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Tratamiento Medico de Apendicitis Aguda No Complicada
Tratamiento Medico de Apendicitis Aguda No Complicada
Tratamiento Medico de Apendicitis Aguda No Complicada
Visual Abstract
IMPORTANCE Antibiotics are an effective and safe alternative to appendectomy for managing Editorial page 351
uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known.
Multimedia
OBJECTIVE To compare oral antibiotics with combined intravenous followed by oral antibiotics in
Supplemental content
the management of computed tomography–confirmed uncomplicated acute appendicitis.
CME Quiz at
DESIGN, SETTING, AND PARTICIPANTS The Appendicitis Acuta (APPAC) II multicenter,
jamacmelookup.com and CME
open-label, noninferiority randomized clinical trial was conducted from April 2017 until Questions page 395
November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with
computed tomography–confirmed uncomplicated acute appendicitis were enrolled in the
trial. The last date of follow-up was November 29, 2019.
MAIN OUTCOMES AND MEASURES The primary end point was treatment success (ⱖ65%) for
both groups, defined as discharge from hospital without surgery and no recurrent
appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were
noninferior to intravenous and oral antibiotics, with a margin of 6% for difference.
RESULTS Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263
[44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success
rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ⬁) for patients treated with oral
antibiotics and 73.8% (1-sided 95% CI, 69.5% to ⬁) for patients treated with intravenous
followed by oral antibiotics. The difference was −3.6% ([1-sided 95% CI, −9.7% to ⬁]; P = .26
for noninferiority), with the confidence limit exceeding the noninferiority margin.
(Reprinted) 353
© 2021 American Medical Association. All rights reserved.
A
ntibiotic therapy is a safe, efficient, feasible, and cost-
effective alternative to appendectomy for patients with Key Points
computed tomography (CT)–confirmed uncomplicated
Question Is treatment with oral antibiotics alone noninferior
acute appendicitis at short-term and long-term follow-up.1-5 The to a combination of intravenous and oral antibiotics for
World Society of Emergency Surgery 2020 guideline recom- treatment of computed tomography–confirmed uncomplicated
mended discussing antibiotics as a safe alternative to surgery for acute appendicitis?
uncomplicated acute appendicitis without appendicolith (high
Findings This multicenter randomized clinical trial included 583
quality of evidence; strong recommendation).6 During the coro- adults with uncomplicated acute appendicitis who were treated
navirus disease 2019 (COVID-19) pandemic, this was also ac- with either 7 days of oral moxifloxacin or 2 days intravenous
knowledged by the American College of Surgeons (COVID-19 ertapenem followed by 5 days of levofloxacin and metronidazole.
Guideline for Triage of Emergency General Surgery Patients).7 Treatment success (discharge from hospital without need for
In the first APPAC trial, at the 5-year follow-up, 61% of 256 surgery and no recurrent appendicitis within 1 year) occurred in
70.2% who received oral antibiotics alone vs 73.8% of patients
patients who initially presented with uncomplicated acute ap-
who received intravenous followed by oral antibiotics, with the
pendicitis were successfully treated with antibiotics, and those confidence limit of the difference exceeding the noninferiority
who ultimately developed recurrent appendicitis had no ad- margin of 6%.
verse outcomes related to the delay in appendectomy.2 Qual-
Meaning Patients with acute, uncomplicated appendicitis treated
ity of life was also similar after these 2 treatment alternatives.8,9
with oral antibiotics alone met the prespecified threshold for
In previous trials, the length of hospital stay for both antibi- treatment success, but failed to demonstrate noninferiority
otics and appendectomy has been similar,10 but for antibiot- relative to systemic antibiotics followed by oral antibiotics.
