TO:

Surgery Residents, Surgery Faculty at Altru, Sanford, & VA Medical Center and Medical students

FROM:

Geralyn Lunski, Conference Coordinator - 777-2589

DATE:

October 21, 2016

Meeting Information Date:

Tuesday, October 25, 2016

Time:

6:00 PM

Locations:

Sanford Clinic, Fargo, North Dakota and Altru Hospital, Grand Forks, North Dakota

Rooms:

Clinic B2, Sanford Health SurgSimLab, Altru Hospital

Topic:

Great Debates: Diverticulitis – Are Antibiotics Overrated?

Moderators: Patrick Kane, MD – Con Patrick Lamb, MD – Pro abx side ARTICLES: Attached.

Dinner will be provided by Merck

Systematic review

Use of antibiotics in uncomplicated diverticulitis ¨ u, N. de Korte, C. ¸ Unl ¨ M. A. Boermeester, M. A. Cuesta, B. C. Vrouenreats and H. B. A. C. Stockmann Department of Surgery, Kennemer Gasthuis, Postbus 417, 2000 AK Haarlem, The Netherlands Correspondence to: Dr N. de Korte (e-mail: [email protected])

Background: The value of antibiotics in the treatment of acute uncomplicated left-sided diverticulitis is not well established. The aim of this review was to assess whether or not antibiotics contribute to the (uneventful) recovery from acute uncomplicated left-sided diverticulitis, and which types of antibiotic and route of administration are most effective. Methods: Medline, the Cochrane Library and Embase databases were searched. Randomized controlled trials (RCTs), prospective or retrospective cohort studies addressing conservative treatment of mild uncomplicated left-sided diverticulitis and use of antibiotics were included. Results: No randomized or prospective studies were found on the topic of effect on outcome. One retrospective cohort study was retrieved that compared a group treated with antibiotics with observation alone. This study showed no difference in success rate between groups. Only one RCT of moderate quality compared intravenous and oral administration of antibiotics, and found no differences. One other RCT of very poor quality compared two different kinds of intravenous antibiotic and also found no difference. A small retrospective cohort study comparing antibiotics with and without anaerobe coverage showed no difference in group outcomes. Conclusion: Evidence on the use of antibiotics in mild or uncomplicated diverticulitis is sparse and of low quality. There is no evidence mandating the routine use of antibiotics in uncomplicated diverticulitis, although several guidelines recommend this.

Paper accepted 4 November 2010 Published online 6 January 2011 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.7376

Introduction

Diverticular disease is the most common disease of the colon, being found in one in three people over the age of 60 years in the Western world1 . The lifetime prevalence of diverticulitis is 10–25 per cent among patients with diverticular disease, and is increasing1,2 . Acute diverticulitis is usually graded as ‘complicated’ or ‘uncomplicated’ according to the classification of the European Association for Endoscopic Surgery3 , as ‘mild’ or ‘severe’ according to the Ambrosetti computed tomography (CT) criteria4 , or according to the modified Hinchey classification5 . As only 0–10 per cent of admitted patients present with complicated disease and require surgery or percutaneous drainage, conservative treatment is the management of choice in the majority of patients1 . The mainstay of treatment for uncomplicated diverticulitis has been bowel rest, intravenous fluids and antibiotics1 . Usually coverage against both Gram-negative  2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

and anaerobic bacteria is recommended1,6 – 9 . Contrary to complicated disease, the effect of treatment in uncomplicated disease has rarely been the subject of research. Recommendations are based on expert opinion and medical dogma. Surveys conducted among American, British and Dutch surgeons and gastroenterologists show that the choice of antibiotics and the route of administration differ. Most American and British surgeons use antibiotics for the treatment of uncomplicated diverticulitis, but the majority of surgeons and gastroenterologists in the Netherlands believe antibiotics are not mandatory in the treatment of uncomplicated diverticulitis10 – 12 . First, to assess the grounds for use of antibiotics in uncomplicated diverticulitis, guidelines issued by professional organizations worldwide were evaluated. The systematic review aimed to investigate the overall effect of antibiotics in the treatment of diverticulitis, the effect of administration route and the effect of different types of British Journal of Surgery 2011; 98: 761–767

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antibiotic in the treatment of acute mild (uncomplicated) diverticulitis of the sigmoid colon in adult patients. Methods

The latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting and reporting a systematic review or a metaanalysis were used13 .

Search strategy Two reviewers independently searched the following databases: MEDLINE (January 1966 to May 2010, search strategy: (‘Diverticulitis’[Mesh] OR ‘Diverticulitis, Colonic’[Mesh]) AND (‘Anti-Bacterial Agents’[Mesh] OR ‘Anti-Bacterial Agents’[Pharmacological Action])); Cochrane Database of Systematic Reviews, Cochrane Clinical Trials Register, Database of Abstracts on Reviews and Effectiveness (search strategy: Diverticulitis AND antibiotics); and Embase (January 1950 to May 2010, search strategy: (‘Diverticulitis’) AND (‘Anti-Bacterial Agents’)). After identifying relevant titles, all abstracts were read and eligible articles retrieved. A manual cross-reference search of the bibliographies of relevant articles was performed to identify other studies not found in the search. The ‘related articles’ function in PubMed was also used to identify articles not found in the original search. Clinical studies published in English, German or Dutch were included. No unpublished data or abstracts were included. The last search update was 1 June 2010.

study: characteristics of trial participants (including age, severity of disease, and method of diagnosis) and the trial’s inclusion criteria; type of intervention (antibiotics versus observation, different types of antibiotic, and route of antibiotic administration); and types of outcome measure.

Risk of bias in individual studies Two authors independently assessed the methodological quality and bias of the RCTs using the Jadad score14 and the checklist of the Cochrane Collaboration15 . Disagreement was resolved by consensus. For each study included, other forms of bias were evaluated on a case-by-case basis. This was done specifically for method of diagnosing diverticulitis.

Statistical analysis The effectiveness of a specific therapy compared with that of its control group for the primary outcome measure of success rate was expressed using odds ratios (ORs) with 95 per cent confidence intervals, and calculated from the original data, if not provided. An OR of less than 1 favours the intervention group over the control group. As none of the three research questions concerning antibiotic use in uncomplicated diverticulitis revealed more than one RCT, pooling of data was not possible or necessary. Data analysis was performed using Review Manager (RevMan) 5 (Cochrane Collaboration, Oxford, UK).

Inclusion and exclusion criteria

Results

Because of the paucity of data on the conservative treatment of diverticulitis of the sigmoid colon, the authors chose to include not only randomized controlled trials (RCTs) but all comparative studies addressing the conservative treatment of uncomplicated or mild diverticulitis of the sigmoid colon and the use of antibiotics. Participants included were patients aged 18 years or more diagnosed with acute uncomplicated or mild diverticulitis of the sigmoid colon. Studies that compared antibiotics versus observation alone, different types of antibiotic, or oral versus intravenous regimens were included. The primary outcome parameter was the success rate of the treatment.

Published guidelines and practice parameters

Data collection process Data were registered on preformatted sheets. The following information was extracted from each included  2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

Four guidelines were identified after searching MEDLINE. The Society for Surgery of the Alimentary Tract8 , the American Society of Colon and Rectal Surgeons7 , the European Association for Endoscopic Surgery3 and the American College of Gastroenterology6 have published guidelines concerning the treatment of mild diverticulitis of the sigmoid colon and the use of antibiotics. A further search using Google identified one other guideline by the World Gastroenterology Organisation16 . All guidelines recommend the use of antibiotics, but references to original research are lacking. For the recommendation on the type of antibiotic, in only two guidelines (the American Society of Colon and Rectal Surgeons and the American College of Gastroenterology) is there a reference to original research17 . All guidelines indicate that antibiotics should be given intravenously, but can be given orally in www.bjs.co.uk

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mild disease where outpatient treatment is being considered. Broad-spectrum antibiotics covering Gram-negative and anaerobic bacteria are recommended in all guidelines. No references to original research are given.

Retrieved references n = 549 PubMed n = 221 Embase n = 320 Cochrane n = 8 Atricles considered not relevant based on title n = 537

Systematic review The first search resulted in a combined total of 549 articles from all databases. After reviewing the abstracts only four articles were found specifically to address the use of antibiotics in colonic diverticulitis and met the inclusion criteria (Fig. 1). A summary of included studies is shown in Table 1. Individual study quality assessment is listed per methodological item in Table S1 (supporting information). Two RCTs were found. In addition, two studies were found that compared two cohorts of patients.

