendectomy
(ST). We combined database-specific search terms for AT
(acute, appendicitis, antibiotic, nonoperative treatment, conservative
management, nonoperative management, medical treatment), and
ST (acute, appendicitis, appendectomy, appendicectomy, laparos-
copy). The search was then extended to related articles sug-
gested by the databases and supplemented with manual
searches for reference lists of all relevant articles. Literature
search was completed in May 2016.
Selection of studies
RCTs comparing AT and ST as primary treatment for un-
complicated AA in adults were included in the systematic
review and meta-analysis, irrespective of language or publi-
cation status. Studies meeting the inclusion criteria had to
describe well-defined treatment protocols.

Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
The exclusion criteria were as follows: studies not report-
ing data on the selected outcomes of interest or articles in
which the outcomes of interest could not be calculated;
studies not specifying the patients selection criteria; studies
not reporting the specific antibiotics used for the AT; studies
that only included pediatric patients; non-human studies,
review articles, editorials, letters and case reports.
Types of outcome measures
Primary outcomes
1. Treatment efficacy based on 1 year follow-up. Efficacy for
AT was defined as achieving a definitive improvement
without requiring surgery within a median follow-up of 1
year. Lack of efficacy in the AT group included both
persistence of AA during the hospitalization (i.e. non-
resolving AA) and recurrences. On the other hand, effi-
cacy for the ST was defined as AA confirmed at the time of
the surgical operation and resolution of symptoms after
surgical treatment.
2. Recurrence at 1 year follow-up. Recurrence of AA was
defined as an episode of appendicitis being diagnosed
again after the initial antibiotic treatment was completed
and the patient had been discharged home.
3. Complicated appendicitis with peritonitis identified at the
time of surgical operation. In the AT group the analysis was
carried out within the cohort of patients who underwent
appendectomy after the failure of the AT.
4. Overall post-intervention complications. The number and
rate of abscesses, postoperative peritonitis, surgical site
infections, incisional hernias, incisional pain or obstructive
symptoms and other general complications were analyzed
as intention-to-treat analysis. Moreover, complications were
analyzed both for patients who underwent ST as random-
ized treatment and for those who underwent surgery as
second line approach, after primary randomization to AT.
Secondary outcomes
1. Length of primary hospital stay.
2. Period of sick leave, intended as “absence from work”.
Two reviewers (MP and NC) independently considered the
eligibility of potential titles and extracted data. Discrepancies
were resolved with the involvement of a third party (SDS). The
risk of bias for the trials enrolled in the meta-analysis was
evaluated according to the Cochrane Handbook for Systematic
Reviews of Interventions.9
Statistical analysis, data synthesis and reporting of the
results
The present meta-analysis has been performed in accordance
with the recommendations from the Preferred Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) statement.10
The meta-analysis was conducted by searching for a nu-
merical estimate of the outcome of interest. The effect sizes
were calculated by risk ratio (RR) or odds ratio (OR) for
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
3
dichotomous variables and standardized mean differences
(SMDs) for continuous outcome measures with 95% confi-
dence intervals (CIs). The point estimate of the RR and OR
value was considered statistically significant at P level of less
than 0.05 if the 95% CI did not cross the value 1. The point
estimate of the SMD value was considered statistically sig-
nificant at P level of less than 0.05 if the 95% CI did not cross
the value 0. Heterogeneity of the results across studies was
assessed using the Higgins' I2 and Chi-square tests.
A P value of Chi-square less than 0.10 with an I2 value of
greater than 50% were considered as indicative of substantial
heterogeneity. Fixed-effects model was applied if statistically
significant heterogeneity was absent; otherwise, a random-
effects model was used for meta-analysis if statistically sig-
nificant heterogeneity was found, according to the method of
DerSimonian and Laird.11 Statistical analysis was performed
using Reviewer Manager software.12
Results
Description of studies
A total of 938 references were identified through electronic
database searches. 930 searches were excluded based on titles
and abstract reviews because they did not match the inclusion
criteria of the meta-analysis. The remaining eight publications
underwent full text article review. A further two publications
were excluded due to a lack of randomization.13,14 Specifically,
in the study published by Hansson et al., patients, once ran-
domized to a specific treatment, were allowed to cross-over
and receive the alternative treatment based on their prefer-
ence or medical judgment. Therefore, being as such this study
cannot be considered a RCT. One prospective randomized trial
was excluded because the inclusion of patients showed sub-
stantial biases.15 A total of five RCTs comparing AT and ST
qualified for inclusion in this systematic review and meta-
analysis, with a total of 1.351 patients: 632 in the AT group
and 719 in the ST16e20 (Fig. 1).
The general characteristics of patients enrolled in each
study included in this systematic review and meta-analysis
are shown in Table 1.
Most studies included in the current systematic review and
meta-analysis described standardized diagnostic criteria that
must be met for study eligibility. However, there was not ho-
mogeneity amongst studies regarding the imaging techniques
utilized to assess the inclusion of patients in the trials. Styrud
et al. did not use any imaging technique to achieve a precise
diagnosis of uncomplicated AA, and the reported inclusion
criteria were based on clinical findings associated to CRP level
>10 mg/dL. On the other hand, the remaining four studies have
used US or CT scan to rule in or rule out the diagnosis of AA, but
only two studies described a radiographic diagnostic protocol for
diagnosing AA, and this was different in each one.19,20 Salminen
et al. reported a CT scan diagnostic protocol based on the
appendiceal diameter (>than 6 mm was considered indicative
for acute appendicitis) with wall thickening, associated with at
least one of the following parameters: abnormal contrast
enhancement of the appendiceal wall, inflammatory edema or
fluid collections around the appendix. The CT scan protocol
4 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2

Fig. 1 e The PRISMA flow chart for systematic search and selection of articles for review and meta-analysis.