ics alone, hospitalization was required to administer broad-
spectrum intravenous antibiotics to ensure patient safety.1,9,11
Successful outpatient treatment has since been reported.12 De- alternative to appendectomy. The aim of the current study
spite prolonged hospitalizations, antibiotic therapy is associ- was to avoid the use of intravenous antibiotics by replacing
ated with significantly lower treatment costs compared with them with oral antibiotics. The hypothesis of the current
appendectomy.3,4 A shorter hospital stay for antibiotic treat- study was that oral antibiotics were (1) effective alone and
ment could further enhance cost savings, patient satisfac- (2) noninferior to intravenous antibiotics for the manage-
tion, and quality of life. Avoidance of hospitalizations during ment of uncomplicated acute appendicitis as first-line
the COVID-19 pandemic is also a desirable potential benefit for therapy in a large prospective patient cohort. Any potential
the management of appendicitis using oral rather than intra- worse outcomes attributable to the use of oral antibiotics
venous antibiotics. might offset the need for hospitalization and the use of
The randomized, clinical, multicenter Appendicitis intravenous antibiotics for the management of uncompli-
Acuta II (APPAC II) trial was designed to compare oral antibi- cated appendicitis.1,15
otic monotherapy with a combination of similar-spectrum
intravenous antibiotics followed by oral antibiotics in the Patients
management of CT-confirmed uncomplicated acute appendi- Patients aged 18 to 60 years admitted to the emergency
citis. Given that nonoperative treatment for appendicitis is department with a clinical suspicion of acute appendicitis
now well established based on outcomes from several clinical and uncomplicated acute appendicitis confirmed by CT
trials,1,2,13,14 the primary objective of this study was to dem- imaging were evaluated for study enrollment. Based on the
onstrate (1) the ability of oral antibiotics alone to manage research hospital CT device, intravenous contrast-enhanced
acute appendicitis and (2) the noninferiority of oral antibiot- CT imaging was performed either by the standard 120 kV
ics compared with intravenous followed by oral antibiotics. imaging (in patients with body mass index >30), the opti-
mized 100 kV low-dose protocol (in patients with body mass
index <30), or using a CT scanner with tube current modula-
tion (Tampere University Hospital). Uncomplicated acute
Methods appendicitis was defined as having an appendiceal diameter
Trial Design larger than 6 mm with a thickened, contrast-enhanced wall
This was a randomized, open-label, noninferiority multi- along with periappendiceal edema and/or minor fluid col-
center trial performed at 9 Finnish hospitals (4 university hos- lection and the absence of the criteria of complicated acute
pitals [Turku, Oulu, Tampere, and Kuopio] and 5 central appendicitis (presence of appendicolith, perforation,
hospitals [Pori, Seinäjoki, Jyväskylä, Mikkeli, and Rovaniemi]). abscess, or suspicion of tumor). A standardized CT imaging
The trial protocol is available in Supplement 1. All patients gave report was used. The trial inclusion criteria were age 18 to
written informed consent. The trial protocol was approved by 60 years, diagnosis of uncomplicated acute appendicitis
the ethics committee at the Hospital District of Southwest confirmed by CT imaging, and absence of the criteria of
Finland and by institutional research boards at each partici- complicated appendicitis. The exclusion criteria were age
pating site. The trial was performed in accordance with the younger than 18 or older than 60 years, pregnancy or lacta-
Declaration of Helsinki. tion, allergy to contrast media or iodine, allergy or contrain-
It is well established that nonoperative management dication to antibiotic therapy, kidney insufficiency or serum
of appendicitis with intravenous antibiotics is a suitable creatinine value exceeding the upper reference limit, type 2
354 JAMA January 26, 2021 Volume 325, Number 4 (Reprinted) jama.com
diabetes and use of metformin medication, severe systemic discharge from the hospital without the need for surgi-
illness (eg, malignancy, medical condition requiring immu- cal intervention and no recurrent appendicitis during the
nosuppressant medication), inability to cooperate and give 1-year follow-up.
informed consent, or complicated acute appendicitis based The predefined secondary end points included postinter-
on CT findings. vention adverse events related to antibiotics or appendec-
All patients with acute appendicitis at CT imaging who were tomy, with possible postoperative adverse events classified
evaluated for enrollment were recorded in the database, and using the Clavien-Dindo classification (grades 1 to 4), 19
the aim was to also record all patients undergoing CT imaging abdominal symptoms, duration of hospital stay, visual analog
for suspected acute appendicitis. scale scores for pain (range, 0-10), and length of sick leave.