Studies retrieved for more detailed evaluation n = 12

Studies excluded n = 8 Compared conservative with operative management n = 4 Patients also had other abdominal infections n = 2 Review article n = 1 RCT comparing dfferent durations of antibiotic treatment n = 1

Potentially appropriate studies to be included in systematic review n=4

Antibiotics versus no antibiotics No RCTs were found. Only one study was retrieved in the search strategy. Hjern and colleagues18 performed a retrospective case–control study in a group of patients with diverticulitis treated without antibiotics and compared their outcome with that in a group of patients treated with antibiotics. The groups were comparable at baseline for age, sex and co-morbidity. Diagnosis was confirmed by means of CT. Disease severity was compared using laboratory parameters and the Ambrosetti CT classification4 . The group that received antibiotics had Table 1

Fig. 1

Search strategy. RCT, randomized controlled trial

significantly higher infection parameters and more severe diverticulitis on CT at baseline. The primary outcome measure was success rate, which was similar between antibiotic (115 of 118, 97·5 per cent)

Characteristics of included studies

Reference

Patient included

Group intervention

n

CT

Antibiotics

118

Observation alone

193

Adults with acute diverticulitis

Clinical grounds

Oral regimen

41

Intravenous regimen

38

UK

Adults with acute diverticulitis

Cefoxitin

30

Gentamicin– clindamycin

21

USA

Adults with acute diverticulitis

Combination of clinical grounds and radiology, pathology or surgical evidence of diverticular disease NS

Anaerobic coverage

15

No anaerobic coverage

52

Design

Interval

Country

Retrospective comparative cohort study

2000– 2002

Sweden

Adults with acute diverticulitis

Oral versus intravenous regimen 19

RCT

2002– 2004

UK

Different types of antibiotic 17

RCT

1992

Retrospective comparative cohort study

1974– 1978

Antibiotics versus observation alone 18

20

Studies included in systematic review n = 4

Method of diagnosis

Control

n

CT, computed tomography; RCT, randomized controlled trial; NS, not stated.

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and control (186 of 193, 96·4 per cent) groups. No ORs or confidence intervals were reported for the primary outcome, but could be calculated: the OR for success of treatment without antibiotics was 1·44 (0·37 to 5·69). Time to recovery also did not differ significantly between the groups. Hospital stay was significantly shorter in the control group than in the antibiotics group (3 versus 5 days respectively; P < 0·001). During follow-up 29 per cent of patients receiving antibiotics had further events (recurrent acute diverticulitis and/or subsequent surgery) compared with 28 per cent of those treated without antibiotics. In a multivariable analysis, the risk of a further event was not influenced by previous antibiotic treatment (OR 1·03, 0·61 to 1·74).

Different types of antibiotic Only one RCT was found that had examined this question. Kellum and co-workers17 conducted a randomized trial comparing cefoxitin and gentamicin–clindamycin in the treatment of acute uncomplicated diverticulitis. The primary outcome measure was success rate. No power calculation was reported. Diagnosis was based on clinical grounds and contrast enema or CT. The two patient groups were comparable with respect to baseline characteristics and clinical disease severity (fever, laboratory parameters and abdominal tenderness). No difference in success rate was found between patients treated with cefoxitin (27 of 30) versus gentamicin–clindamycin (18 of 21) (P = 0·48). No ORs or confidence intervals were reported, but could be calculated: the OR for success of gentamicin–clindamycin treatment was 1·50 (0·27 to 8·26). Quality assessment revealed a Jadad score of 0, indicating very poor quality. A retrospective study by Fink et al.20 evaluated two different intravenous antibiotic regimens with and without anaerobic coverage, defined as in vitro activity against Bacteroides fragilis. The primary outcome measure was success rate of treatment. The two groups were comparable with respect to baseline characteristics (age and sex). Fever, laboratory findings and abdominal tenderness were used to assess disease severity. How diverticulitis was diagnosed was not stated. The authors found no difference in success rate between the no anaerobic coverage group (34 of 52) and the anaerobic coverage group (10 of 15) (P > 0·050). No ORs or confidence intervals were reported for the primary outcome, but could be calculated: the OR for success of treatment with anaerobic coverage was 1·06 (0·31 to 3·57). The extremely small numbers of patients in this study, especially in the anaerobic group, hampered interpretation of the data.  2011 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

No pooling of data was possible for these two studies because of differences in design and the use of antibiotic cover.

Oral versus intravenous regimens Ridgeway and colleagues19 conducted a RCT comparing an oral antibiotic regimen (41 patients) with an intravenous regimen (38) of clindamycin and metronidazole in patients with uncomplicated diverticulitis. Diagnosis was based solely on clinical grounds. The two patient groups were comparable with respect to baseline characteristics and laboratory infection parameters. The primary outcome parameter was resolution of disease. Resolution of left iliac fossa tenderness (by Wexford tenderness score), length of stay and failures of oral therapy (requiring supplemental parenteral therapy) were used as surrogate markers for resolution of disease or success of treatment. There was no significant difference in Wexford tenderness score on day 3 between the oral treatment and the intravenous arm (score 1·26 versus 1·20 respectively; P = 0·79). Hospital stay did not differ between the two regimens (5·5 versus 6·6 days; P = 0·12). There was a 100 per cent success rate as neither group had any treatment failures; no OR calculation was possible for that reason. Quality assessment showed a Jadad score of 4, indicating moderate quality. Discussion

Diverticulitis of the sigmoid colon is one of the most common disorders of the gastrointestinal tract, with a huge healthcare burden. Nevertheless, evidence of the use of antibiotics in mild uncomplicated diverticulitis is sparse and of low quality. There is no evidence mandating the routine use of antibiotics in mild uncomplicated diverticulitis, although several guidelines recommend this. In the present systematic review four studies were identified, shedding some additional light on the use of antibiotics in uncomplicated left-sided diverticulitis. A recent retrospective case–control study18 found no advantage of antibiotics in patients with uncomplicated diverticulitis. There is some evidence from one RCT that treatment of uncomplicated diverticulitis with oral antibiotics alone was as effective as treatment with intravenous antibiotics, although verification of the diagnosis of diverticulitis was suboptimal in that study19 . High-quality evidence regarding the most effective type of antibiotic is lacking. It has long been believed that all forms of diverticulitis are the result of a colonic (micro)perforation. The original Hinchey classification was based on this premise21 . More www.bjs.co.uk

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recently a different or complementary pathogenesis of diverticulitis was proposed, in which diverticulitis is regarded as a form of inflammatory bowel disease22 . This concept of some form of chronic inflammation (not infection) of the colon in the presence of diverticula was substantiated recently in a study that showed inflammation in pathological specimens taken from around the mucosa of diverticula in asymptomatic individuals with no endoscopic evidence of inflammation23 . This chronic low-grade inflammation could be a precursor stage to the clinically manifest stages of diverticulitis. Recent success in preventing attacks of diverticulitis with probiotics and mezasaline contribute to this notion24,25 . Uncomplicated diverticulitis could be a self-limiting disease in which local host defences can eradicate bacterial invasion of a diverticulum without antibiotics in immunocompetent individuals. Antibiotics may, therefore, not be necessary in the treatment of uncomplicated disease. Potential benefits of a more liberal treatment strategy for acute diverticulitis without antibiotics include shorter duration of hospital admission (no intravenous medication needed), cost reduction, less development of antibiotic resistance and fewer side-effects. Antibiotic resistance, in particular, is becoming a serious and hard-to-combat healthcare threat. In this light the cohort study of Hjern et al.18 is interesting, with its conclusion that antibiotics may not be necessary in the majority of patients. The study was, however, retrospective and non-randomized, and affected by selection bias. No firm conclusions can be drawn, but this study does provide some evidence for the common practice in some European countries of not using antibiotics in the treatment of uncomplicated diverticulitis12,18 . Intra-abdominal infections have been studied extensively but recommendations on the use of antibiotics in diverticulitis are based largely on findings from studies that did not specifically investigate diverticulitis26 . Only one study tackled this subject for perforated diverticulitis and showed a similar microbiology in diverticulitis compared with that in other forms of intra-abdominal infection27 . The two studies17,20 found in this review were of very poor quality and added nothing to the existing narrative on antibiotic choice in intra-abdominal infections in general. The only randomized trial performed to compare oral and intravenous antibiotics in mild diverticulitis was underpowered19 , and the authors’ conclusion that treatment with oral antibiotics alone is as effective as treatment with intravenous antibiotics cannot be accepted without reservation. The results of this trial were, however, in line with recommendations from published

guidelines. Recent literature shows that patients with mild diverticulitis are increasingly being treated safely as outpatients with oral antibiotic regimens28 . In addition, a prospective randomized trial on complicated intraabdominal infections of all origins showed that a switch from intravenous to oral antibiotics was safe when oral intake was tolerated29 . One of the problems with the design of three of the four retrieved studies related to verification of the diagnosis of diverticulitis. Were the correct patients included in the studies? Diagnosis on clinical grounds alone leads to a high percentage of included patients not actually having diverticulitis30,31 . CT or ultrasonography should be the method of choice in identifying patients with diverticulitis32 . Two recent papers have stated that there may be a subset of patients who can be positively diagnosed without imaging based on a decision rule33,34 . However, this decision rule needs first to be externally validated. The treatment of mild uncomplicated left-sided diverticulitis lacks evidence. Future patients with mild diverticulitis could benefit from the results of prospective trials with sound criteria for diagnosis, with stratification of disease stage and adequate power, investigating one of the many unproven issues of diverticulitis treatment. The results of two RCTs (NCT01111253 and NCT01008488; http://www.clinicaltrials.gov) in the Netherlands and Sweden, randomizing patients with uncomplicated diverticulitis to antibiotics or observation alone, are not expected for several years. Until these results become available it is useful to note that current guidelines advising the use of antibiotics in uncomplicated diverticulitis are not evidencebased. In the majority of patients with mild diverticulitis, antibiotics can probably be omitted.

