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Figure.  Significant Preintervention Factors on Admission Associated With Primary Nonresponsiveness to Antibiotic Therapy
Significant Preintervention Factors on Admission Associated With Primary Nonresponsiveness to Antibiotic Therapy

Adjusted relative risk (RR) with 95% CIs. The model was analyzed with log-binomial model. For 5 patients, data for body temperature on admission was unavailable.

aPatients with primary nonresponsiveness to antibiotics (ie, undergoing appendectomy during primary hospitalization with a finding of complicated acute appendicitis at surgery and histologic findings). Two patients with nonresponsiveness had both appendiceal diameter greater than or equal to 15 mm and body temperature greater than 38 °C at admission.

1.
Minneci  PC, Deans  KJ.  Evolving issues in the use of antibiotics for the treatment of uncomplicated appendicitis.   JAMA. 2021;325(4):351-352. doi:10.1001/jama.2020.23607 PubMedGoogle ScholarCrossref
2.
Sippola  S, Haijanen  J, Grönroos  J,  et al.  Effect of oral moxifloxacin vs intravenous ertapenem plus oral levofloxacin for treatment of uncomplicated acute appendicitis: the APPAC II randomized clinical trial.   JAMA. 2021;325(4):353-362. doi:10.1001/jama.2020.23525 PubMedGoogle ScholarCrossref
3.
Salminen  P, Paajanen  H, Rautio  T,  et al.  Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial.   JAMA. 2015;313(23):2340-2348. doi:10.1001/jama.2015.6154 PubMedGoogle ScholarCrossref
4.
Salminen  P, Tuominen  R, Paajanen  H,  et al.  Five-year follow-up of antibiotic therapy for uncomplicated acute appendicitis in the APPAC randomized clinical trial.   JAMA. 2018;320(12):1259-1265. doi:10.1001/jama.2018.13201 PubMedGoogle ScholarCrossref
5.
American College of Surgeons. COVID 19: elective case triage guidelines for surgical care. Updated December 8, 2020. Accessed August 31, 2021. https://www.facs.org/covid-19/clinical-guidance/elective-case/emergency-surgery
6.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
7.
Flum  DR, Davidson  GH, Monsell  SE,  et al; CODA Collaborative.  CODA Collaborative. A randomized trial comparing antibiotics with appendectomy for appendicitis.   N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320 PubMedGoogle Scholar
Research Letter
October 6, 2021

Factors Associated With Primary Nonresponsiveness to Antibiotics in Adults With Uncomplicated Acute Appendicitis: A Prespecified Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Division of Digestive Surgery and Urology, Turku University Hospital, Turku, Finland
  • 2Department of Biostatistics, University of Turku, Turku, Finland
  • 3Department of Surgery, Oulu University Hospital, Oulu, Finland
JAMA Surg. 2021;156(12):1179-1181. doi:10.1001/jamasurg.2021.5003

Contemporary research suggests that physicians could offer patients with computed tomography (CT)–confirmed uncomplicated acute appendicitis a choice between surgery and antibiotics.1-5 In the recent Appendicitis Acuta (APPAC) II trial2 aiming to optimize antibiotic treatment of uncomplicated acute appendicitis in adults, 70.2% of the patients (207 of 295) randomized to receive oral antibiotic monotherapy and 73.8% of patients (213 of 288) randomized to receive intravenous antibiotics followed by oral antibiotics avoided surgery at 1-year follow-up. To further improve patient selection and subsequently the success rate of nonoperative treatment for uncomplicated acute appendicitis, accurate differential diagnosis between uncomplicated and complicated acute appendicitis ruling out complicated appendicitis is essential. The objective of this study was to assess potential preintervention findings associated with primary nonresponsiveness to antibiotics in the APPAC II trial.

Methods

This study is a predefined secondary analysis of the APPAC II randomized clinical trial comparing oral antibiotic monotherapy with intravenous followed by oral antibiotics for CT-confirmed uncomplicated acute appendicitis in adults aged 18 to 60 years in 9 Finnish hospitals. Data were obtained from a trial that enrolled patients from April 2017 to November 2018. Data were analyzed from December 1, 2018, to July 20, 2020. The detailed methods and primary results have been previously published.2 Data on race and ethnicity were not collected for this study. The standardized CT diagnostic criteria are presented in the Box. The study was approved by ethics committee of the Hospital District of Southwest Finland and by institutional research boards at each participating site. All patients gave written informed consent. The trial was performed in accordance with the tenets of the Declaration of Helsinki6 and followed the relevant portions of the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol and statistical analysis plan are available in Supplement 1. This APPAC II trial subgroup analysis compares patients with primary nonresponsiveness to antibiotics undergoing appendectomy during the primary hospitalization with a finding of complicated acute appendicitis with patients either undergoing surgery for uncomplicated acute appendicitis during the primary hospitalization or patients with successful antibiotic treatment (eFigure in Supplement 2).

