Antibiotic Duration After Laparoscopic Appendectomy for Acute Complicated Appendicitis

Importance  Optimal duration of antibiotic treatment to reduce infectious complications after an appendectomy for acute complicated appendicitis remains unclear.

Objective  To investigate the effect of antibiotic duration on infectious complications after laparoscopic appendectomy for acute complicated appendicitis.

Design, Setting, and Participants  National multicenter prospective, observational, surgical resident–led cohort study conducted in June and July 2014. This study involved academic teaching hospitals (n = 8), community teaching hospitals (n = 38), and community nonteaching hospitals (n = 16), and all consecutive patients (n = 1975) who underwent surgery for suspected acute appendicitis.

Exposures  Patients treated laparoscopically for whom the antibiotic regimens were prolonged postoperatively because of complicated appendicitis.

Main Outcomes and Measures  Receiving either 3 or 5 days of antibiotic treatment as planned and additional variables were explored as risk factors for infectious complications using regression analyses.

Results  A total of 1975 patients were included in 62 participating Dutch hospitals; 1901 (96.3%) of these underwent an appendectomy for acute appendicitis and laparoscopy was used in 74.4% of these patients (n = 1415). In 415 laparoscopically treated patients, antibiotic treatment was continued for more than 24 hours because of acute complicated appendicitis (29.3%). The prescribed antibiotic duration varied between 2 and 6 days in all of these patients. In 123 patients (29.6%), the length of treatment was adjusted. A shorter duration of antibiotic treatment (3 days instead of 5) had no significant effect on any infectious complication (odds ratio [OR], 0.93; 95% CI, 0.38-2.32; P = .88) or on intra-abdominal abscess development (OR, 0.89; 95% CI, 0.34-2.35; P = .81). Perforation of the appendix was the only independent risk factor for the development of an infectious complication (OR, 4.90; 95% CI, 1.41-17.06; P = .01) and intra-abdominal abscess (OR, 7.46; 95% CI, 1.65-33.66; P = .009) in multivariable regression analysis.

Conclusions and Relevance  Lengthening of postoperative antibiotic treatment to 5 days was not associated with a reduction in infectious complications. Further restriction of antibiotic treatment can be considered in nonperforated complicated appendicitis.

Uncomplicated and complicated appendicitis are currently distinguished as 2 different disease entities that require different treatments.¹ The role of antibiotic treatment as an alternative for surgery in simple or uncomplicated appendicitis has been studied in adults^2-4 and, more recently, in children.^5,6 Acute complicated appendicitis with necrosis or perforation of the appendix is treated by appendectomy and usually followed by additional antibiotic treatment aimed at reducing postoperative infectious complications. Restriction and proper use of antibiotics are important for reducing and preventing harmful adverse effects to the patients and preventing antibiotic resistance.⁷ In American guidelines, an antibiotic length of 4 to 7 days is advised after complicated appendicitis.⁸ To our knowledge, few studies have investigated the reduction of antibiotic administration after appendectomy and these were mostly performed in children.^9-11 Restricting antibiotic duration to fewer than 5 days after surgery in complicated appendicitis is seldom done, fearing infectious complications. However, 3 days of antibiotic treatment has been observed to be feasible and safe in a retrospective cohort of adults with complicated appendicitis.¹²

The objectives of this prospective study were to investigate the relation of antibiotic duration and infectious complications and to identify possible risk factors for a postoperative infectious complication after laparoscopic appendectomy for acute complicated appendicitis.

A surgical resident–led prospective, observational, cohort study was conducted in 62 Dutch hospitals including all consecutive patients who underwent surgery for suspected acute appendicitis between June 1, 2014, and July 31, 2014, preceded by a pilot phase in 8 hospitals in May 2014. All patients were treated according to the local hospital protocol that was based on the Dutch guideline for appendicitis.¹³ One local investigator was responsible for identifying patients and collecting the data that were entered anonymized into an electronic database.

The medical ethics committee in the Academic Medical Center in Amsterdam approved the study design and judged that no informed consent from the patients was necessary because of the observational study design without additional burden for the patient.