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Acknowledgements

The authors declare no conflict of interest.

References 1 Jacobs DO. Clinical practice. Diverticulitis. N Engl J Med 2007; 357: 2057–2066. 2 Etzioni DA, Mack TM, Beart RW, Kaiser AM. Diverticulitis in the United States: 1998–2005: changing patterns of disease and treatment. Ann Surg 2009; 249: 210–217. ¨ 3 Kohler L, Sauerland S, Neugebauer E. Diagnosis and treatment of diverticular disease: results of a consensus development conference. The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc 1999; 13: 430–436.

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4 Ambrosetti P, Grossholz M, Becker C, Terrier F, Morel P. Computed tomography in acute left colonic diverticulitis. Br J Surg 1997; 84: 532–534. 5 Wasvary H, Turfah F, Kadro O, Beauregard W. Same hospitalization resection for acute diverticulitis. Am Surg 1999; 65: 632–635. 6 Stollman NH, Raskin JB. Diagnosis and management of diverticular disease of the colon in adults. Ad Hoc Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999; 94: 3110–3121. 7 Rafferty J, Shellito P, Hyman NH, Buie WD; Standards Committee of American Society of Colon and Rectal Surgeons. Practice parameters for sigmoid diverticulitis. Dis Colon Rectum 2006; 49: 939–944. 8 Patient Care Committee of the Society for Surgery of the Alimentary Tract (SSAT). Surgical treatment of diverticulitis. J Gastrointest Surg 1999; 3: 212–213. 9 Kaiser AM, Jiang JK, Lake JP, Ault G, Artinyan A, Gonzalez-Ruiz C et al. The management of complicated diverticulitis and the role of computed tomography. Am J Gastroenterol 2005; 100: 910–917. 10 Schechter S, Mulvey J, Eisenstat TE. Management of uncomplicated acute diverticulitis: results of a survey. Dis Colon Rectum 1999; 42: 470–475. 11 Munikrishnan V, Helmy A, Elkhider H, Omer AA. Management of acute diverticulitis in the East Anglian region: results of a United Kingdom regional survey. Dis Colon Rectum 2006; 49: 1332–1340. 12 Van der Linde MJ, Wikkeling M, Driesen WM, Croiset van Uchelen FA, Roumen RM. Is er een rol voor antibiotica bij de conservatieve behandeling van acute diverticulitis coli? Ned Tijdschr Heelk 1996; 5: 194–197. 13 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6: e1000100. 14 Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ. Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 2008; 88: 156–175. 15 The Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions (formerly the Reviewers’ Handbook). http://www.cochrane.org/resources/handbook/ [accessed 1 June 2010]. 16 World Gastroenterology Organisation. http://www.worldgastroenterology.org [accessed 1 September 2009]. 17 Kellum JM, Sugerman HJ, Coppa GF, Way LR, Fine R, Herz B et al. Randomized, prospective comparison of cefoxitin and gentamicin–clindamycin in the treatment of acute colonic diverticulitis. Clin Ther 1992; 14: 376–384. ¨ B, 18 Hjern F, Josephson T, Altman D, Holmstrom Mellgren A, Pollack J et al. Conservative treatment of acute colonic diverticulitis: are antibiotics always mandatory? Scand J Gastroenterol 2007; 42: 41–47.

19 Ridgeway P, Latif A, Shabbir J, Ofriokuma F, Hurley MJ, Evoy D et al. Randomised controlled trial of oral versus intravenous therapy for clinically diagnosed acute uncomplicated diverticulitis. Colorectal Dis 2009; 11: 941–946. 20 Fink M, Smith LE, Rosenthal D. Antibiotic choice in the nonoperative management of acute diverticulitis coli. Am Surg 1981; 47: 201–203. 21 Hinchey EJ, Schaal PG, Richards GK. Treatment of perforated diverticular disease of the colon. Adv Surg 1978; 12: 85–109. 22 Floch MH. A hypothesis: is diverticulitis a type of inflammatory bowel disease? J Clin Gastroenterol 2006; 40 (Suppl 3): S121–S125. 23 Tursi A, Brandimarte G, Elisei W, Giorgetti GM, Inchingolo CD, Danese S et al. Assessment and grading of mucosal inflammation in colonic diverticular disease. J Clin Gastroenterol 2008; 42: 699–703. 24 White JA. Probiotics and their use in diverticulitis. J Clin Gastroenterol 2006; 40(Suppl 3): S160–S162. 25 Gatta L, Vakil N, Vaira D, Pilotto A, Curlo M, Comparato G et al. Efficacy of 5-ASA in the treatment of colonic diverticular disease. J Clin Gastroenterol 2010; 44: 113–119. 26 Mazuski JE, Sawyer RG, Nathens AB, DiPiro JT, Schein M, Kudsk KA et al.; Therapeutic Agents Committee of the Surgical Infections Society. The Surgical Infection Society guidelines on antimicrobial therapy for intra-abdominal infections: evidence for the recommendations. Surg Infect (Larchmt) 2002; 3: 175–233. 27 Brook I, Frazier EH. Aerobic and anaerobic microbiology in intra-abdominal infections associated with diverticulitis. J Med Microbiol 2000; 49: 827–830. 28 Malangoni MA, Song J, Herrington J, Choudhri S, Pertel P. Randomized controlled trial of moxifloxacin compared with piperacillin–tazobactam and amoxicillin–clavulanate for the treatment of complicated intra-abdominal infections. Ann Surg 2006; 244: 204–211. 29 Solomkin JS, Reinhart HH, Dellinger EP, Bohnen JM, Rotstein OD, Vogel SB et al. Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/ cilastatin for intra-abdominal infections. The IntraAbdominal Infection Study Group. Ann Surg 1996; 223: 303–315. 30 Lam´eris W, van Randen A, van Es HW, van Heesewijk JP, van Ramshorst B, Bouma WH et al.; OPTIMA study group. Imaging strategies for detection of urgent conditions in patients with acute abdominal pain: diagnostic accuracy study. BMJ 2009; 338: b2431. 31 Toorenvliet BR, Bakker RF, Breslau PJ, Merkus JW, Hamming JF. Colonic diverticulitis: a prospective analysis of diagnostic accuracy and clinical decision making. Colorectal Dis 2010; 12: 179–186. 32 Lam´eris W, van Randen A, Bipat S, Bossuyt PM, Boermeester MA, Stoker J. Graded compression

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ultrasonography and computed tomography in acute colonic diverticulitis: meta-analysis of test accuracy. Eur Radiol 2008; 18: 2498–2511. 33 Lam´eris W, van Randen A, van Gulik TM, Busch OR, Winkelhagen J, Bossuyt PM et al. A clinical decision rule to

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establish the diagnosis of acute diverticulitis at the emergency department. Dis Colon Rectum 2010; 53: 896–904. 34 Andeweg CS, Knobben L, Bleichrodt RP, van Goor H. How to diagnose acute colonic diverticulitis. Proposal for a clinical scoring system. Ann Surg (in press).

Supporting information

Additional supporting information may be found in the online version of this article: Table S1 Quality assessment (Word document) Please note: John Wiley & Sons Ltd is not responsible for the functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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British Journal of Surgery 2011; 98: 761–767

Randomized clinical trial

Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis A. Chabok1 , L. Pa˚ hlman2 , F. Hjern3 , S. Haapaniemi4 and K. Smedh1 , for the AVOD Study Group 1 ˚ 2 Colorectal Unit, Colorectal Unit, Department of Surgery, and Centre for Clinical Research Uppsala University, V¨astmanlands Hospital, V¨asteras, Department of Surgical Sciences, Uppsala University, Uppsala, 3 Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska ¨ Institute, Stockholm, and 4 Department of Surgery, Vrinnevi Hospital, Norrkoping, Sweden Correspondence to: Dr K. Smedh, Department of Surgery, Central Hospital, SE-72189 V¨aster˚as, Sweden (e-mail: [email protected])