Box Section Ref ID
Box.

Structured Radiological Report Including Radiological Criteria and Categorization of Acute Appendicitis

Appendix Visualization
  • Report 1 of the following:

    • Not visualized

    • Partly or unclearly visualized

    • Completely visualized

Appendix Transverse Diameter (mm)
Probability of Appendicitis
  • Report 1 of the following:

    • Not likely

    • Rather unlikely

    • Rather likely

    • Very likely

Categorization of the Appendicitis
  • Report either uncomplicated appendicitis or complicated appendicitis, if any:

    • Uncomplicated appendicitis: transverse diameter >6 mm with typical findings

      • Wall thickening and enhancement

      • Periappendiceal edema and/or minor amount of fluid

    • Complicated appendicitis: above-mentioned criteria for appendicitis with at least 1 of the following:

      • Appendicolith: >3 mm stone within appendix

      • Abscess: periappendiceal walled-off collection with enhancing walls

      • Perforation: appendiceal wall enhancement defect and periappendiceal excess of fluid and/or infectious phlegmon and/or extraluminal air

      • Tumor: tumorlike prominence of appendix

Other Diagnosis
  • Report if any:

    • Diverticulitis

    • Complicated ovarian cyst

    • Pelvic inflammatory disease

    • Colitis

    • Ileitis

    • Intestinal obstruction or ileus

    • Ureter stone

    • Hydronephrosis

    • Tumor

    • Other diagnosis

Potential factors associated with antibiotic nonresponsiveness registered on admission (age, sex, body mass index, visual analog scale pain score, leukocyte count, C-reactive protein, body temperature, symptom duration, and CT findings of appendiceal diameter, minor fluid collection, or periappendiceal edema) were first evaluated in a univariate approach using binomial generalized linear models, ie, log-binomial model including study center and randomization group as study design factors. The potentially significant factors in the univariate model were then included in a multivariable model and optimal cutoff points were evaluated for continuous variables. Two-tailed P values less than .05 were considered statistically significant. The analyses were generated using SAS, version 9.4 (SAS Institute Inc).

Results

Of the 583 patients (251 [43%] were women; mean [SD] age, 35 [11.5] years) with CT-confirmed uncomplicated acute appendicitis randomized to receive antibiotics and eligible for analysis, 29 patients (5.0%) were primary nonresponders to antibiotics who underwent a surgical procedure with a finding of complicated acute appendicitis during initial hospitalization.2 Appendiceal diameter greater than or equal to 15 mm on CT and a body temperature of greater than 38 °C on admission were associated with primary nonresponsiveness to antibiotic therapy. The adjusted risk ratio for primary antibiotic nonresponsiveness for appendiceal diameter of greater than or equal to 15 mm was 5.5 (95% CI, 2.4-12.5; P < .001) and for a body temperature greater than 38 °C was 4.1 (95% CI, 1.6-10.7; P = .004) (Figure).

Discussion

Among adults with CT-confirmed uncomplicated acute appendicitis, patients with an appendiceal diameter greater than or equal to 15 mm or a body temperature above 38 °C were found to have an increased risk for primary antibiotic nonresponsiveness. Oral antibiotic monotherapy has been recently reported to be a feasible treatment option for uncomplicated acute appendicitis,2 possibly enabling future outpatient management, that would even further highlight the potential benefits of nonoperative treatment. This approach also underlines the need for accurate identification of potential objective prognostic parameters to rule out complicated acute appendicitis with high sensitivity and negative predictive value. Ruling in complicated appendicitis is less important because patients with a false-positive test result for complicated appendicitis actually having uncomplicated appendicitis will undergo surgery, which is an accepted treatment for acute appendicitis. The main limitation of this study is the small number of patients with nonresponsiveness to antibiotics, which is due to the already selected study population of patients with CT-confirmed uncomplicated acute appendicitis. Another limitation is the potential administration of antifebrile drugs prior to measuring the body temperature, possibly affecting these measurements. Accurate patient selection, enhanced by identifying factors associated with both primary nonresponsiveness to antibiotics and appendicitis recurrence is important in optimizing the treatment outcomes of nonoperative management of uncomplicated acute appendicitis. The results of this secondary analysis of the APPAC II trial suggest that in patients with uncomplicated acute appendicitis, appendiceal diameter greater than or equal to 15 mm or a body temperature exceeding 38 °C should be considered as risk factors for nonresponsiveness to antibiotics. Optimal treatment outcomes for these patients might be achieved with initial appendectomy instead of nonoperative treatment, similar to patients presenting with an appendicolith, which has been reported to be associated with a more complicated course of appendicitis.7

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Article Information

Accepted for Publication: June 27, 2021.