For this analysis, only patients who underwent a laparoscopic appendectomy for acute complicated appendicitis were included. Both pediatric and adult patients were included in this analysis. The primary outcome was the effect of antibiotic treatment length on the infectious complication rate. To identify in-hospital and out-hospital complications during the 30-day follow-up, the electronic patient database system was checked to monitor visits at the emergency department, postoperative imaging or intervention, unscheduled outpatient visits, and hospital readmission.

Complicated appendicitis was defined as necrosis or perforation of the appendix or if an extensive purulent peritonitis was found during laparoscopy for which the surgeon prolonged antibiotic treatment for more than 24 hours. Two lengths of antibiotic treatment were registered; the duration as prescribed by the local surgeon directly after surgery and the duration that the patient eventually received. The actual received duration of antibiotics was retrieved from the medical prescription system. Intravenous antibiotics or a combination with an oral regimen was also registered. In case of the latter, the total duration of antibiotic treatment was calculated and used for analysis. A new course of antibiotics that was started for a complication after the initial course was finished was not included in the registered treatment duration.

Patients were treated according to the local hospital protocol based on local resistance pattern (in the Netherlands, usually a combination of cephalosporin and metronidazole).

Superficial surgical site infection was recorded when administration of antibiotics (restart or lengthening for this reason), whether in combination with drainage of a wound abscess, was necessary. An intra-abdominal abscess was defined as a postoperative intra-abdominal fluid collection diagnosed by cross-sectional imaging for which administration of antibiotics (restart or lengthening) or a radiological or surgical intervention was needed. Any infectious complication was defined as a superficial surgical site infection, an intra-abdominal abscess, or both. Postoperative ileus was reported as an adverse event when resumption of oral diet was not achieved within 5 days after surgery.¹⁴

Dichotomous outcomes were compared using the χ² test or Fisher exact test where appropriate and comparison of nonparametric outcome (medians) was calculated with the Mann-Whitney U test. A 2-sided P < .05 was considered significant. Univariable odds ratios (ORs) and 95% CIs were calculated using logistic regression analysis for identifying risk factors for infectious complications and intra-abdominal abscesses. A multivariable logistic regression model was built for variables with P < .20 in univariable analysis and 3 or 5 days of postoperative antibiotic treatment as planned.

Statistical analyses were performed using SPSS version 21 (IBM).

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement was used in the study design and for preparing the article.¹⁵

A total of 1975 patients underwent surgery for suspected acute appendicitis in 62 Dutch hospitals in the 2-month period (3 months in pilot centers). Among the participating hospitals were all academic teaching hospitals (n = 8), 84% of the community teaching hospitals (n = 38) and 41% of the community nonteaching hospitals (n = 16). The laparoscopic approach was used in 1415 patients (74.4%) who underwent an appendectomy for acute appendicitis (n = 1901) and more frequently in adults than in children (79.5% vs 61.0%). In 415 patients, the local surgeon continued antibiotic treatment for more than 24 hours after laparoscopic appendectomy because of acute complicated appendicitis and these patients were included in the analysis. The conversion rate in these complicated cases was 8.0%. The demographics and outcomes of patients with prolonged antibiotic treatment after laparoscopic appendectomy for complicated appendicitis are displayed in Table 1.

The duration of antibiotics as prescribed directly after surgery by the surgeon varied between 2 and 6 days; most frequently, the prescribed doses lasted 3 days or 5 days (Table 2). Quiz Ref IDA change in antibiotic duration was ordered in 29.6% of the patients (n = 123), a longer duration in 106 patients (25.5%), and a shorter duration in 17 patients (4.1%). Reasons for continuing antibiotic treatment longer than initially ordered varied and consisted of superficial surgical site infection in 3.8% (4 of 106), intra-abdominal abscess in 22.6% (24 of 106), or were dictated by the clinical course without an objective complication. The actual received duration of antibiotics varied between 2 and 10 days, almost 25% of the patients received eventually more than 5 days of antibiotic treatment (Table 2). In the patients who were treated longer than 5 days, appendicitis seemed more severe, with a higher rate of perforation, conversion, and participation of a senior surgeon. A higher rate of complications and intra-abdominal abscesses and a longer hospital stay were observed in these patients (Table 1).