described by Vons et al. for diagnosis of AA, required a clear
visualization of the appendix (appendix diameter >6 mm and no
contrast enhancement of the appendix in patients with enema),
and absence of any of the three following criteria of complicated
AA with peritonitis: extra luminal gas, periappendiceal fluid, or
disseminated intraperitoneal fluid. An appendix diameter
greater than 15 mm was a criterion for exclusion from the study,
because of risk of malignancy.
Each study had a standardized antibiotic treatment pro-
tocol, and they varied greatly within the five studies (Table 2).
Risk of bias in the included randomized controlled trials
The risk of bias in the 5 RCTs16e20 was assessed through the
Cochrane Collaboration Risk of Bias Tool. Random sequence
generation and allocation sequence generation were clearly
described by authors in the three studies.17,19,20 Blinding of
participants and personnel could not be achieved due to rea-
sons inherent to the extremely different types of treatments.
Adequate assessment of each outcome and selective
outcome-reporting were determined for all RCTs except for
Eriksson et al., for which the assessment was unclear. All
authors but Eriksson et al. and Turhan et al. declared an
intention-to-treat analysis for outcomes, although this was
clearly reported only by Vons et al. Power analysis calculation
for minimum sample size has been provided by Salminen
et al. and Vons et al. Crossover rates from antibiotics first
approach to surgery during the primary hospital stay varied
from 0% to 53%. Handling of missing data remained unclear.
Furthermore, the follow-up length was unclear in most of the
RCTs. As a consequence, the methodological quality of the
RCTs included in the systematic review and meta-analysis
was rather poor, with two studies judged as being at high
risk,16,18 two moderate17,19 and only one at low risk of bias.20
Meta-analyses: effects of interventions
Primary outcome measures
The meta-analysis of studies comparing treatment efficacy
based on one year follow-up after AT (75.9%) and ST (98.3%) was
conducted on five RCTs. A higher rate of efficacy was found in
the ST group (P < 0.0001, OR ¼ 0.07, 95% CI ¼ 0.02e0.24; het-
erogeneity was found: P ¼ 0.01, I2 ¼ 70%) (Table 3, Fig. 2).
Recurrence at 1 year follow-up was reported for a total of 142
patients in the AT group (22.5%).
The forest plot of comparison for risk of complicated
appendicitis with peritonitis identified at the time of surgical oper-
ation showed a statistically significant difference between
antibiotic treatment and appendectomy groups: 34 cases of
peritonitis up to 171 patients who underwent appendectomy
(19.9%) were reported in the AT group and 61 cases up to 719
(8.5%) were reported in the ST group (P ¼ 0.02, RR ¼ 5.29, 95%
CI ¼ 1.37e20.45; heterogeneity was found: P ¼ 0.0008, I2 ¼ 82%)
(Table 3, Fig. 3). Data on the outcomes of interest were re-
ported by four authors. When analyzing the cases of compli-
cated AA reported in the AT group, we found that peritonitis
were reported in 23 cases of persistency (patients were oper-
ated on within the first 48 h of antibiotic treatment) and 14
cases were reported as recurrence. However, a lack of data
was found regarding the modality of treatment used for the
recurrences.
On the other hand, no statistically significant differences
were found when comparing AT and ST groups for the
outcome of interest overall post-intervention complications (4.3%
vs 10.9%, P ¼ 0.32, RR ¼ 0.51, 95% CI ¼ 0.13e1.95; heterogeneity
was found: P < 0.0001, I2 ¼ 84%) and post-intervention compli-
cations based on the number of patients who underwent appendec-
tomy (15.8% vs 10.9%, P ¼ 0.35, RR ¼ 1.89, 95% CI ¼ 0.49e7.28;
heterogeneity was found: P < 0.0001, I2 ¼ 85%) (Table 3). The

Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated

Table 1 e General characteristics of patients enrolled in each RCT included in the meta-analysis.
Eriksson S. et al. (1995) Styrud J. Turhan AN. Vons C. et al. (2011) Salminen P. Total (%), ±SD
et al. (2006) et al. (2009) et al. (2015)
Study type RCT RCT RCT RCT RCT 5 RCT
Study duration 12 Months 36 Months 12 Months 34 Months 31 Months 25 ± 12
Study period 05/1992e03/1994 03/1996e06/1999 03/2005e03/2006 03/2004e01/2007 11/2009e6/2012
Study location 1 Swedish hospital 6 Swedish hospitals 1 Turkish hospital 6 French hospitals 6 Finnish hospitals 20 Hospitals
No. of patients randomized A 20 128 107 120 257 632 (46.8%)
S 20 124 183 119 273 719 (53.2%)
Sex (M/F) A 14:6 128:0 65:42 73:47 155:102 435:197 (68.8% vs 31.2%) P ¼ 0.577