Background: The standard of care for acute uncomplicated diverticulitis today is antibiotic treatment,

although there are no controlled studies supporting this management. The aim was to investigate the need for antibiotic treatment in acute uncomplicated diverticulitis, with the endpoint of recovery without complications after 12 months of follow-up. Methods: This multicentre randomized trial involving ten surgical departments in Sweden and one in Iceland recruited 623 patients with computed tomography-verified acute uncomplicated left-sided diverticulitis. Patients were randomized to treatment with (314 patients) or without (309 patients) antibiotics. Results: Age, sex, body mass index, co-morbidities, body temperature, white blood cell count and C-reactive protein level on admission were similar in the two groups. Complications such as perforation or abscess formation were found in six patients (1·9 per cent) who received no antibiotics and in three (1·0 per cent) who were treated with antibiotics (P = 0·302). The median hospital stay was 3 days in both groups. Recurrent diverticulitis necessitating readmission to hospital at the 1-year follow-up was similar in the two groups (16 per cent, P = 0·881). Conclusion: Antibiotic treatment for acute uncomplicated diverticulitis neither accelerates recovery nor prevents complications or recurrence. It should be reserved for the treatment of complicated diverticulitis. Registration number: NCT01008488 (http://www.clinicaltrials.gov). Presented to the Fifth Annual Meeting of the European Society of Coloproctology, Sorrento, Italy, September 2010; published in abstract form as Colorectal Dis 2011; 12(Suppl S3): 1 Paper accepted 20 December 2011 Published online 30 January 2012 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.8688

Introduction

Diverticulosis of the colon is an increasingly common, benign disorder in Western countries. It occurs in about one-third of the population older than 45 years and in up to two-thirds of the population aged above 85 years1 . Diverticulitis is defined as inflammation or infection in a diverticula-bearing colonic segment. Although a majority of individuals with diverticulosis remain asymptomatic, 10–25 per cent will develop diverticulitis during their lifetime2 . Uncomplicated diverticulitis presents most frequently with abdominal pain, fever and raised inflammatory parameters, and more than 70 per cent of patients are treated conservatively3,4 . Uncomplicated  2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

diverticulitis is a costly disease with an increasing incidence and a decreasing age at acute admission4 – 6 . Antibiotics have been used in the treatment of uncomplicated diverticulitis since their introduction, as the condition has been suggested to be caused by bacterial infection. Despite the lack of controlled studies and previously demonstrated disease resolution without antibiotic treatment7,8 , treatment with antibiotics has become the standard of care for uncomplicated diverticulitis. Some authors, however, have suggested that diverticulitis could be a form of inflammatory bowel disease and not the result of microperforation9,10 , questioning the rationale behind prescribing antibiotics for the treatment of uncomplicated diverticulitis. British Journal of Surgery 2012; 99: 532–539

Use of antibiotics in acute uncomplicated diverticulitis

It is widely believed that the unnecessary use of antimicrobials is a major cause of the widespread emergence of resistant organisms, which is beginning to threaten the continued effectiveness of antibiotics. Although resistance to antibiotics is a natural phenomenon, it has been aggravated by their overuse11 . The aim of the present study was to evaluate whether antibiotic treatment for acute uncomplicated left-sided diverticulitis is necessary for recovery without complications after a 12-month follow-up interval. Methods

Study design The AVOD (Antibiotika Vid Okomplicerad Divertikulit – Swedish for ‘antibiotics in uncomplicated diverticulitis’) study was conducted as an open multicentre randomized controlled trial that ran between October 2003 and January 2010 with the participation of ten surgical departments in Sweden and one in Iceland. Patients aged over 18 years with acute uncomplicated left-sided diverticulitis were eligible. Inclusion and exclusion criteria are shown in Table 1. Uncomplicated diverticulitis was defined as an episode with a short history and with clinical signs of diverticulitis, without sepsis, with an increased body temperature and inflammatory parameters, verified by computed tomography (CT), and without any sign of complications such as abscess, free air or fistula. Patients with clinical signs of acute diverticulitis and a body temperature of 38° C or more either at or within 12 h before admission were evaluated by clinical examination, blood tests, and CT of the abdomen and pelvis. CT scans Table 1

533

were assessed by the radiologist on duty at each centre. An immediate preliminary report was given and later checked by a senior staff radiologist. After confirmation of the diagnosis of uncomplicated diverticulitis by CT12 and screening for eligibility, informed consent was obtained. Randomization in blocks of four and stratified by centre was performed by opening a sealed envelope, distributed by the Centre for Clinical Research in V¨astera˚ s. The sizes of the blocks were unknown to the participating units. At each centre, a local investigator was responsible for recruiting patients to the trial and controlling the randomization process. A case record form (CRF) was completed for each patient, including demographic data, medical history, previous symptoms of diverticulitis, physical examination and laboratory results, and abnormalities seen on CT. Pain was recorded on a visual analogue scale (VAS, 0–10 cm) and abdominal tenderness at palpation on a scale of 0–4 (Table 2). To clarify the selection of the cohort, all eligible patients who were not included in the study were to be registered, stating the reasons for not participating according to the Consolidated Standards for Reporting Trials (CONSORT) statement13 . The study was commenced at two centres (V¨astera˚ s and Uppsala) in October 2003 and at the other nine centres between 2004 and 2006. According to the expected inclusion rate, the study was estimated to end in January 2009. The study was approved by the ethics committee of the Faculty of Medicine, Uppsala University, and followed the Declaration of Helsinki guidelines.

Table 2

Demographic data and patient characteristics No antibiotics (n = 309)

Study inclusion and exclusion criteria

Inclusion criteria Adult patient aged over 18 years Acute lower abdominal pain with tenderness Body temperature ≥ 38° C at admission or during the last 12 h before admission Raised WBC and C-reactive protein level, or at least increased WBC if short history Signs of diverticulitis on CT Informed consent Exclusion criteria Signs of complicated diverticulitis on CT with abscess, fistula or free air in abdomen or pelvis Signs of other diagnosis on CT Receiving immunosuppressive therapy Pregnancy Ongoing antibiotic therapy High fever, affected general condition, peritonitis or sepsis

WBC, white blood cell count; CT, computed tomography.

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Antibiotics (n = 314)

Age (years) 57·1(13·2) 57·4(12·8) Sex ratio (M : F) 110 : 199 110 : 204 Co-morbidity*‡ 91 (29·4) 92 of 312 (29·5) Previous diverticulitis* 137 of 306 (44·8) 110 of 309 (35·6) Body mass index (kg/m2 ) 28·2(4·4) 27·9(4·4) 12·3(3·3) 12·6(3·1) WBC (× 109 cells/l) CRP (mg/l) 91(61) 100(62) Body temperature (° C) 38·1(0·6) 38·1(0·6) Abdominal pain† 6 (4–8) 6 (5–8) Tenderness score§ 3 (2–3) 3 (2–3)

P¶ 0·853 0·882# 0·992# 0·020# 0·437 0·276 0·070 0·350 0·503** 0·950**

Values are mean(s.d.) unless indicated otherwise; *values in parentheses are percentages. †Median (interquartile range, i.q.r.) visual analogue scale (VAS, 1–10) score; §median (i.q.r.) tenderness score: 0, none; 1, mild local tenderness; 2, moderate local tenderness; 3, severe local tenderness; 4, local peritonitis. ‡Includes cardiovascular disease, pulmonary disease, renal failure and diabetes mellitus. WBC, white blood cell count; CRP, C-reactive protein. ¶Student’s t test, except #Pearson’s χ2 test and **Mann–Whitney U test.

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Study procedure Eligible patients were randomized to treatment with intravenous fluids only (no-antibiotics group) or in combination with antibiotic therapy (antibiotics group). Broad-spectrum antibiotics were used according to the participating centres’ routines, covering Gram-negative and anaerobic bacteria. Treatment was initiated with an intravenous combination of a second- or thirdgeneration cephalosporin (cefuroxime or cefotaxime) and metronidazole, or with carbapenem antibiotics (ertapenem, meropenem or imipenem) or piperacillin–tazobactam. Orally administrated antibiotics such as ciprofloxacin or cefadroxil combined with metronidazole were initiated subsequently on the ward or at discharge. The total duration of antibiotic therapy was at least 7 days. The decision to discharge patients was made by the attending surgeon based on an improvement in clinical status as well as a reduction in the white blood cell count (WBC) and C-reactive protein (CRP) level, and the absence of fever. These signs were taken as surrogates for recovery and reflected the pragmatic design of the study. Complications during hospital stay were defined as bowel perforation with free air, abscess or fistula. Complications during follow-up were admission to hospital owing to recurrence and need for emergency or elective surgery.

A. Chabok, L. P˚ahlman, F. Hjern, S. Haapaniemi and K. Smedh

The results were analysed on an intention-to-treat and per-protocol basis. Pearson’s χ2 test was used for discrete variables. The study arms were compared using an independent-samples t test for continuous variables with normal distribution. The Mann–Whitney U test was used for ordinal data or for data without normal distribution. A multivariable binary logistic model was performed to analyse relationships between the different variables and the occurrence of complications and recurrence. In the primary analysis, short-term results regarding the occurrence of complications, need for surgery, hospital stay, abdominal pain, fever and abdominal tenderness were analysed. In the follow-up analysis, recurrence, need for surgery, changes in bowel habit, abdominal pain and results of colorectal examinations were analysed. Statistical significance was set at P < 0·050, two-sided tests. All data analysis was performed using the SPSS software package version 17.0 (SPSS, Chicago, Illinois, USA). Results

At 6–8 weeks after discharge, patients had a colonic investigation by colonoscopy, barium enema or CT colonography if none of these had been done within 1 year before admission. The results of the investigations were registered and the extent of diverticular disease noted. After a minimum of 12 months, patients were contacted by telephone or letter to complete a questionnaire regarding abdominal pain, bowel symptoms or recurrence demanding readmission to hospital. If no answer was received after three reminders, the patient was registered as a dropout from follow-up.