All adverse events or symptoms related to antibiotic treat-
Randomization and Interventions ment comparable with grade 1 or higher in the Clavien-Dindo
Participants were randomized in a 1:1 ratio with random per- classification 19 for postoperative complications and any
muted blocks of 10 (SAS system for Windows, version 9.4) to symptoms resulting in discontinuation of the randomized
receive either oral moxifloxacin (400 mg once daily) for 7 days treatment were classified as antibiotic-associated adverse
or intravenous ertapenem sodium (1 g once daily) for 2 days events. Cost and quality of life are not reported in this article.
followed by oral levofloxacin (500 mg a day) and metronida- Based on the actual clinical diagnosis, the true primary fail-
zole (500 mg 3 times daily) for 5 days, with the first doses of ure rate (nonresponders with complicated acute appendicitis
the randomized treatment administered in the emergency de- based on surgical findings during the initial hospitalization),
partment. The intravenous followed by oral antibiotic therapy true recurrence rate (acute appendicitis based on histopa-
was selected based on its efficacy and safety in the previous thology findings after appendectomy for suspected recur-
APPAC trial.2 To evaluate a broad-spectrum antibiotic with- rence), and primary nonresponder rate (ie, all patients who
out the need for intravenous administration, once-daily ad- underwent appendectomy during the initial hospitalization)
ministered and commonly accessible moxifloxacin was found are reported.
to be a practical choice for the oral antibiotic with proven ef- Recurrent appendicitis was diagnosed clinically as
ficacy in intra-abdominal infections16,17 and inclusion in cur- determined by the surgeon on-call without repeated CT
rent practical guidelines.18 Randomization was stratified by imaging or predefined clinical criteria. Patients with sus-
center by a study statistician. pected appendicitis recurrence underwent laparoscopic
Minimum follow-up at the hospital was 20 to 24 hours, appendectomy based on the study protocol. Surgical finding
depending on the time of day of admission and patient sta- and histopathological examination (appendicitis defined as
tus, allowing for administration of 2 intravenous doses. The transmural neutrophil invasion involving the appendiceal
clinical condition of the patient was evaluated twice daily, muscularis layer) of the removed appendix were used to
approximately 12 hours after admission by the on-call sur- confirm the diagnosis.
geon. If the patient was suspected of not responding to the
antibiotic therapy, the patient underwent laparoscopic Statistical Analysis
appendectomy based on the surgeon’s decision and the rea- Sample size calculations were based on noninferiority tests
sons for proceeding to appendectomy were recorded. for binomial proportion. The success rate was estimated to be
73% for the intravenous followed by oral antibiotic group
Follow-up during the 1-year follow-up based on the results of the APPAC
Patient outcomes were assessed daily during hospitalization trial.1 The difference between the groups (oral antibiotic
and after discharge by telephone interviews at 1 week, 2 monotherapy − intravenous followed by oral antibiotics) was
months, and 1 year. For patients not reached for telephone set to zero and the noninferiority margin was set to −6%. The
follow-up, electronic hospital records were searched for in- −6% noninferiority margin was set based on the results of the
formation on possible appendectomy or other additional APPAC trial (ie, difference between the 1-year treatment suc-
intervention-associated visits or hospitalizations. cess of 73% and the lower 95% CI of 67%).1 We estimated that
To validate the accuracy of the differential diagnosis a total of 469 patients would yield a power of 0.9 (1 − β) to
between uncomplicated and complicated acute appendicitis, establish whether oral antibiotic monotherapy was noninfe-
all patients were assessed using clinical data and CT findings rior to intravenous followed by oral antibiotics using a one-
for patients with uncomplicated acute appendicitis treated sided significance level of α = .05. With an estimated dropout
with antibiotics or additionally for patients undergoing rate of 15%, a total of 552 patients (276 patients per group)
appendectomy using surgical and histopathological findings. needed to be enrolled. The analyses included all randomized
All clinical diagnoses were assessed in a blinded manner by 2 patients (according to their randomization group), with the
investigators unaware of the other’s evaluation (S.S. and exclusion of erroneously randomized patients w ith
J.H.). In cases of disagreement, the clinical diagnosis was CT-confirmed complicated acute appendicitis and early drop-
reviewed by a third investigator (P.S.). outs (Figure 1).