t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
S 13:7 124:0 125:58 70:49 174:99 506:213 (70.4% vs 29.6%)
Age e years: mean A 27.8 (18e53) 34.0 (18e50) 30.98 ± 1.30 31.0 ± 9.0 33.0 (26e47) 31.34 ± 2.38 P ¼ 0.471
(range or SD) S 35.0 (19e75) 34.0 (18e50) 26.25 ± 0.79 34.0 ± 12.0 35.0 (27e46) 32.84 ± 3.74
Mean WBC count A 13.8 ± 4.4 12.5 ± 3.8 NR 13.6 ± 3.6 11.7 ± 3.9 12.90 ± 0.98 P ¼ 0.940
(109/l) e admission S 13.9 ± 4.1 12.4 ± 3.5 NR 13.1 ± 3.4 12.0 ± 4.0 12.85 ± 0.83
Mean body A 37.2 ± 0.7 37.5 ± 0.7 NR NR NR 37.35 ± 0.21 P ¼ 0.683
temperature e admission S 37.1 ± 0.7 37.4 ± 0.8 NR NR NR 37.25 ± 0.21
Mean CRP concentration A 41 ± 30 55 ± 44 NR NR 29.0 (11e63) 41.66 ± 13.01 P ¼ 0.866
(mg/l) e admission S 40 ± 38 54 ± 49 NR NR 36.0 (14e61) 43.33 ± 9.45
Mean Alvarado score A NR NR 6.57 ± 0.12 NR NR
S NR NR 6.43 ± 0.07 NR NR
Mean AIR score A NR NR NR NR NR
S NR NR NR NR NR
Type of appendectomy: 20/0 116/8 150/33 41/78 258/15 585/134 (81.4% vs 18.6%) P ¼ 0.07
open/laparoscopic
Follow-up (months) A 17.2 ± 8.0 NR 19.91 ± 0.35 NR NR 18.55 ± 1.91
S 17.0 ± 6.3 NR NR NR NR 17.0 ± 6.3
Patients lost to follow-up A 1 NR NR 4 30 35 (5.5%) P ¼ 0.406
S 0 NR NR 5 58 63 (8.8%)

RCT ¼ randomized controlled trial; A ¼ antibiotics; S ¼ surgery (open/laparoscopic appendicectomy); NR ¼ not reported; SD ¼ standard deviation; WBC: white blood cells; CRP ¼ C-reactive protein.

5

pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
Table 2 e Characteristics of included studies.
Author (year) Inclusion criteria
Eriksson S. Adult patients with typical
et al. (1995) history of AA and clinical
signs, positive findings
following US, and either
increased WBC and CRP
values or elevated WBC and
CRP levels as measured on
two separate occasions
within a 4-h interval.
Styrud J. Male patients (18e50 years)
et al. (2006) admitted for suspected
acute appendicitis with CRP
level >10 mg/l in whom
perforation was not
suspected.
Turhan AN. Patients with acute
et al. (2009) appendicitis, confirmed by
physical examination,
blood cell count
(leukocytosis), abdominal
US and CT scan
Vons C. All adults examined in the
et al. (2011) emergency department and
suspected to have an acute
appendicitis were assessed
for possible inclusion in the
study.
After informed consent was
obtained, a CT scan was
done. Diagnosis of
uncomplicated appendicitis
was assessed by CT imaging
Exclusion criteria
N.R.
Women (by decision of the
ethics committee); patients
with suspicion of
perforation of the appendix;
patients unwilling to
participate, patients with C-
reactive protein (CRP) level
<10 mg/l; patients with
positive anamnesis for
allergic reaction to the
antibiotics to be used in the
treatment protocol
N.R.
Age <18 years (no upper age
limit); antibiotic treatment 5
days before; allergy to beta-
lactam antibiotics; known
intolerance to amoxicillin
plus clavulanin acid
(nausea, vomiting);
receiving steroids or
anticoagulant treatments;
past history of
inflammatory bowel
disease; pregnancy or a
positive pregnancy test; life
expectancy less than 1 year;
allergy to iodine or blood
Sample size Interventions
calculation
A S (open/laparoscopic)
N.R. 2 g of cefotaxime every 12 h, 0.8 g of
tinidazole administered
intravenously every 24 h for a
period of 2 days, 200 mg of
ofloxacin twice a day, and 500 mg
of tinidazole per os twice a day for a
period of 8 days following
discharge; i.v. fluids administered
during the first 48 h.
N.R. 2 days 2 g cefotaxime, 12 hourly
and tinidazole 0.8 g daily. Fluids
administered during the first 24 h.
Patients who received antibiotics
alone were discharged after 2 days
of i.v. therapy and received oral
treatment with ofloxacin 200 mg
twice daily and tinidazole 500 mg
twice daily for 10 days.
N.R. Intravenous fluid þ antibiotic
therapy with ampicillin (1 g 4  1
daily) þ gentamicin (160 mg/
day) þ metronidazole (500 mg 3  1
daily) and analgesic with
diclofenac sodium (50e75 mg 3  1
i.m. daily)
YES Amoxicillin plus clavulanic acid
(3 g per day for patients weighing
<90 kg, and 4 g per day for patients
90 kg) given I.V. to those with
nausea or vomiting, and orally to
all others. Patients continued the
same antibiotic treatment at home,
with the same dose, for 8 days.
NS; antibiotics
administered for a period of
24 h, but only when bowel
perforation or abdominal
spillage occurred.
Open or laparoscopically at
the surgeon's discretion.
82.0% of the patients
underwent open
appendectomy and 18.0%
laparoscopic appendectomy
65.5% laparoscopic and
34.5% open (McBurney)
appendectomy. Antibiotic
prophylaxis with 2 g
amoxicillin plus clavulanic
acid. Post-operative
antibiotics in case of
complicated appendicitis.
6
Outcomes
Primary endpoints: hospital stay,
complications, pain, analgesic
consumption, inflammatory
laboratory tests and body
temperature.
Secondary endpoints: NS
Primary endpoints: hospital stay,
level of pain, sickness, days of sick
leave from work, complications,
recurrences, diagnosis at
operation.
t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
Secondary endpoints: NS
Primary endpoints: Resistance to
therapy, recurrence, costs,
complications, hospital stay,
histopathologic outcome,
mortality and morbidity, Alvarado
score.
Secondary endpoints: N.S.
Primary endpoints: 30-day post-
therapeutic peritonitis;
complicated appendicitis with
peritonitis identified at surgery,
postoperative peritonitis.
Secondary endpoints: number of
days with a postintervention
visual-analog-scale (VAS) pain
score 4 (on a 0e10 scale); length of
hospital stay and absence from
work (total days including any
additional hospital stays);
incidence of complications other
than peritonitis within 1 year
(postoperative wound abscess,

pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
Salminen P. Patients aged 18 to 60 years
et al. (2015) admitted to the emergency
department with clinical
suspicion of uncomplicated
acute appendicitis,
confirmed by a CT scan.
A ¼ antibiotics; S ¼ surgery (open/laparoscopic appendectomy); N.R. ¼ not reported; N.S. ¼ not stated.
creatinine 200 mmol/L or
more; inability to
understand information
about the protocol or to sign
the consent form.
Patients with complicated
appendicitis (defined as the
presence of an
appendicolith, perforation,
abscess, or suspicion of a
tumor on the CT scan). Age
younger than 18 years or
older than 60 years;
contraindications for CT
(pregnancy or lactating,
allergy to contrast media or
iodine, renal insufficiency
with serum creatinine level
>150 mmol/L, actively taking
metformin), peritonitis,
patients unable to
cooperate and provide
informed consent, presence
of serious systemic illness.
YES Intravenous ertapenem sodium
(1 g/day) was administered for 3
days to patients in the antibiotic
group, with the first dose given in
the emergency department.
Intravenous antibiotic treatment
was followed by 7 days of oral
levofloxacin (500 mg once daily)
and metronidazole (500 mg 3 times
per day)
Open McBurney (94.5%) or
laparoscopic (5.5%)
appendectomy.
Prophylactic antibiotics
(1.5 g of cefuroxime and
500 mg of metronidazole)
was administered
approximately 30 min
before the incision was
made. No further antibiotics
were given to patients in the
surgical group unless a
wound infection was
suspected postoperatively.
incisional hernia, adhesive
occlusion) and recurrence of
appendicitis after antibiotic
treatment (appendicectomy done
between 30 days and 1 year of
follow-up, with confirmed
diagnosis of appendicitis).
Primary endpoints: the primary
end point for patients in the
antibiotic group was the resolution
of acute appendicitis, resulting in
discharge from the hospital
without the need for surgical
intervention and no recurrent
appendicitis during a minimum
follow-up of 1 year. Treatment
success in the appendectomy
group was defined as a patient
successfully undergoing an
t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
appendectomy.
Secondary endpoints: overall
postintervention complications
(surgical site infections,
pneumonia, adverse effects of the
antibiotic treatment, incisional
hernia, bowel obstruction,
persistent abdominal or incisional
pain), late recurrence (after 1 year)
of acute appendicitis after
conservative treatment, length of
hospital stay, sick leave,
postintervention pain scores and
the use of pain medication.
7
8 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2

Table 3 e Summary of outcomes.

Patient characteristics Eriksson S. Styrud J. Turhan AN. Vons C. Salminen P. Total or
et al. (1995) et al. (2006) et al. (2009) et al. (2011) et al. (2015) mean (%)
Treatment efficacy based on 1 year A 12 (60%) 113 (88.2%) 88 (82.2%) 81 (68%) 186 (72.7%) 480 (75.9%)
follow-up (%)a S 17 (85%) 120 (96.8%) 183 (100%) 117 (98.3%) 270 (98.9%) 707 (98.3%)
Recurrence at 1 year follow-up (%) A 7 (35%) 16 (15%) 10 (9.3%) 44 (36.7%) 65 (25.3%) 142 (22.5%)
S e e e e e e
Length of primary hospital stay A 3.1 ± 0.3 3.0 ± 1.4 3.14 ± 0.10 3.96 ± 4.87 3.03e3 3.24 ± 0.40
(days) emean, SD (range) S 3.4 ± 1.9 2.6 ± 1.2 2.4 ± 0.14 3.04 ± 1.50 3.02e3 2.88 ± 0.39
Complicated appendicitis with A 1 (14.3%) 12 (38.7%) e 9 (20.5%) 12 (17.1%) 34 (19.9%)
peritonitis identified at the time S 1 (5%) 6 (5%) 31 (16.9%) 21 (18%) 2 (0.7%) 61 (8.5%)
of the surgical operation, n (%)b
Overall post-intervention A 0 (0%) 4 (3.1%) 5 (4.7%) 12 (10%) 6 (2.3%) 27 (4.3%)
complications (%)b S 2 (10%) 17 (14%) 8 (4.4%) 3 (2.5%) 49 (22.3%) 79 (10.9%)
Wound infection A e NRx 5 2 6 13
S 1 NR 6 1 24 32
Other (intra-abdominal abscess, A e NR e 10 5 15
incisional pain, obstructive S 1 NR 2 2 25 30
symptoms, enterocolitis,
enterocutaneous fistula)
Post-intervention complications A 0 (0%) 4 (12.9%) 5 (26.3%) 12 (27.3%) 6 (8.6%) 27 (15.8%)
based on number of patients S 2 (10%) 17 (14%) 8 (4.4%) 3 (2.5%) 49 (22.3%) 79 (10.9%)
underwent appendectomy (%)b
Period of sick leave e mean (days) A NR 8.0 ± 8.0 NR 9.82 ± 10.51 NR 8.91 ± 1.28
S NR 10.1 ± 7.6 NR 10.45 ± 8.20 NR 10.27 ± 0.24

A ¼ antibiotics; S ¼ surgery (open/laparoscopic appendicectomy); SD ¼ standard deviation; N.R. ¼ not reported.

a
For surgical treatment (S), efficacy means positive diagnosis of acute appendicitis during operation and resolution of symptoms after surgical
treatment.
b
In the antibiotic group, after failure of the primary treatment and subsequent surgery.