In total, 669 patients were randomized, of whom 46 were excluded. Seven patients interrupted participation and one patient was excluded because of protocol violation. Thirty-eight patients did not meet the inclusion criteria: 13 had a diagnosis other than diverticulitis, eight were randomized despite previous inclusion in the study, seven had insufficient inclusion criteria (no fever, no inflammatory parameters), and five had other reasons for exclusion (linguistic problems, unclear CT reports and cardiac disease). Five patients were excluded on the day after randomization because of important changes between the preliminary and the definitive CT report, which showed complications of diverticulitis such as abscess formation or free air (Fig. 1). Some 623 patients (403 women) with CTverified acute uncomplicated diverticulitis were enrolled in the study: 309 patients in the no-antibiotics and 314 in the antibiotics group (Table 3). The median age was 58 (range 23–88) years and median body mass index (BMI) 27·7 (range 18·4–44·1) kg/m2 .

Statistical analysis

Clinical characteristics

Sample size was calculated from an estimated complication rate with antibiotic therapy of 1·5 per cent. An increase in the complication rate in the no-antibiotics group to a maximum of 6·5 per cent was regarded as acceptable. With α = 0·05 and a power of 80 per cent, each group should consist of 240 patients; with an estimated dropout rate of 20 per cent, the necessary sample size was calculated to be 600 patients.

At the time of admission (all patients had a history of acute abdominal pain and fever), the groups presented with similar symptoms. Some 599 (96·6 per cent) of 620 patients had left lower abdominal pain. Fever (body temperature of 38° C or above) was noted in 557 (89·8 per cent) of 620 patients; 212 (34·2 per cent) of 619 patients reported a change in stool habit with constipation or loose stools; and 49 (7·9 per cent) of 619 had urinary tract symptoms such as

 2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

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Follow-up

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535

Enrolment

Randomized n = 669

Allocated to no antibiotic therapy n = 334

Allocated to antibiotic therapy n = 335 Excluded n = 21 Did not meet inclusion criteria n = 18 Interrupted participation n = 3 Protocol violation n = 0

Received allocated intervention n = 299 Did not receive allocated intervention n = 10

Received allocated intervention n = 311 Did not receive allocated intervention n = 3

Lost to follow-up n = 19

Lost to follow-up n = 22

Primary analysis after 30 days n = 309 Excluded from primary analysis n = 0 Follow-up analysis n = 290

Primary analysis after 30 days n = 314 Excluded from primary analysis n = 0 Follow-up analysis n = 292

Analysis

Follow-up

Allocation

Excluded n = 25 Did not meet inclusion criteria n = 20 Interrupted participation n = 4 Protocol violation n = 1

Fig. 1

CONSORT diagram for the trial

Table 3

Numbers of patients per hospital No antibiotics

Antibiotics

Total

¨ Vaster˚ as Danderyd ¨ Norrkoping Uppsala Reykjavik Sunderby ¨ Linkoping Hudiksvall Mora ¨ Gavle ¨ Orebro

98 (31·7) 50 (16·2) 37 (12·0) 33 (10·7) 22 (7·1) 17 (5·5) 17 (5·5) 15 (4·9) 10 (3·2) 5 (1·6) 5 (1·6)

98 (31·2) 52 (16·6) 37 (11·8) 29 (9·2) 21 (6·7) 24 (7·6) 16 (5·1) 15 (4·8) 9 (2·9) 7 (2·2) 6 (1·9)

196 (31·4) 102 (16·4) 74 (11·9) 62 (10·0) 43 (6·9) 41 (6·6) 33 (5·3) 30 (4·8) 19 (3·0) 12 (1·9) 11 (1·8)

Total

309 (100)

314 (100)

623 (100)

Hospital

Values in parentheses are percentages.

frequent micturition. There were no differences between the two groups with regard to these parameters. Clinical details are listed in Table 2. The two groups were equally balanced regarding age, sex, BMI, co-morbidity and inflammatory parameters such as WBC, CRP level and body temperature. A history of previous diverticulitis was more frequent in the no-antibiotics group (P = 0·020).  2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

Clinical bedside signs, such as pain measured by VAS and tenderness on abdominal palpation at admission, did not differ between the groups. Abdominal pain, body temperature and abdominal tenderness on palpation decreased rapidly in both groups during the hospital stay (Fig. 2). Differences from baseline (the time of admission) for every patient were calculated for VAS, body temperature and tenderness score for each day in hospital. There were no differences between the groups for VAS (P = 0·253–0·886). Normalization of body temperature after 2 days was similar in the two groups (P = 0·343). For the tenderness score, there was a statistically significant difference on the second day (P = 0·041), with a mean difference from baseline of 0·8 for the no-antibiotics and 1·0 for the antibiotics group. The median hospital stay for both groups was 3 (range 0–25) days.

Primary analysis: complications and emergency surgery during hospital stay Nine patients (1·4 per cent) suffered from complications, six with sigmoid perforation and three with abscess formation. In the no-antibiotics group, three had www.bjs.co.uk

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2

3

4

4

38·5

No antibiotics Antibiotics

Tenderness score

10 9 8 7 6 5 4 3 2 1 0 Baseline 1

Temperature (°C)

VAS score

536

38·0 37·5 37·0 36·5 36·0 Baseline 1

5

Time after admission (days)

a

3

4

1

1

2

3

4

5

Time after admission (days)

c

Temperature

2

0 Baseline

5

Time after admission (days)

b

Abdominal pain

2

3

Abdominal tenderness

Clinical bedside signs after admission for acute uncomplicated diverticulitis: a mean abdominal pain according to the visual analogue scale (VAS) score (0–10); b mean body temperature; c mean abdominal tenderness score at palpation (0–4)

Fig. 2

perforations and three developed abscesses. In the antibiotics group, three patients had perforations. One patient with a perforation in the no-antibiotics group underwent emergency sigmoid resection but the other five patients with complications were treated without surgery, by means of antibiotics and percutaneous drainage when appropriate. In the antibiotic treatment group, all three patients with perforations underwent emergency sigmoid resection. There were no differences between the groups regarding complications or surgical procedures during the hospital stay (Table 4). Ten patients (3·2 per cent) allocated to no antibiotics were started on antibiotic treatment because of increasing CRP level, fever or abdominal pain. No complications occurred during the hospital stay in these patients. In the antibiotics group, three patients (1·0 per cent) terminated antibiotic therapy because of allergic side-effects (Fig. 1). In a logistic regression model adjusting for age, sex, temperature, WBC, CRP, BMI, previous diverticulitis, number of previous episodes of diverticulitis, abdominal pain, abdominal tenderness score, co-morbidity and antibiotic treatment, there was no significant relationship with complications (data not shown). Complications, surgery, hospital stay and recurrent diverticulitis

Table 4

Complications Sigmoid perforation Abscess Sigmoid resections During hospital stay During follow-up Hospital stay (days)* Recurrent diverticulitis

No antibiotics (n = 309)

Antibiotics (n = 314)

P†

6 (1·9) 3 (1·0) 3 (1·0) 7 (2·3) 1 (0·3) 6 (1·9) 2·9(1·6) 47 of 290 (16·2)

3 (1·0) 3 (1·0) 0 (0) 5 (1·6) 3 (1·0) 2 (0·6) 2·9(1·9) 46 of 292 (15·8)

0·302 0·985 0·080 0·541 0·324 0·148 0·717‡ 0·881

Values in parentheses are percentages, unless indicated otherwise; *values are mean(s.d.). †Pearson’s χ2 test, except ‡Student’s t test.