Quiz Ref IDA postoperative complication was seen in 22.9% of the patients with complicated appendicitis. A superficial surgical site infection was seen in 2.2% (n = 9) and an intra-abdominal abscess in 12.0% (n = 50) (Table 1). The median time after which a complication was diagnosed after surgery was 6 days (range, 1-24 days) and 7 days (range, 2-24 days) for an intra-abdominal abscess. In 41 patients with a prescribed regimen of 3 days, the antibiotic regimen was continued longer than this, and in these patients, a superficial surgical site infection was seen in 7.3% (n = 3) and an intra-abdominal abscess in 14.6% (n = 6).

In converted cases, the superficial surgical site infection rate was 15.2% and the intra-abdominal abscess rate was 21.2%. The conversion rate was comparable between pediatric and adult patients (10.4% vs 7.4%; P = .36).

In patients with a perforated appendix, the intra-abdominal abscess rate was 16.0% in contrast to a rate of 3.8% when the appendix was not perforated but when necrosis or pus was the reason for continuing antibiotics (P < .001).

In 292 of the 415 laparoscopically treated patients (70.4%), the received antibiotic length was the same as prescribed. In 266 of these patients, antibiotic length was 3 or 5 days; 75 patients (28.2%) received 3 days and 191 patients (71.8%) received 5 days. The demographics and outcomes of these patients are displayed in Table 3. Quiz Ref IDNo differences in complications were observed after 3 or 5 days of antibiotic treatment (infectious complication: OR, 0.93; 95% CI, 0.38-2.32; P = .88 and intra-abdominal abscess development: OR, 0.89; 95% CI, 0.34-2.35; P = .81;Table 4); Quiz Ref IDhowever, patients who were treated for 3 days had a shorter hospital stay (Table 3). Neither in the univariable nor the multivariable analysis was 3 vs 5 days of antibiotic treatment identified as a risk factor for infectious complications and intra-abdominal abscess (Table 4). Perforation of the appendix was the only independent risk factor for developing an infectious complication (OR, 4.90; 95% CI, 1.41-17.06; P = .01) and intra-abdominal abscess (OR, 7.46; 95% CI, 1.65-33.66; P = .009) in multivariable regression analysis (Table 4).

One of the main findings in this large prospective cohort was that there was no difference in either 3 or 5 days of antibiotic treatment, according to protocol, on the development of infectious complications after laparoscopic appendectomy for complicated appendicitis. Perforation of the appendix was the only identified risk factor for developing an infectious complication. Different regimens of antibiotic duration after an appendectomy for complicated appendicitis were seen in this cohort that reflects nationwide variance in current treatment practice. Most frequently used standard lengths were 3 or 5 days, with a predominance of the latter.

The results of this study are in accordance with the results of an observational cohort study¹¹ and a small randomized clinical trial comparing 3 and 5 days of antibiotic treatment in secondary peritonitis in which half of the patients had a complicated appendicitis.¹⁶Quiz Ref ID The importance of restricting antibiotic treatment when possible was pointed out in a report of the World Health Organization,⁷ concluding that the most important reason for antibiotic resistance is the misuse of and overtreatment with antibiotics.

Switching to oral antibiotics can be considered when diet resumption is sufficient.¹⁷ In the current cohort, this switch was not applied in most patients, leading to a significantly shorter hospital stay in the 3-day group. This is not only beneficial to the patient, but this reduction of hospital stay can lead to a substantial cost reduction, although no cost analyses were conducted in this study. On a macroeconomic level, shortening of antibiotic treatment duration could lead to a cost reduction in this frequent disease.

Histological severity did not match with clinical severity in more than half of the clinically assessed complicated cases. This discordance between histological and surgical judgment has also been seen in other studies.^18,19 Histological severity was no risk factor for infectious complications in logistic regression analysis in contrast to a clinically assessed perforation of the appendix. This is in concordance with another study²⁰ that showed that perforation of the appendix was associated with a higher risk for infectious complications compared with necrosis or pus without perforation. Therefore, proper intraoperative assessment of disease severity is important because further restriction of antibiotic treatment may be justified in the absence of perforated appendicitis. The interobserver variation in scoring appendicitis as complicated can vary among surgeons. However, necrosis or perforation of the appendix is mostly an obvious finding.