Fig. 2 e Antibiotics versus appendectomy for uncomplicated appendicitis: forest plot for treatment efficacy based on 1-year
follow-up.

majority of post-intervention complications were wound in- Secondary outcome measures

fections and minor complications, such as incisional pain,
obstructive symptoms and enterocolitis. One case of intesti-
nal adhesive occlusion, one of intra-abdominal abscess
following surgery and two cases of incisional hernias have
also been reported. Data on the outcomes of interest were
reported by all the five authors.
Five RCTs reported data about the length of primary hospital
stay, although Salminen et al. have not reported any value for
standard deviations. The meta-analysis was therefore con-
ducted based on four studies. No statistically significant dif-
ference was found when comparing AT (3.24 ± 0.40) and ST
(2.88 ± 0.39) for the outcome of interest (P ¼ 0.13, SMD ¼ 1.54,

Fig. 3 e Antibiotics versus appendectomy for uncomplicated appendicitis: forest plot for complicated appendicitis with
peritonitis identified at the time of surgical operation.

Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
95% CI ¼ 0.47 to 3.54; heterogeneity was found: P < 0.00001,
I2 ¼ 99%) (Table 3, Fig. 4).
There was no statistically significant difference when
comparing AT and ST groups regarding the period of sick leave,
although data for the outcome of interest were available only
from two RCTs (8.91 ± 1.28 vs 10.27 ± 0.24, P ¼ 0.06,
SMD ¼ 0.17, 95% CI ¼ 0.35 to 0.01; no heterogeneity was
found: P ¼ 0.27, I2 ¼ 19%) (Table 3).
Analyses of failures (persistency or recurrence) after
primary antibiotic treatment
Patients who underwent appendectomy within the first 48 h of
antibiotic therapy were 42 (6.6%), and 142 patients (22.5%)
presented with a recurrence of AA within the first year of
follow-up. The mean length of time for recurrence was
4.65 ± 1.60 months.
Discussion
AA is one of the most common indications for urgent
abdominal surgery. Traditionally, appendectomy has been
considered as being the treatment of choice.
To date, one Cochrane review,21 eight meta-
analyses,22e29 five systematic reviews30e34 and seven
RCTs13,15e20 comparing AT and ST for uncomplicated AA have
been published in the literature.
Even though trials and reviews previously published have
concluded that the majority of patients with acute uncom-
plicated AA can be treated with an AT-first approach avoiding
ST, conflicting data about rates of efficacy of AT, especially
regarding long-term outcomes, have been obtained. In fact,
the rate of efficacy ranged from 60% reported by Eriksson to
90.8% reported by Hansson, with variable length of follow-
up.13,16
Each of the trials published in the literature show several
limitations, especially in terms of patient selection bias, defi-
nition of primary endpoints, lack of a standardized CT/US
diagnosis, as well as a standardized pathologic criteria for the
diagnosis of potentially clinically significant appendicitis,
making it difficult to achieve meaningful conclusions about
the real effectiveness of the AT approach when compared to
ST.26,28 A new high-quality RCT of 530 adult patients,
comparing AT and ST for uncomplicated AA has been
included in this meta-analysis.20 We have decided to exclude
from the pooled analysis both the studies by Hansson et al.,
because this is biased by significant cross-over rate and lack of
well-defined criteria for randomization, and the study by
Fig. 4 e Antibiotics versus appendectomy for uncomplicated appendicitis: forest plot for length of primary hospital stay.
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
9
Malik et al., which showed to be affected by substantial se-
lection biases.13,15 Moreover, we have decided exclude the
study by Svensson et al., which was instead included in the
more recent pooled analysis published recently by Sallinen
et al., as it was conducted on a pediatric cohort of patients and
the meta-analysis should only focus on the outcomes
of conservative treatment with antibiotics in adult
patients.23,35 In fact the diagnosis and management of AA in
children carries significantly different implications, starting
from the need of avoiding radiation exposure for diagnosis
and the common belief of delayed presentation compared to
adults patients, as well as considering the traditionally
observed higher incidence of perforated appendicitis and
lower rates of spontaneous resolution in pediatric patients.
Our results showed that AT was associated with a signifi-
cant lower treatment efficacy based on one year follow-up
when compared to ST (75.9% vs 98.3%, P < 0.0001). In partic-
ular, recurrence rate was 22.5%, with a mean length of time for
recurrence of 4.65 months. A persistence rate of 6.6% has also
been reported.
These results confirmed previous data published in other
systematic reviews and meta-analyses. In 2011, Wilms et al.
concluded that ST remains the standard of care for AA due to
the higher success rate (97.4%) when compared to AT (73.4%).
The same conclusion was achieved by Mason et al. in 2012,
although the authors stated that non-operative management
was associated with significantly fewer complications, better
pain control and shorter sick leave than AT.21,27
Shorter length of hospital stay and early return to daily
normal activity are two cited advantages of the
antibiotic management, especially in terms of cost-
effectiveness.20,23 Conversely, Vons et al. reported a longer
mean length of hospital stay for patients treated with AT when
compared with those treated surgically, although the median