All main statistical analyses were planned in the study
Outcomes protocol and performed according to statistical analysis
The primary end point was treatment success at 1 year, plan (Supplement 2). To explore the possibility of site
defined as resolution of acute appendicitis resulting in effects, a post hoc analysis was conducted using a binomial
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Figure 1. Flow of Patients in a Study of the Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin
for Uncomplicated Acute Appendicitis
2909 Excluded
2317 Did not meet inclusion criteria
1403 Complicated acute appendicitis on CTa
292 Younger than 18 y or older than 60 y
215 Unsuitable or lacking diagnostic imagingb
176 Alternative diagnosis on CTc
97 Normal finding on CT
134 Other exclusion criteria metd
433 Declined to participate
23 Participation in the APPAC III triale
136 Unknown
603 Randomized
302 Randomized to the oral antibiotic 301 Randomized to the intravenous followed
monotherapy group by oral antibiotics group
295 Received intervention as randomized 288 Received intervention as randomized
7 Did not receive intervention 13 Did not receive intervention
as randomized as randomized
6 Excluded due to early consent 10 Excluded due to early consent
withdrawalf withdrawalf
1 Excluded due to randomization 3 Excluded due to randomization
protocol violationg protocol violationg
295 Analyzed for primary outcome 286 Analyzed for primary outcome
a f
Includes appendicolith, perforation, abscess, or suspicion of tumor. Patients who withdrew consent within 24 hours of randomization who
b
The majority of these patients underwent ultrasonography examination, received a maximum of 1 dose of the randomized treatment were excluded
magnetic resonance imaging, or non–contrast-enhanced computed from the analyses. Two patients, who withdrew their consent 5 and 7 days
tomography (CT). Twelve patients underwent an operation without after randomization, were included in the analyses.
g
diagnostic imaging. Patients erroneously randomized despite a finding of complicated acute
c
The alternative diagnoses were as follows: diverticulitis (n = 36), ovarian appendicitis initially seen on CT imaging were excluded from the analyses
mass/cyst (n = 25), colitis (n = 24), pelvic inflammatory disease (n = 12), according to the study protocol.
h
mesenterial lymphadenitis (n = 11), pyelonephritis (n = 8), kidney/ureteral Operative or histopathological findings of appendicolith, gangrene, perforation,
stone (n = 4), bowel obstruction (n = 1), and miscellaneous pathological abscess, or tumor were classified as complicated acute appendicitis.
findings or suspicion of such (n = 55). i
One patient in the oral antibiotic monotherapy group mistakenly received the
d
Additional exclusion criteria were pregnancy, lactation, allergy to contrast media, treatment intended for the intravenous followed by oral antibiotics group. Four
kidney insufficiency, use of metformin, systemic illness, and inability to consent. patients received 1 dose of moxifloxacin and thereafter cephalexin and
e
Arandomized,placebo-controlled,double-blind,multicentertrialcomparingantibiotic metronidazole (2 due to suspected reactions to moxifloxacin, 1 due to lactation, and
therapy with placebo in the treatment of uncomplicated acute appendicitis.20 1 to prevent a possible adverse interaction with the patient’s antidepressant).
generalized linear model with study group as a fixed effect assessment of the time to appendectomy was performed
and study center as a random effect. In addition, a post hoc using a Kaplan-Meier analysis.