Published Online: October 6, 2021. doi:10.1001/jamasurg.2021.5003

Corresponding Author: Paulina Salminen, MD, PhD, Turku University Hospital, University of Turku, PO Box 52, 20520 Turku, Finland (paulina.salminen@tyks.fi).

Author Contributions: Drs Salminen and Haijanen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Haijanen, Löyttyniemi, Grönroos Salminen.

Critical revision of the manuscript for important intellectual content: Sippola, Löyttyniemi, Hurme, Grönroos, Rautio, Salminen.,

Statistical analysis: Haijanen, Löyttyniemi, Hurme, Salminen.

Obtained funding: Haijanen, Salminen.

Administrative, technical, or material support: Haijanen, Rautio, Salminen.

Supervision: Grönroos, Rautio, Salminen.

Conflict of Interest Disclosures: Dr Haijanen reported grants from Orion Research Foundation, grants from Government research grant awarded to Turku University Hospital, grants from Gastroenterological Research Foundation, grants from Paulo Foundation, and grants from Finnish medical Foundation during the conduct of the study. Dr Sippola reported grants from the Orion Research Foundation, grants from the Gastroenterological Research Foundation, and grants from a Government research grant awarded to Turku University Hospital during the conduct of the study; grants from the Mary and Georg C. Ehrnrooth Foundation and grants from the Finnish Medical Foundation outside the submitted work. Dr Salminen reported grants from Sigrid Juselius Foundation Research grant and grants from Academy of Finland Research grant during the conduct of the study; personal fees from Orion Pharma lecture fee and personal fees from Merck lecture fee outside the submitted work. No other disclosures were reported.

Funding/Support: The study was supported by research grants from Mary and Georg C. Ehrnrooth foundation (Dr Salminen), from Sigrid Juselius Foundation (Dr Salminen), from the Finnish Academy (Dr Salminen), from Orion research foundation (Drs Haijanen and Sippola), the Gastroenterological Research Foundation (Drs Haijanen and Sippola), from Finnish medical foundation (Drs Haijanen and Sippola), the Paulo Foundation (Dr Haijanen) and a government research grant awarded to Turku University Hospital (Drs Salminen, Sippola, and Haijanen).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Trial Registration: This study was registered at ClinicalTrials.gov (Identifier: NCT03236961).

Data Sharing Statement: See Supplement 3.

References
1.
Minneci  PC, Deans  KJ.  Evolving issues in the use of antibiotics for the treatment of uncomplicated appendicitis.   JAMA. 2021;325(4):351-352. doi:10.1001/jama.2020.23607 PubMedGoogle ScholarCrossref
2.
Sippola  S, Haijanen  J, Grönroos  J,  et al.  Effect of oral moxifloxacin vs intravenous ertapenem plus oral levofloxacin for treatment of uncomplicated acute appendicitis: the APPAC II randomized clinical trial.   JAMA. 2021;325(4):353-362. doi:10.1001/jama.2020.23525 PubMedGoogle ScholarCrossref
3.
Salminen  P, Paajanen  H, Rautio  T,  et al.  Antibiotic therapy vs appendectomy for treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial.   JAMA. 2015;313(23):2340-2348. doi:10.1001/jama.2015.6154 PubMedGoogle ScholarCrossref
4.
Salminen  P, Tuominen  R, Paajanen  H,  et al.  Five-year follow-up of antibiotic therapy for uncomplicated acute appendicitis in the APPAC randomized clinical trial.   JAMA. 2018;320(12):1259-1265. doi:10.1001/jama.2018.13201 PubMedGoogle ScholarCrossref
5.
American College of Surgeons. COVID 19: elective case triage guidelines for surgical care. Updated December 8, 2020. Accessed August 31, 2021. https://www.facs.org/covid-19/clinical-guidance/elective-case/emergency-surgery
6.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
7.
Flum  DR, Davidson  GH, Monsell  SE,  et al; CODA Collaborative.  CODA Collaborative. A randomized trial comparing antibiotics with appendectomy for appendicitis.   N Engl J Med. 2020;383(20):1907-1919. doi:10.1056/NEJMoa2014320 PubMedGoogle Scholar
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