length of hospital stay for patients approached with antibiotics
was predefined in the protocol of the trial and it may possibly
be shortened in further daily practice.19 Compared to previous
systematic reviews, our meta-analysis reported no statistically
significant difference between the two groups regarding the
length of hospital stay and period of sick leave.23,24,29 Moreover,
the majority of patients submitted to surgery underwent open
appendectomy (81.4%). Only 5.5% and 6% of patients random-
ized to surgical treatment underwent a laparoscopic appen-
dectomy (LA) in the studies by Salminen et al. and Styrud et al.,
respectively.17,20 Probably, the rapid widespread diffusion of
laparoscopy and minimally invasive surgical techniques,
including amongst their advantages a significant reduction of
postoperative pain, might result in an earlier recovery from
surgery in the next future.
10 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
Conversely to the results published by other Authors,23,24 a
higher rate of complicated appendicitis with peritonitis
identified at the time of surgical operation in the AT group was
found in our analysis, with a statistically significant difference
(19.9% vs 8.5%, P ¼ 0.02). The majority of cases were reported
for patients with persistent appendicitis (62%).
Following such finding, the question arises as to whether this
could be related to a lack of accuracy on the diagnostic process
for those patients for whom peritonitis was detected during
surgery after the failure of AT. In fact, complicated appendicitis
might already have been present in a percentage of patients at
the time of randomization, as suggested by Vons et al.19
Although CT scan is used in many centers due to its high
sensitivity and specificity for the diagnosis of perforated
appendicitis and abscess, only three studies included in this
meta-analysis used CT scan to rule out perforated
appendicitis.18e20
Time to the administration of antibiotics in case of sus-
pected AA can also play an important role in the effectiveness
of the treatment. Gurin et al. in 1992 published the results of a
review of conservative treatment in 252 patients with acute
appendicitis on ships of the Kalingrad Fishing Industry from
1975 to 1987. Authors reported a recovery rate of 84.1%.
However, the conservative treatment was most effective
when administered within 12 h of symptom onset, and even
more within the first 6 h.36
No statistically significant differences were found when
comparing AT and ST for overall post-intervention compli-
cations in our systematic review and meta-analysis. More-
over, the majority of post-intervention complications were
found to be wound infections and other types of minor com-
plications, such as incisional pain and mild obstructive
symptoms.
When looking at previous systematic reviews, this is a
novel finding. In fact, other authors stated that advantages of
the antibiotic-first approach included lower rates of major and
minor complications, as well as shorter length of primary
hospital stay.23,24,26 We found that not only AT and ST groups
had similar rates of overall complications (4.3% vs 10.9%,
P ¼ 0.32) but also when analyzing patients who underwent
surgery after failure of the AT, rates of complications were
similar in both groups (15.8% vs 10.9%, P ¼ 0.35), suggesting
that the decision to delay appendectomy can be safely made
with low risk of developing postoperative complications
following delayed surgery.
The inferiority of non-operative therapy versus appen-
dectomy could also be related to the type of antibiotic used.
Current evidences show that resistance of Escherichia coli to
amoxicillin plus clavulanic acid is increasing and perhaps
more appropriate antibiotic schemes should be
administered.37 The T.E.A. study concluded that a three-day
ertapenem treatment regimen is more effective than a
three-day regimen of ampicillin-sulbactam in treating pa-
tients with localized intra-abdominal infections. Clinical res-
olution was achieved in 97% of patients treated with
ertapenem compared to 86% of cases in the ampicillin-sul-
bactam group, with a statistically significant difference.38
Hansson et al. showed a significant difference in hospital
costs for the AT and ST groups, with decreased costs for those
patients managed with antibiotics. A decision-making algorithm
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
to compare NOM of AA with LA was constructed by Wu et al.
These authors reported that the AT approach without interval
appendectomy was the least costly and most effective treatment
for uncomplicated AA. However, the non-operative strategy
resulted to be cost-effective whether an interval appendectomy
is not required. In fact, the expected cost of LA was 12.213 dollars,
whereas the AT resulted in 1.865 dollars less. When the interval
appendectomy was associated to an initial AT, costs increased
up to 4.271 dollars more than the status quo.39
Further investigations in the field of non-operative man-
agement (NOM) of non-complicated appendicitis are stimu-
lated following the findings of the NOTA study. The results of
the study demonstrate that if patients are correctly addressed
to the proper treatment option, AT for suspected acute
appendicitis is safe and effective, with low recurrence rates
(13.8%), short sick leave time (5.8 days) and a positive impact
on human and surgical operating room utilization, as well as
on social and health care costs. However, the mean AIR score
and Alvarado score in the cohort of patients were stated to be
4.9 and 6.2, respectively, which relate with “indeterminate”
and “equivocal” probabilities for AA.40