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mainly because of the inclusion of patients with appendico- patients without), confirming the findings of earlier trials,23
liths, but the antibiotic choice was also suboptimal because and reinforced appendicolith as a finding associated with
of possible nonsusceptibility for Escherichia coli. To avoid complicated appendicitis, although the nature of appendico-
this limitation, oral moxifloxacin was used in the current liths (eg, large vs small) and how it influences nonoperative
trial. Moxifloxacin is a potent broad-spectrum oral antibiotic management of appendicitis remains unknown.14
with efficacy for managing intraabdominal infections16,18 and Complicated and uncomplicated appendicitis may be dif-
an advantage of once-daily administration. Given several ferent diseases.36 Future trials investigating nonoperative man-
years of experience with managing appendicitis nonopera- agement of appendicitis will need to refine the diagnosis of ap-
tively, the median hospitalization in this trial was shorter pendicitis severity using uniform and standardized criteria.
than in previous trials.1,23 A US-based pilot randomized clini- If nonoperative therapy is considered, complicated appendi-
cal trial that compared antibiotics with appendectomy in an citis should be ruled out, requiring that the sensitivity and nega-
outpatient setting showed that 87% of patients who received tive predictive value for tests establishing the diagnosis for ap-
antibiotics were successfully treated with antibiotics alone, pendicitis must be high, which is the case for CT imaging.
and no major adverse events occurred in either group at 1 Preintervention potential findings of complicated appendici-
year.12 These findings were corroborated recently by 90-day tis, such as the presence of an appendicolith,14,23 are factors
results from the CODA trial, with 47% of the patients in the predictive of primary antibiotic treatment failure. Optimiz-
antibiotic group being discharged from the emergency ing the patient selection for antibiotic treatment of uncompli-
department without hospitalization.14 Uncomplicated acute cated appendicitis requires standardized imaging and identi-
appendicitis appears to be similar to uncomplicated acute fying CT finding features for complicated appendicitis, such
diverticulitis, for which recent studies have demonstrated no as contrast enhancement defect of the appendiceal wall and
benefit of antibiotics compared with symptomatic treatment larger appendiceal diameter.37
alone. 29-34 Nonoperative management of uncomplicated
appendicitis may succeed even without antibiotics,35 which Limitations
is an area of active research.20 This trial has several limitations. First, moxifloxacin is a
In a pediatric study by Minneci et al,13 patients and their broad-spectrum antibiotic that risks the development of
families were given a choice between appendectomy and an- antibiotic resistance. Second, some patients (n = 4) were
tibiotic treatment for uncomplicated acute appendicitis after incorrectly enrolled in the study despite meeting exclusion
receiving information on these treatments based on a script. criteria on primary CT findings, and 136 eligible patients
Antibiotics were chosen by 370 of 1068 participants (35%) and who should have been evaluated for enrollment were not.
treatment with antibiotics was successful in 245 participants Third, both the predefined difference of 0% and the nonin-
(67%) at 1-year follow-up, which corresponds to the results of feriority margin for clinical importance of 6% in the sample
the current study in an adult population. size calculations between the study groups were set some-
Primary nonresponsiveness to antibiotics and recurrence what arbitrarily because no previous trials were available
are factors that need to be both discussed with the patient comparing oral and intravenous antibiotics for uncompli-
and taken into consideration when choosing the optimal cated acute appendicitis.
treatment alternative. With accurate patient selection using
CT imaging, one of the most important findings associated
with antibiotic therapy is the absence of major complications
attributable to delaying surgery for patients who eventually
Conclusions
needed an operation for up to 5 years.2 The CODA trial was a Among adults with uncomplicated acute appendicitis, treat-
pragmatic trial with 90-day follow-up of patients randomized ment with 7 days of oral moxifloxacin compared with 2 days
to receive antibiotics or appendectomy.14 The CODA trial of intravenous ertapenem followed by 5 days of levofloxacin
showed that patients presenting with an appendicolith had a and metronidazole resulted in treatment success rates greater
higher risk for both appendectomy (41% for patients with than 65% in both groups, but failed to demonstrate noninfe-
appendicolith and 25% for patients without) and complica- riority for treatment success of oral antibiotics compared with
tions (20% for patients with appendicolith and 4% for intravenous followed by oral antibiotics.