Laparoscopy was the prevailing approach in the treatment of acute appendicitis in this nationwide Dutch cohort, especially in adult patients. Patients who underwent primary open appendectomy were not included in this analysis because of the small numbers in this cohort.

The duration of antibiotic prescription was changed in almost 30% of the patients because the clinical evaluation of the patient demanded it. Patients who eventually received more than 5 days of antibiotic treatment were different in disease severity and outcome compared with patients with a shorter regimen and could therefore not be compared with patients receiving 3 or 5 days of antibiotic treatment.

Patients who received either 3 or 5 days of antibiotic treatment according to protocol without a modification of the length were comparable in disease severity and outcome. Continuation of antibiotics beyond day 3 may be mandated by findings of persisting clinical infection, although it does not seem to prevent formation of an infectious complication. Therefore, antibiotic treatment beyond day 3 must be considered supportive therapy while the source of persistent infection is identified.

Three days of antibiotic treatment for complicated appendicitis appeared to be sufficient. Longer administration of antibiotics was not associated with prevention of intra-abdominal abscesses and a reactive strategy based on clinical condition of the patient is therefore advised.

Corresponding Author: Charles C. van Rossem, MD, Tergooi Hospital, Department of Surgery, PO Box 10016, 1201 DA Hilversum, the Netherlands (cvanrossem@tergooi.nl).

Accepted for Publication: August 11, 2015.

Published Online: November 18, 2015. doi:10.1001/jamasurg.2015.4236.

Author Contributions: Drs van Rossem and Schreinemacher 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.

Study concept and design: All authors.

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

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Van Rossem, Schreinemacher.

Administrative, technical, or material support: Schreinemacher, Bemelman.

Study supervision: Schreinemacher, van Geloven, Bemelman.

Conflict of Interest Disclosures: None reported.