An important limitation of this systematic review and
meta-analysis is the small number of well-designed ran-
domized controlled trials that have published on this subject
to date.
Missing or unclear data regarding randomization methods,
allocation sequence generation and the impossibility to take
measures to effectively blind both patients and investigators
to the administered treatment may lead to bias and can
possible distort the conclusions. A further limitation is that
the majority of the appendectomies for patients enrolled in
this meta-analysis were performed using the open approach,
whereas LA has being increasingly performed worldwide and
probably will be elected as gold standard of surgical approach
in the next future.
Conclusions
With its high efficacy and low complication rates, appendec-
tomy remains undoubtedly the most effective treatment for
patients with uncomplicated AA. Similar complication rates
have been reported when comparing appendectomy and AT,
even among patients who underwent surgery after failure of
the AT. However, for the latter patients, higher rates of peri-
tonitis have been reported at the time of surgical intervention
and this suggests that a close clinical surveillance must be
carried out if non-operative treatment strategy is chosen. In
fact, excessive delay in deciding the failure of NOM and/or
underestimating the patients who are not improving solely
with antibiotics may lead to higher incidence of peritonitis
and delay in surgical source control of the intra-abdominal
infection. We suggest that, when AT approach is considered,
patient should be accurately selected and assessed, and the
choice of most appropriate treatment option must be carried
out through a precise clinical evaluation of potential advan-
tages and risks of expectant management vs a straightforward
appendectomy. More importantly the issues of such strategy
must be accurately explained and discussed with the patients
and/or relatives and informed consent must be obtained.
 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
Declaration of interests
Mauro Podda, Nicola Cillara, Salomone di Saverio, Antonio Lai,
Francesco Feroci, Gianluigi Luridiana, Ferdinando Agresta and
Nereo Vettoretto declare no competing interests.
Authorship
Podda M: Study conception and design, literature search,
acquisition, interpretation and analysis of data; drafting and
critically revising the article for important intellectual con-
tent; and final approval of the version to be published.
Cillara N: Acquisition, literature search, acquisition, inter-
pretation and analysis of data; drafting and critically revising
the article for important intellectual content; and final
approval of the version to be published.
Di Saverio S: Interpretation and analysis of data; drafting
and critically revising the article for important intellectual
content; editing and revising the English for the final version
to be published; and final approval of the version to be
published.
Lai A: Acquisition, interpretation and analysis of data;
drafting and critically revising the article for important intel-
lectual content; and final approval of the version to be
published.
Feroci F: Acquisition, interpretation and analysis of data;
drafting and critically revising the article for important intel-
lectual content; and final approval of the version to be
published.
Luridiana G: Interpretation and analysis of data; critically
revising the article for important intellectual content; and
final approval of the version to be published.
Agresta F: Interpretation and analysis of data; critically
revising the article for important intellectual content; and
final approval of the version to be published.
Vettoretto N: Study conception and design, literature
search, acquisition, interpretation and analysis of data;
drafting and critically revising the article for important intel-
lectual content; and final approval of the version to be
published.
Acknowledgements
The authors would like to thank and express gratitude to
Professor Silvio Garattini, Doctors Vittorio Bertele and Chiara
Gerardi (Mario Negri Institute for Pharmacological Research,
Milan, Italy) for the intellectual review of the ACOI study
project on acute appendicitis.
references
1. Gwynn LK. The diagnosis of acute appendicitis: clinical
assessment versus computed tomography evaluation. J Emerg
Med 2001;21:119e23.
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
11
2. Addiss DG, Shaffer N, Fowler BS, Tauxe RV. The epidemiology
of appendicitis and appendectomy in the United States. Am J
Epidemiol 1990;132:910e25.
3. Fitz R. Perforating inflammation of the vermiform appendix.
Am J Med Sci 1886;92:321e46.
4. Harrison PW. Appendicitis and antibiotics. Am J Surg
1953;85:160e3.
5. Coldrey E. Treatment of acute appendicitis. Br Med J
1956;2:1458e61.
6. Di Saverio S, Birindelli A, Kelly MD, Catena F, Weber DG,
Sartelli M, et al. WSES Jerusalem guidelines for diagnosis and
treatment of acute appendicitis. World J Emerg Surg
2016;11:34. http://dx.doi.org/10.1186/s13017-016-0090-5.
7. Vettoretto N, Cirocchi R, Randolph J, Morino M. Acute
appendicitis can be treated with single-incision laparoscopy:
a systematic review of randomized controlled trials. Colorectal
Dis 2015;17:281e9.
8. Agresta F, Ansaloni L, Baiocchi GL, Bergamini C,
Campanile FC, Carlucci M, et al. Laparoscopic approach to
acute abdomen from the Consensus Development
Conference of the Societa
Italiana di Chirurgia Endoscopica e
nuove tecnologie (SICE), Associazione Chirurghi Ospedalieri
Italiani (ACOI), Societa
Italiana di Chirurgia (SIC), Societa