 2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

Follow-up analysis In the no-antibiotics group, six patients were operated on during follow-up because of symptomatic diverticular disease, stricture, fistula, recurrent diverticulitis, recurrent diverticulitis with abscess formation, and colonic perforation that occurred during preparation for colonic examination (1 patient each). In the antibiotic treatment group, two patients had surgery for stricture during followup. There was no difference between the groups regarding surgery during follow-up (Table 4). Of the ten patients who crossed over from the no-antibiotics to the antibiotics arm, none had complications during follow-up although one patient was operated on for symptomatic diverticular disease. Of the 623 patients, 41 were lost to follow-up. Recurrent diverticulitis occurred in 93 (16·0 per cent) of the remaining 582 patients during follow-up, with no significant difference between the two groups (Table 4). In a logistic regression model, adjusting for age, sex, temperature, WBC, CRP, BMI, previous diverticulitis, number of previous episodes of diverticulitis, abdominal pain, abdominal tenderness score, co-morbidity and antibiotic treatment, there was a significant relationship between previous diverticulitis and recurrence (odds ratio 2·78, 95 per cent confidence interval 1·76 to 4·41; P = 0·009). Previous diverticulitis explained 5·8 per cent of the variation in recurrence outcome (Nagelkerke R2 ). No other variable was related to recurrence. At the 1-year follow-up, symptoms of abdominal pain and changes in bowel habit did not differ between the groups (Fig. 3a,b). Colonic investigations were performed in 545 patients by colonoscopy, barium enema or CT colonography. There was no significant difference between the groups with respect to the findings or extent of diverticulosis (Fig. 3c). One patient in the antibiotics group died 9 months after discharge from metastatic gastric cancer. No patient had colorectal malignancy or Crohn’s disease in the colon. www.bjs.co.uk

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537

60

% of patients

No antibiotics Antibiotics 40

20

0

a

No pain

Mild periodic pain

Moderate periodic pain

Severe periodic pain

Chronic pain

Abdominal pain

In selected groups of patients with more severe symptoms and higher inflammatory parameters (CRP level greater than 150 mg/l, WBC 15 × 109 cells/l or above, temperature higher than 38·5° C, abdominal pain score of 8 or more, and tenderness score of 3 or above) there were no significant differences between the groups regarding complications or diverticulitis recurrence (P = 0·087–0·978). When surgery during follow-up was added to the inhospital complications, there was no significant difference between the two groups (P = 0·121). When all events including recurrences were analysed, there was still no difference (P = 0·463).

80

Discussion

% of patients

60

40

20

0

b

No change

Loose stool

Hard stool

Altemate loose and hard stool

Bowel habit

% of patients

60

40

20

0

0

1–5

6–15

> 15

Lumen narrowing

No. of diverticula

c

Colonic findings

a Abdominal pain at 1-year follow-up. b Change in bowel habit at 1-year follow-up. c Results of colonic investigations. a P = 0·959, b P = 0·275, c P = 0·247 (Mann–Whitney U test)

Fig. 3

Subgroup analysis Per-protocol analysis, including the ten patients in the no-antibiotics group who received antibiotics, showed no differences between the groups regarding complications, operations, recurrences or hospital stay (P = 0·071–0·982).  2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

This large multicentre randomized clinical trial of patients with CT-verified acute uncomplicated left-sided diverticulitis demonstrated a low overall complication rate with perforation and abscess formation (1·4 per cent), with no significant differences between patients treated, or not treated with antibiotics. Moreover, no differences were found between the groups with regard to frequency of surgery, length of hospital stay, recurrence of diverticulitis, abdominal pain, or changes in bowel habit after 12 months of follow-up. From these results it may be postulated that antibiotic treatment of acute uncomplicated diverticulitis does not prevent complications, accelerate recovery or prevent recurrence. According to current guidelines, bowel rest or intake of oral fluids and a 7–10-day regimen of broadspectrum antibiotics is recommended in patients with uncomplicated diverticulitis14,15 . This treatment strategy has been reported to be successful in 85–100 per cent of patients16,17 . The recommendations of antibiotic therapy are based on tradition and expert opinions, and not on evidence derived from controlled trials. There are some prospective studies regarding choice and duration of antibiotic therapy, but none challenging the use of antibiotics in this condition8 . The only two studies evaluating the need for antibiotics in uncomplicated diverticulitis have been retrospective audits, with all the inherent limitations of such a design, that did not show any benefit of antibiotics18,19 . There is an escalating problem with antibiotic resistance among bowel pathogens20,21 . As antimicrobial use generally precedes the emergence of resistance, preventing the spread of resistant pathogens clearly requires optimal use of antibiotics. During the past decade, the prescription of antibiotics for children has been reduced by approximately 50 per cent in Sweden for certain diagnoses22 . A similar www.bjs.co.uk

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policy with strict indications for antibiotic use might be adopted for uncomplicated diverticulitis. Apart from allergic reactions, we did not register any antibiotic side-effects such as antibiotic-associated abdominal pain, nausea, or diarrhoea with or without a Clostridium difficile infection. The possible development of such symptoms provides another important reason for reducing the frequent use of antibiotics in these patients. Eleven departments participated in this study with different inclusion rates, which may raise the question of selection bias. However, both study groups were similar with regard to important clinical symptoms, fever, inflammatory parameters, grade of abdominal pain and tenderness score, co-morbidity, age, sex and BMI. The only variable that differed was previous episodes of diverticulitis, which were less frequent in the antibiotic treatment group. Some studies have reported that perforation is most frequent during the first attack23 – 25 , which would give patients in the no-antibiotics group a possible advantage in this respect. However, these patients would have been excluded by the CT findings. As the study was randomized, this difference can be regarded as a chance finding. Moreover, the results from logistic regression models adjusting for eventual episodes of previous diverticulitis did not detect any relationship with complications. It could be argued that some centres included sicker patients than others, but owing to the block randomization and stratification by centre this should not have affected the results. In terms of symptoms and laboratory parameters, this cohort of patients was comparable to those of other studies that, in different ways, have evaluated antibiotic therapy in uncomplicated diverticulitis17,26 . Moreover, there were no differences between the groups regarding complications or recurrence of diverticulitis in patients with more severe symptoms and higher values for inflammatory parameters. An important limitation of the study was the failure to register all eligible patients at participating centres in order to clarify the cohort selection. The most significant reason for this was the large number of clinicians per centre involved in the study, where patients were enrolled in the emergency department or on the surgical ward after CT had been performed. Studies on patients with an emergency condition commonly encounter problems in registering all patients and completing the CRFs. A further criticism could be that the study was not blinded, although this might prove to be a strength owing to the lack of a placebo effect in patients in the no-antibiotics group. The study was designed as a superiority study in order to evaluate the necessity for antibiotics for recovery without complications from acute uncomplicated diverticulitis.  2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

A. Chabok, L. P˚ahlman, F. Hjern, S. Haapaniemi and K. Smedh

The results indicate that antibiotics do not prevent complications. However, the observed complication rate was 1 per cent in the antibiotics group, but almost 2 per cent in the no-antibiotics group. To show a possible significant difference between the groups with a power of 80 per cent, a trial would need to include at least 5500 patients. The logistics needed to include such a large number of patients might prove impossible, and perhaps be clinically irrelevant. A non-inferiority designed study with a lower significance level, however, would require many more patients. An interesting finding in this study was the low frequency of elective surgery in patients who had an attack of uncomplicated diverticulitis. This situation reflects the Swedish policy of recommending surgery only for complicated diverticulitis. The study indicates that patients with CT-proven uncomplicated diverticulitis have a very low risk (1·4 per cent) of developing severe complications such as perforations or abscesses. The question is whether or not hospital admission is necessary, and whether patients in that case could return home without antibiotics. The authors will investigate this in their next study. This study evaluated the need for antibiotic treatment in acute uncomplicated diverticulitis. It showed that antibiotic therapy does not prevent surgical complications or recurrence, and does not shorten hospital stay. Antibiotics should be reserved mainly for patients with complicated diverticulitis. Acknowledgements

The authors wish particularly to thank Eva Strand, Centre for Clinical Research, Central Hospital, V¨astera˚ s, for her dedicated and skilful assistance and support with data collection and running the study. They also thank L. Bergkvist and K. Nilsson, Centre for Clinical Research, Central Hospital, V¨astera˚ s, for statistical support. Financial support for the study was provided by the ¨ Uppsala and Orebro Regional Research Foundation. The Foundation had no involvement in the design and conduct of the study, data analysis or publication. Disclosure: The authors declare no other conflict of interest. Collaborators

The AVOD study group consists of A. Chabok, K. Smedh, E. Strand (V¨astera˚ s Central Hospital), L. Pa˚ hlman (Uppsala University Hospital), F. Hjern (Danderyd University Hospital), S. Haapaniemi (Vrinnevi Hospital ¨ Norrkoping), T. Stefansson (National University Hospital, www.bjs.co.uk