Group Information: The Snapshot Appendicitis Collaborative Study Group members, who provided study patients and collected data, included: G. J. D. van Acker, MD, PhD (Medical Center Haaglanden, Den Haag), B. Akkermans, MD (Bronovo Hospital, Den Haag), G. J. M. Akkersdijk, MD, PhD (Spaarne Hospital, Hoofddorp), G. D. Algie, MD (M. C. Groep Zuiderzee, Lelystad), J. H. Allema, MD, PhD (Haga-Juliana Children’s Hospital, Den Haag), C. S. Andeweg, MD, PhD (St Jansdal Hospital, Harderwijk), N. Appeldorn (Röpcke-Zweers Hospital, Hardenberg), J. G. van Baal, MD, PhD (Ziekenhuisgroep Twente, Almelo), C. M. den Bakker, MD (Kennemer Gasthuis, Haarlem), S. A. L. Bartels, MD, PhD (Albert Schweitzer Hospital, Dordrecht), C. van den Berg, MD (Diaconessenhuis, Leiden), B. Boekestijn (Groene Hart Hospital, Gouda), F. C. den Boer, MD, PhD (Zaans Medical Center, Zaandam), D. Boerma, MD, PhD (St Antonius Hospital, Nieuwegein), A. L. van den Boom, MD (Reinier de Graaf Groep, Delft), M. C. Boute, MD (Westfriesgasthuis, Hoorn), S. A. W. Bouwense, MD (Canisius-Wilhelmina Hospital, Nijmegen), J. Bransen, MD (Catharina Hospital, Eindhoven), F. A. van Brussel, MD (Spaarne Hospital, Hoofddorp), O. R. C. Busch, MD, PhD (Academic Medical Center, Amsterdam), S. M. M. de Castro, MD, PhD (Sint Lucas Andreas Hospital, Amsterdam), H. A. Cense, MD, PhD (Rode Kruis Hospital, Beverwijk), C. Croese, MD (Medical Center Haaglanden, Den Haag), T. van Dalen, MD, PhD (Diakonessenhuis, Utrecht), I. Dawson, MD, PhD (IJsselland Hospital, Capelle aan Den IJssel), E. van Dessel, MD (ZorgSaam Zeeuws-Vlaanderen, Terneuzen), R. Dettmers, MD (Rijnland Hospital, Leiderdorp), N. Dhar, MD (BovenIJ Hospital, Amsterdam), F. Y. M. Dohmen (St Jans Gasthuis, Weert), K. W. van Dongen, MD, PhD (Diaconessenhuis, Leiden), P. van Duijvendijk, MD, PhD (Gelre Hospital, Apeldoorn), R. R. Dulfer, MD (Sint Franciscus Gasthuis, Rotterdam), B. J. Dwars, MD, PhD (Slotervaart Hospital, Amsterdam), J. P. Eerenberg, MD, PhD (Tergooi Hospital, Hilversum), M. van der Elst, MD, PhD (Reinier de Graaf Groep, Delft), E. D. van den Ende, MD, PhD (Röpcke-Zweers Hospital, Hardenberg), L. M. M. Fassaert, MD (Orbis Medical Center, Sittard), J. T. Fikkers, MD (Haga Hospital, Den Haag), J. W. Foppen (St Jansdal Hospital, Harderwijk), E. J. B. Furnee, MD, PhD (Diakonessenhuis, Utrecht), F. P. Garssen, MD (Amstelland Hospital, Amstelveen), M. F. Gerhards, MD, PhD (Onze Lieve Vrouwe Gasthuis, Amsterdam), H. van Goor, MD, PhD (Radboud University Medical Center, Nijmegen), R. R. Gorter, MD (Emma Children’s Hospital–Academic Medical Center/Free University Medical Center, Amsterdam and Rode Kruis Hospital, Beverwijk), J. S. de Graaf, MD, PhD (Medical Center Leeuwarden, Leeuwarden), L. J. Graat, MD (Elisabeth-TweeSteden Hospital, Tilburg), J. Groote, MD (Wilhelmina Hospital, Assen), A. C. van der Ham, MD, PhD (Sint Franciscus Gasthuis, Rotterdam), J. F. Hamming, MD, PhD (Leids University Medical Center, Leiden), J. T. H. Hamminga, MD (University Medical Center Groningen and Beatrix Children’s Hospital, Groningen), E. van der Harst, MD, PhD (Maasstad Hospital, Rotterdam), J. Heemskerk, MD (Laurentius Hospital, Roermond), H. A. Heij, MD, PhD (Emma Children’s Hospital–Academic Medical Center/Free University Medical Center, Amsterdam), A. Heijne, MD (Zaans Medical Center, Zaandam), J. T. Heikens, MD, PhD (Rivierenland Hospital, Tiel), E. Heineman, MD, PhD (University Medical Center Groningen and Beatrix Children’s Hospital, Groningen), R. Hertogs, MD (Wilhelmina Hospital, Assen), E. van Heurn, MD, PhD (Maastricht University Medical Center, Maastricht), L. C. L. van den Hil, MD (Laurentius Hospital, Roermond), A. G. M. Hoofwijk, MD, PhD (Orbis Medical Center, Sittard), C. C. C. Hulsker, MD (Wilhelmina Children’s Hospital–University Medical Center Utrecht, Utrecht), D. R. M. Hunen, MD (Elkerliek Hospital, Helmond), M. S. Ibelings, MD, PhD (TweeSteden Hospital, Tilburg), J. M. Klaase, MD, PhD (Medical Spectrum Twente, Enschede), R. Klicks, MD, PhD (BovenIJ Hospital, Amsterdam), L. Knaapen, MD (Radboud University Medical Center and Amalia Children’s Hospital, Nijmegen), R. T. J. Kortekaas, MD, PhD (Vlietland Hospital, Schiedam), F. Kruyt, MD, PhD (Gelderse Vallei Hospital, Ede), S. Kwant (Zuwe Hofpoort Hospital, Woerden), S. S. Lases, MD (Isala Hospital, Zwolle), T. Lettinga, MD (St Jans Gasthuis, Weert), A. Loupatty, MD (Leids University Medical Center, Leiden), R. A. Matthijsen, MD, PhD (Academic Medical Center, Amsterdam), R. C. Minnee, MD, PhD (Onze Lieve Vrouwe Gasthuis, Amsterdam), B. Mirck, MD (Medical Center Alkmaar, Alkmaar), L. Mitalas, MD (Maastricht University Medical Center, Maastricht), D. E. Moes, MD (Slotervaart Hospital, Amsterdam), A. M. Moorman, MD (Ziekenhuisgroep Twente, Almelo), V. B. Nieuwenhuijs, MD, PhD (Isala Hospital, Zwolle), G. A. P. Nieuwenhuijzen, MD, PhD (Catharina Hospital, Eindhoven), P. D. Nijk, MD (Diakonessenhuis, Utrecht), J. M. T. Omloo, MD, PhD (Gelre Hospital, Apeldoorn), A. G. Ottenhof, MD (Flevo Hospital, Almere), H. W. Palamba, MD (Gelre Hospital, Zutphen), D. L. van der Peet, MD, PhD (Free University Medical Center, Amsterdam), I. T. A. Pereboom, MD, PhD (Medical Center Leeuwarden, Leeuwarden), P. W. Plaisier, MD, PhD (Albert Schweitzer Hospital, Dordrecht), A. P. T. van der Ploeg, MD, PhD (Maasstad Hospital, Rotterdam), M. H. Raber, MD (Medical Spectrum Twente, Enschede), M. M. P. J. Reijnen, MD, PhD (Rijnstate Hospital, Arnhem), H. Rijna, MD, PhD (Kennemer Gasthuis, Haarlem), C. Rosman, MD, PhD (Canisius-Wilhelmina Hospital, Nijmegen), R. M. H. Roumen, MD, PhD (Máxima Medical Center, Veldhoven), R. F. Schmitz, MD, PhD (Groene Hart Hospital, Gouda), A. P. Schouten van der Velden, MD, PhD (Maas Hospital Pantein, Boxmeer), W. H. Schreurs, MD, PhD (Medical Center Alkmaar, Alkmaar), T. A. Sigterman, MD (Atrium Medical Center, Heerlen), H. J. Smeets, MD, PhD (Bronovo Hospital, Den Haag), D. J. A. Sonneveld, MD, PhD (Westfriesgasthuis, Hoorn), M. N. Sosef, MD, PhD (Atrium Medical Center, Heerlen), S. F. Spoor (M. C. Groep Zuiderzee, Lelystad), L. P. S. Stassen, MD, PhD (Maastricht University Medical Center, Maastricht), L. van Steensel, MD, PhD (Ikazia Hospital, Rotterdam), E. Stortelder, MD (Rijnstate Hospital, Arnhem), J. Straatman, MD (Free University Medical Center, Amsterdam), H. J. van Susante, MD (Amstelland Hospital, Amstelveen), D. E. N. M. Suykerbuyk de Hoog, MD (Máxima Medical Center, Veldhoven), C. E. J. Terwisscha van Scheltinga, MD (Sophia Children’s Hospital–Erasmus Medical Center, Rotterdam), B. R. Toorenvliet, MD, PhD (Ikazia Hospital, Rotterdam), B. M. Verbeek, MD (Vlietland Hospital, Schiedam), P. C. M. Verbeek, MD, PhD (Flevo Hospital, Almere), M. Verseveld, MD (IJsselland Hospital, Capelle aan Den IJssel), J. H. Volders, MD (Gelderse Vallei Hospital, Ede), M. R. Vriens, MD, PhD (University Medical Center Utrecht, Utrecht), P. W. H. E. Vriens, MD, PhD (St Elisabeth Hospital, Tilburg), B. C. Vrouenraets, MD, PhD (Sint Lucas Andreas Hospital, Amsterdam), B. J. M. van de Wall, MD, PhD (University Medical Center Utrecht, Utrecht), J. A. Wegdam, MD (Elkerliek Hospital, Helmond), E. Westerduin, MD (Tergooi Hospital, Hilversum), J. J. Wever, MD, PhD (Haga Hospital, Den Haag), N. A. T. Wijffels, MD, PhD (Zuwe Hofpoort Hospital, Woerden), B. P. L. Wijnhoven, MD, PhD (Erasmus Medical Center, Rotterdam), T. A. Winkel, MD (Erasmus Medical Center and Sophia Children’s Hospital, Rotterdam), D. C. van der Zee, MD, PhD (Wilhelmina Children’s Hospital–University Medical Center Utrecht, Utrecht), A. M. Zeillemaker, MD, PhD (Rijnland Hospital, Leiderdorp), and C. Zietse, MD (St Antonius Hospital, Nieuwegein).