Italiana di Chirurgia d'Urgenza e del Trauma (SICUT), Societa

Italiana di Chirurgia nell'Ospedalita
Privata (SICOP), and the
European Association for Endoscopic Surgery (EAES). Surg
Endosc 2012;26:2134e64.
9. Higgins JP, Green S. Cochrane handbook for systematic reviews of
interventions. Version 5.1.0 [updated March, 2011]. The
Cochrane Collaboration; 2011. Available from:, http://www.
cochrane-handbook.org.
10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC,
Ioannidis JP, et al. The PRISMA statement for reporting
systematic reviews and meta-anlyses of studies that evaluate
healthcare interventions: explanation and elaboration. Ann
Intern Med 2009;151:W65e94.
11. DerSimonian R, Laird N. Meta-analysis in clinical trials.
Control Clin Trials 1986;7:177e88.
12. Review Manager (RevMan) [computer program]. Version 5.3.5. The
Nordic Cochrane Centre, Cochrane Collaboration; 2014. www.
cochrane-handbook.org.
13. Hansson J, Ko € rner U, Khorram-Manesh A, Solberg A,
Lundholm K. Randomized clinical trial of antibiotic therapy
versus appendicectomy as primary treatment of acute
appendicitis in unselected patients. Br J Surg 2009;96:473e81.
14. Liu K, Ahanchi S, Pisaneschi M, Lin I, Walter R. Can acute
appendicitis be treated by antibiotics alone? Am Surg
2007;73:1161e5.
15. Malik AA, Bari SU. Conservative management of acute
appendicitis. J Gastrointest Surg 2009;13:966e70.
16. Eriksson S, Granstro € m L. Randomized controlled trial of
appendicectomy versus antibiotic therapy for acute
appendicitis. Br J Surg 1995;82:166e9.
17. Styrud J, Eriksson S, Nilsson I, Ahlberg G, Haapaniemi S,
Neovius G, et al. Appendectomy versus antibiotic treatment
in acute appendicitis. A prospective multicenter randomized
controlled trial. World J Surg 2006;30:1033e7.
18. Turhan AN, Kapan S, Kutukcu E, Yigitbas H, Hatipoglu S,
Aygun E. Comparison of operative and non operative
management of acute appendicitis. TJTES 2009;15:459e62.
19. Vons C, Barry C, Maitre S, Pautrat K, Leconte M, Costaglioli B,
et al. Amoxicillin plus clavulanic acid versus appendicectomy
for treatment of acute uncomplicated appendicitis: an open-
label, non-inferiority, randomised controlled trial. Lancet
2011;377:1573e9.
20. Salminen P, Paajanen H, Rautio T, Nordstro € m P, Aarnio M,
Rantanen T, et al. Antibiotic therapy vs appendectomy for
12 t h e s u r g e o n x x x ( 2 0 1 7 ) 1 e1 2
treatment of uncomplicated acute appendicitis. The APPAC
randomized clinical trial. JAMA 2015;313:2340e8.
21. Wilms IM, de Hoog DE, de Visser DC, Janzing HM.
Appendectomy versus antibiotic treatment for acute
appendicitis. Cochrane Database Syst Rev 2011:CD008359.
http://dx.doi.org/10.1002/14651858.CD008359.pub2.
22. Ansaloni L, Catena F, Coccolini F, Ercolani G, Gazzotti F,
Pasqualini E, et al. Surgery versus conservative antibiotic
treatment in acute appendicitis: a systematic review and
meta-analysis of randomized controlled trials. Dig Surg
2011;28:210e21.
23. Sallinen V, Akl EA, You JJ, Agarwal A, Shoucair S, Vandvik PO,
et al. Meta-analysis of antibiotics versus appendicectomy for
non-perforated acute appendicitis. Br J Surg Mar 17 2016.
http://dx.doi.org/10.1002/bjs.10147 [Epub ahead of print].
24. Rollins KE, Varadhan KK, Neal KR, Lobo DN. Antibiotics
versus appendicectomy for the treatment of uncomplicated
acute appendicitis: an updated meta-analysis of randomised
controlled trials. World J Surg 2016 May 19 [Epub ahead of
print].
25. Kirby A, Hobson RP, Burke D, Cleveland V, Ford G, West RM.
Appendicectomy for suspected uncomplicated appendicitis is
associated with fewer complications than conservative
antibiotic management: a meta-analysis of post-intervention
complications. J Infect 2015;70:105e10.
26. Liu K, Fogg L. Use of antibiotics alone for treatment of
uncomplicated acute appendicitis: a systematic review and
meta-analysis. Surgery 2011;150:673e83.
27. Mason RJ, Moazzez A, Sohn H, Katkhouda N. Meta-analysis of
randomized trials comparing antibiotic therapy with
appendectomy for acute uncomplicated (no abscess or
phlegmon) appendicitis. Surg Infect (Larchmt) 2012;13:74e84.
28. Varadhan KK, Humes DJ, Neal KR, Lobo DN. Antibiotic
therapy versus appendectomy for acute appendicitis: a meta-
analysis. World J Surg 2010;34:199e209.
29. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of
antibiotics compared with appendicectomy for treatment of
uncomplicated acute appendicitis: meta-analysis of
randomised controlled trials. BMJ 2012;344:e2156.
30. Mason RJ. Surgery for appendicitis: is it necessary? Surg Infect
(Larchmt) 2008;9:481e8.
31. Sakorafas GH, Mastoraki A, Lappas C, Sampanis D, Danias N,
Smyrniotis V. Conservative treatment of acute appendicitis:
Please cite this article in press as: Podda M, et al., Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated
with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing ap-
pendectomy and non-operative management with antibiotics, The Surgeon (2017), http://dx.doi.org/10.1016/j.surge.2017.02.001
heresy or an effective and acceptable alternative to surgery?
Eur J Gastroenterol Hepatol 2011;23:121e7.
32. Gorter RR, Heij HA, Eker HH, Kazamier G. Laparoscopic
appendectomy: state of the art. Tailored approach to the
application of laparoscopic appendectomy? Best Pract Res Clin
Gastroenterol 2014;28:211e24.
33. Fitzmaurice GJ, McWilliams B, Hurreiz H, Epanomeritakis E.
Antibiotics versus appendectomy in the management of
acute appendicitis: a review of the current evidence. Can J
Surg 2011;54:307e14.
34. Ehlers AP, Talan DA, Moran GJ, Flum DR, Davidson GH.
Evidence for an antibiotics-first strategy for uncomplicated
appendicitis in adults: a systematic review and gap analysis. J
Am Coll Surg 2016;222:309e14.
35. Svensson JF, Patkova B, Almstro € m M, Naji H, Hall NJ, Eaton S,
et al. Nonoperative treatment with antibiotics versus surgery
for acute nonperforated appendicitis in children: a pilot
randomized controlled trial. Ann Surg 2015;261:67e71.
36. Gurin NN, Slobodchuk luS, Gavrilov luF. The efficacy of the
conservative treatment of patients with acute appendicitis on
board ships at sea. Vestn Khir Im I I Grek 1992;148:144e50.
37. de Kraker ME, Wolkewitz M, Davey PG, Koller W, Berger J,
Nagler J, et al. Burden of antimicrobial resistance in European
hospitals: excess mortality and length of hospital stay
associated with bloodstream infections due to Escherichia coli
resistant to third-generation cephalosporins. J Antimicrob
Chemother 2011;66:398e407.
38. Catena F, Vallicelli C, Ansaloni L, Sartelli M, Di Saverio S,
Schiavina R, et al. T.E.A. study: three-day ertapenem versus
three-day ampicillin-sulbactam. BMC Gastroenterol 2013;13:76.
http://dx.doi.org/10.1186/1471-230X-13-76.
39. Wu JX, Dawes AJ, Sacks GD, Brunicardi FC, Keeler EB. Cost
effectiveness of nonoperative management versus
laparoscopic appendectomy for acute uncomplicated
appendicitis. Surgery 2015:712e21.
40. Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani S,
Coccolini F, et al. The NOTA Study (Non Operative Treatment
for Acute Appendicitis): prospective study on the efficacy and
safety of antibiotics (amoxicillin and clavulanic acid) for
treating patients with right lower quadrant abdominal pain
and long-term follow-up of conservatively treated suspected
appendicitis. Ann Surg 2014;260:109e17.