ARTICLE INFORMATION (Rautio, Rintala, Meriläinen); Medical Research Finland (Pinta, T. Sippola); Department of Surgery,
Accepted for Publication: December 22, 2020. Center Oulu, University of Oulu, Finland (Rautio, Mikkeli Central Hospital, Mikkeli, Finland (Ilves,
Meriläinen); Department of Gastroenterology and Paajanen); Department of Surgery, Jyväskylä
Published Online: January 11, 2021. Alimentary Tract Surgery, Tampere University Central Hospital, Jyväskylä, Finland (Mattila,
doi:10.1001/jama.2020.23525 Hospital, Tampere, Finland (Nordström, Aarnio); Department of Surgery, Rovaniemi Central
Author Affiliations: Division of Digestive Surgery Laukkarinen); Faculty of Medicine and Health Hospital, Rovaniemi, Finland (Rintala); Department
and Urology, Turku University Hospital, Turku, Technology, University of Tampere, Tampere, of Biostatistics, University of Turku, Turku, Finland
Finland (S. Sippola, Haijanen, Grönroos, Salminen); Finland (Nordström, Laukkarinen); Department of (Löyttyniemi, Hurme); Department of Radiology,
Department of Surgery, University of Turku, Turku, Surgery, Kuopio University Hospital, Kuopio, Turku University Hospital, Turku, Finland
Finland (S. Sippola, Haijanen, Grönroos, Salminen); Finland (Rantanen, Savolainen); Department of (Tammilehto); Department of Hospital Hygiene &
Department of Surgery, Satakunta Central Hospital, Surgery, Institute of Clinical Medicine, University of Infection Control, Turku University Hospital, Turku,
Pori, Finland (Haijanen, Sävelä); Department of Eastern Finland (Rantanen); Department of Finland (Marttila).
Surgery, Oulu University Hospital, Oulu, Finland Surgery, Seinäjoki Central Hospital, Seinäjoki,
360 JAMA January 26, 2021 Volume 325, Number 4 (Reprinted) jama.com
Author Contributions: Drs Salminen and Haijanen Data Sharing Statement: See Supplement 4. 11. Hansson J, Körner U, Khorram-Manesh A,
had full access to all the data in the study and take Additional Contributions: We thank Susanna Solberg A, Lundholm K. Randomized clinical trial of
full responsibility for the integrity of the data and Kulmala, MHA (Division of Digestive Surgery and antibiotic therapy versus appendicectomy as
the accuracy of the data analysis. Drs Sippola and Urology, Turku University Hospital), our research primary treatment of acute appendicitis in
Haijanen contributed equally as co–first authors. coordinator, and Teemu Kemppainen, BBA unselected patients. Br J Surg. 2009;96(5):473-481.
Concept and design: S. Sippola, Haijanen, Gronroos, (Department of biostatistics, University of Turku), doi:10.1002/bjs.6482
Rautio, Nordström, Rantanen, Ilves, Löyttyniemi, for statistical and data monitoring assistance, both 12. Talan DA, Saltzman DJ, Mower WR, et al.
Hurme, Tammilehto, Marttila, Savolainen, Aarnio, of whom received compensation for their role in Antibiotics-first versus surgery for appendicitis:
Salminen. the study. We also thank all of the surgeons on-call a US pilot randomized controlled trial allowing
Acquisition, analysis, or interpretation of data: who took part in the enrollment of trial patients. outpatient antibiotic management. Ann Emerg Med.
S. Sippola, Haijanen, Gronroos, Rautio, Nordström, None of the surgeons who participated in the study 2017;70(1):1-11. doi:10.1016/j.annemergmed.2016.08.
Rantanen, Pinta, Ilves, Mattila, Rintala, Löyttyniemi, received compensation. 446
Hurme, Tammilehto, Meriläinen, Laukkarinen,
Sävelä, T. Sippola, Paajanen, Salminen. 13. Minneci PC, Hade EM, Lawrence AE, et al;
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Orion Research Foundation, a government research Methods of conservative antibiotic treatment of infections treated with moxifloxacin. Clin Infect Dis.
grant awarded to Turku University Hospital, and acute uncomplicated appendicitis: A systematic 2011;53(11):1074-1080. doi:10.1093/cid/cir664
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and Georg C. Ehrnrooth foundation, the Sigrid Surgical Care. American College of Surgeons; 2020. Classification of surgical complications: a new
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antibiotic therapy vs appendectomy for A randomised placebo-controlled double-blind
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