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Reykjavik, Iceland), M. Sund´en (Sunderbys Hospital), ¨ P. Myrelid (Linkoping University Hospital), U. Ersson (Huddiksvall Hospital), H. Laurell (Mora Hospital), G. ¨ Liljegren (University Hospital Orebro) and A. Faraj (G¨avle Central Hospital). References 1 Roberts P, Abel M, Rosen L, Cirocco W, Fleshman J, Leff E et al. Practice parameters for sigmoid diverticulitis. The Standards Task Force American Society of Colon and Rectal Surgeons. Dis Colon Rectum 1995; 38: 125–132. 2 Parks TG, Connell AM. The outcome in 455 patients admitted for treatment of diverticular disease of the colon. Br J Surg 1970; 57: 775–778. 3 Haglund U, Hellberg R, Johns´en C, Hult´en L. Complicated diverticular disease of the sigmoid colon. An analysis of short and long term outcome in 392 patients. Ann Chir Gynaecol 1979; 68: 41–46. 4 Kang JY, Hoare J, Tinto A, Subramanian S, Ellis C, Majeed A et al. Diverticular disease of the colon – on the rise: a study of hospital admissions in England between 1989/1990 and 1999/2000. Aliment Pharmacol Ther 2003; 17: 1189–1195. 5 Etzioni DA, Mack TM, Beart RW Jr, Kaiser AM. Diverticulitis in the United States: 1998–2005: changing patterns of disease and treatment. Ann Surg 2009; 249: 210–217. 6 Papagrigoriadis S, Debrah S, Koreli A, Husain A. Impact of diverticular disease on hospital costs and activity. Colorectal Dis 2004; 6: 81–84. 7 Rankin F. Diverticulitis of the colon. Surg Gynecol Obstet 1930; 50: 836–847. 8 de Korte N, Unlu¨ C, Boermeester MA, Cuesta MA, Vrouenreats BC, Stockmann HB. Use of antibiotics in uncomplicated diverticulitis. Br J Surg 2011; 98: 761–767. 9 Tursi A, Brandimarte G, Giorgetti G, Elisei W, Maiorano M, Aiello F. The clinical picture of uncomplicated versus complicated diverticulitis of the colon. Dig Dis Sci 2008; 53: 2474–2479. 10 Floch MH. A hypothesis: is diverticulitis a type of inflammatory bowel disease? J Clin Gastroenterol 2006; 40(Suppl 3): S121–S125. 11 European Centre for Disease Prevention and Control. European Antimicrobial Resistance Surveillance Network (EARS-Net). http://ecdc.europa.eu/en/activities/surveillance/ EARS-Net/publications/Pages/documents.aspx [accessed 20 November 2011]. 12 Ambrosetti P, Grossholz M, Becker C, Terrier F, Morel P. Computed tomography in acute left colonic diverticulitis. Br J Surg 1997; 84: 532–534.

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13 CONSORT. http://www.consort-statement.org/consortstatement/flow-diagram0/ [accessed 20 November 2011]. 14 American Society of Colon and Rectal Surgeons. http://www.fascrs.org/physicians/education/core_ subjects/2005/diverticultis/ [accessed 20 November 2011]. 15 National Health Service (NHS). http://www.nhs.uk/ Conditions/Diverticular-disease-and-diverticulitis/ Pages/Treatment.aspx [accessed 20 November 2011]. 16 Kellum JM, Sugerman HJ, Coppa GF, Way LR, Fine R, Herz B et al. Randomized, prospective comparison of cefoxitin and gentamicin-clindamycin in the treatment of acute colonic diverticulitis. Clin Ther 1992; 14: 376–384. 17 Ridgway PF, Latif A, Shabbir J, Ofriokuma F, Hurley MJ, Evoy D et al. Randomized controlled trial of oral vs intravenous therapy for the clinically diagnosed acute uncomplicated diverticulitis. Colorectal Dis 2009; 11: 941–946. 18 Hjern F, Josephson T, Altman D, Holmstrom B, Mellgren A, Pollack J et al. Conservative treatment of acute colonic diverticulitis: are antibiotics always mandatory? Scand J Gastroenterol 2007; 42: 41–47. 19 de Korte N, Kuyvenhoven JP, van der Peet DL, Felt-Bersma RJ, Cuesta MA, Stockmann HB. Mild colonic diverticulitis can be treated without antibiotics. A case-controlled study. Colorectal Dis 2011; [Epub ahead of print]. 20 World Health Organization (WHO). http://www.who.int/ topics/drug_resistance/en/ [accessed 20 November 2011]. 21 Chabok A, Tarnberg M, Smedh K, Pahlman L, Nilsson LE, Lindberg C et al. Prevalence of fecal carriage of antibiotic-resistant bacteria in patients with acute surgical abdominal infections. Scand J Gastroenterol 2010; 45: 1203–1210. 22 Strama. SWEDRES 2005: a report on Swedish antibiotic utilisation and resistance in human medicine. http://www.strama.se/dyn/,119,44,20.html?q=swedres+ 2005&x=36&y=13 [accessed 20 November 2011]. 23 Chapman J, Davies M, Wolff B, Dozois E, Tessier D, Harrington J et al. Complicated diverticulitis: is it time to rethink the rules? Ann Surg 2005; 242: 576–581. 24 Lorimer JW. Is prophylactic resection valid as an indication for elective surgery in diverticular disease? Can J Surg 1997; 40: 445–448. 25 Somasekar K, Foster ME, Haray PN. The natural history diverticular disease: is there a role for elective colectomy? J R Coll Surg Edinb 2002; 47: 481–482, 484. 26 Mizuki A, Nagata H, Tatemichi M, Kaneda S, Tsukada N, Ishii H et al. The out-patient management of patients with acute mild-to-moderate colonic diverticulitis. Aliment Pharmacol Ther 2005; 21: 889–897.

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T. W. Eglinton

Commentary

Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis (Br J Surg 2012; 99: 532–539) The incidence of diverticular disease and its associated complications has increased in recent years, placing a significant burden on the healthcare system. Over the past decade, there have been a number of challenges to the traditional management of diverticulitis, all with the potential to mitigate against this increased burden on health resources. Laparoscopic lavage, as opposed to resection, has been used successfully in selected patients1 . The role of elective surgical resection after acute diverticulitis has been revised in light of data suggesting a low risk of subsequent recurrence and complications2 . Most recently, the need for routine colonoscopy after computed tomography-proven uncomplicated diverticulitis has been questioned3 . In this paper, Chabok and colleagues have challenged another long-held principle of the management of diverticular disease: the use of antibiotics in acute diverticulitis. In a well designed multicentre randomized clinical trial, these investigators showed that antibiotics in acute uncomplicated diverticulitis did not shorten hospital stay, prevent complications or reduce recurrence. The aetiology of inflammation in acute diverticulitis remains unclear. The lack of effect of antibiotics demonstrated here suggests that the emerging theory that diverticulitis is, in fact, a type of inflammatory bowel disease deserves further consideration. In addition to the role of antibiotics, studies investigating the efficacy of anti-inflammatory agents are warranted. Does this study represent another successful assault on the traditional management of diverticulitis, and should we omit antibiotics as a result? Caution should be exercised in generalizing these results to all patients with acute uncomplicated diverticulitis. Patients with ‘sepsis’ were excluded from the study, and no definition of ‘sepsis’ was provided. The lack of documentation of excluded patients, large differences in recruitment across participating centres and the very low rate of complications in both arms all point to a selection bias towards mild uncomplicated diverticulitis. Further trials that define more clearly the severity of diverticulitis, and thus better inform from which patients antibiotics could safely be withheld, would be reassuring before altering practice parameters. T. W. Eglinton Department of Surgery, University of Otago, Christchurch 8140, New Zealand (e-mail: [email protected]) DOI: 10.1002/bjs.8687

Disclosure

The author declares no conflict of interest. References 1 Myers E, Hurley M, O’Sullivan GC, Kavanagh D, Wilson I, Winter DC. Laparoscopic peritoneal lavage for generalized peritonitis due to perforated diverticulitis. Br J Surg 2008; 95: 97–101. 2 Eglinton T, Nguyen T, Raniga S, Dixon L, Dobbs B, Frizelle FA. Patterns of recurrence in patients with acute diverticulitis. Br J Surg 2010; 97: 952–957. 3 Westwood DA, Eglinton TW, Frizelle FA. Routine colonoscopy following acute uncomplicated diverticulitis. Br J Surg 2011; 98: 1630–1634.

 2012 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

www.bjs.co.uk

British Journal of Surgery 2012; 99: 540

Int J Colorectal Dis (2015) 30:1229–1234 DOI 10.1007/s00384-015-2258-y

ORIGINAL ARTICLE

Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study D. Isacson 1,3 & A. Thorisson 2,3 & K. Andreasson 1 & M. Nikberg 1,3 & K. Smedh 1,3 & A. Chabok 1,3

Accepted: 12 May 2015 / Published online: 20 May 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose The aim of this study was to evaluate outpatient, non-antibiotic management in acute uncomplicated diverticulitis with regard to admissions, complications, and recurrences, within a 3-month follow-up period. Methods A prospective, observational study in which patients with computer tomography-verified acute uncomplicated diverticulitis were managed as outpatients without antibiotics. The patients kept a personal journal, were contacted daily by a nurse, and then followed up by a surgeon at 1 week and 3 months. Results In total, 155 patients were included, of which 54 were men; the mean age of the patients was 57.4 years. At the time of diagnosis, the mean C-reactive protein and white blood cell count were 73 mg/l and 10.5×109, respectively, and normalized in the vast majority of patients within the first week. The majority of the patients (97.4 %) were managed successfully as outpatients without antibiotics, admissions, or complications. In only four (2.6 %) patients, the management failed because of complications in three and deterioration in one. These patients were all treated successfully as inpatients without surgery. Five patients had recurrences and were treated as outpatients without antibiotics. Follow-up colonic investigations revealed cancer in two patients and polyps in 13 patients.

* D. Isacson [email protected] 1

Colorectal Unit, Department of Surgery, Västmanland’s Hospital Västerås, SE-72189 Västerås, Sweden

2

Department of Radiology, Västmanland’s Hospital Västerås, Västerås, Sweden

3

Centre for Clinical Research of Uppsala University, Västmanland’s Hospital Västerås, Västerås, Sweden

Conclusion Previous results of low complication rates with the non-antibiotic policy were confirmed. The new policy of outpatient management without antibiotics in acute uncomplicated diverticulitis is now shown to be feasible, well functioning, and safe. Keywords Diverticulitis . Outpatient management . Antibiotics

Introduction The most common acute condition in diverticular disease is acute uncomplicated diverticulitis, which is defined by the absence of perforation, abscess, fistula, or bleeding [1], and accounts for 75 % of diagnosed symptomatic diverticular disease [2]. Traditionally, treatment has consisted of antibiotics and bowel rest in hospital [3, 4], but management relies mainly on data from uncontrolled studies and guidelines based on these studies [5]. A multicenter randomized trial [6], as well as one population-based study and one case-control study [7, 8], has now shown no benefit of antibiotic therapy in acute uncomplicated diverticulitis, with reported complication rates of approximately 2 %. Based on the results from these studies, one could assume that outpatient care of patients with acute uncomplicated diverticulitis would be as safe as hospitalization. A recent randomized study [9] showed that patients could be treated as outpatients with antibiotics. In this study, we combined the outpatient and the non-antibiotic policy. The aim of this study was to evaluate the safety and feasibility of outpatient management without the use of antibiotics in acute uncomplicated diverticulitis, with regard to complications, recurrences, and diverticulitis-related admissions, within a 3-month follow-up period.

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Methods This was a prospective, observational study involving two Swedish hospitals, from March 2012 until December 2013 at the Västmanland’s Hospital, Västerås, with a catchment area of 260,000, and from May 2012 until August 2012, at the Mora Hospital with a catchment area of 80,000. Patients presenting at the emergency department with clinical signs of colonic diverticulitis, such as acute abdominal pain, elevated inflammatory markers, and abdominal tenderness, were screened for potential eligibility. Inclusion and exclusion criteria are shown in Table 1. If eligible, the diagnosis of uncomplicated diverticulitis was confirmed with a computer tomography (CT) scan with intravenous contrast, and the patients were treated as outpatients without antibiotics after obtaining a written consent. Diverticulitis was classified radiologically as uncomplicated when there were no signs of perforation, abscess, fistula, or colonic obstruction [1]. Outpatient management was defined as patients being discharged directly from the emergency department, or if admitted pending a CT, and discharged after the CT examination was performed but within 24 h of presentation at the emergency department. All patients filled out a day journal questionnaire assessing daily pain score on a visual analog scale of 1–10, body temperature, oral intake of food and drink, bowel habits, and use of analgesics. Prior to discharge, all patients received written information with recommendations on oral intake of fluids for the first 48 h followed by a liquid diet and then moving on to a full diet as tolerated. The recommended standard analgesic was paracetamol. Patients were contacted daily via telephone by a nurse who assessed their general condition. Patients were monitored with blood tests at the surgical clinic after 1 week. At 3 months, they were again followed by a physician. The patients were offered a colonic investigation (CT colonography or colonoscopy) if this had not been performed during the previous year. A re-admission within 1 month with or without complications was defined as a management failure. A complication was defined as abscess formation, fistula, colonic obstruction, or perforation. A recurrence was defined as a new episode of diverticulitis after 1 month. In order to clarify the cohort selection, all patients who presented at the two hospitals during the study period with the diagnosis acute uncomplicated diverticulitis according to the International Classification of Diseases coding system (ICD-10) (K 57.0-9) were identified. The medical records of all the identified patients were reviewed. Radiological evaluation In addition to the initial assessment of the CT scans by the radiologist on duty together with the review made by a senior

Int J Colorectal Dis (2015) 30:1229–1234 Table 1

Study inclusion and exclusion criteria

Inclusion criteria •Adult patient aged over 18 years •Written informed consent •Acute lower abdominal pain with tenderness experienced within 3 days •Elevated (elevated was defined as any figure above the normal range as pre-determined by the local laboratory) C-reactive protein and/or white blood cell count •Signs of acute uncomplicated left-sided diverticulitis on CT Exclusion criteria •Signs of complicated diverticulitis on CT with abscess, fistula, or free air in the abdomen or pelvis •Signs of other diagnosis on CT •High fever, affected general condition, peritonitis or septicemia •Ongoing antibiotic therapy •Dehydrated patient/persistent vomits, in need of admission for intravenous fluid administration •Pain requiring intravenous/subcutaneous morphine •Immunologically compromised patients, including patients on immunosuppressive therapy •Pregnancy •Dementia •Patients with language barriers •Patients who cannot take care of themselves at home or are unable to follow instructions

staff radiologist at each center, all CT scans were also reevaluated at a later date and graded according to the Ambrosetti [10] classification. The following signs were assessed: diverticula, colonic wall thickening > 5 mm, pericolic fat stranding, length of the involved colonic segment, part of the colon engaged, presence of a fecalith in the inflamed diverticulum, and presence of free fluid or free air and extra-luminal air. Other causes of abdominal pain were looked for, as well as signs of secondary inflammation. Reevaluation was performed using a Sectra RIS and PACS system (IDS7 RIS version 14.2 and PACS version 4.3.1). The study was approved by the ethical committee of the Faculty of Medicine, Uppsala University, and followed the Declaration of Helsinki guidelines (Dnr 2013/433). The trial was registered in Clinicaltrails.gov (NCT01515150) before the inclusion of the first patient.

Statistical analysis A re-admission rate of 2.5 % is reported in the literature for acute uncomplicated diverticulitis patients treated with antibiotics and managed as outpatients [11–13]. Without antibiotic therapy and outpatient management, we predicted a readmission rate of 7.5 %. A sample size of 134 patients was calculated with an α of 5 % and power of 80 %. A total sample

Int J Colorectal Dis (2015) 30:1229–1234

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Table 2 Characteristics of patients at presentation at the emergency department with CT-verified acute uncomplicated diverticulitis Presentation at ED n=155 Agea (years) Sex ratio (M:F) Co-existing conditionb Previous diverticulitis

41 (26.5)

Body temperaturea (centigrade) WBCa (× 109) CRPa (mg/l) Abdominal paina (VAS)

37.1±0.65 10.5±2.9 73±50 5.5±2.1

57±12 54:101 51 (32.9)

Values in parentheses are percentages unless otherwise indicated WBC white blood cell count, CRP C-reactive protein, VAS visual analog scale 1–10 a

Values are means±SD

b

Co-existing conditions: cardiovascular disease, pulmonary disease, renal failure, diabetes mellitus

size of 161 patients would be needed with an anticipated dropout rate of 20 %. Data were analyzed using the Statistical Package for the Social Sciences (SPSS™) version 19. Differences in proportions were calculated using the chi-square test or the t test for independent samples. Unpaired numerical data were analyzed by the Mann–Whitney U test. Fisher’s exact test was used for low numbers. A P value of 24 h following admission 1). The remaining 155 patients were enrolled in the study, 101 women and 54 men with a mean age of 57.4 years (Table 2). In 114

Of the 155 patients included, we were able to obtain and reevaluate computed tomography scans for 154 (99.4 %) patients. Three patients had signs of complicated diverticulitis at the re-evaluation, two with a small pericolic abscess (measuring 2.5 and 1.2 cm) and one with extra-luminal gas. One

Fig. 1 Mean pain score as recorded in patient day journals

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Int J Colorectal Dis (2015) 30:1229–1234

Fig. 2 Analgetic use as recorded in patient day journal

was the patient admitted on day 14 where CT revealed an abscess; the other two were managed with the non-antibiotic policy and developed no further complications. Three patients had findings highly suggestive of malignancy; two proved to have a sigmoid adenocarcinoma. Potentially eligible patients during the study period The review of the medical records of all patients with CTverified uncomplicated diverticulitis during the study period in both centers showed that 66 patients were potentially eligible for the study but failed to be recruited. There were no statistical differences in age, gender, CRP, or WBC between the potentially eligible patients and the patients included in the study, but there was a statistical difference regarding body temperature, obviously without any clinical relevance (Table 3).

Discussion To our knowledge, this is the first study that has looked at outpatient treatment of acute uncomplicated diverticulitis without antibiotic therapy. This study does not only strengthen Table 3 Characteristics of patients included in the study compared with those of potentially includible patients Agea (years) Sex ratio (M:F) Body temperaturea (centigrade) WBCa (× 109) CRPa (mg/l)

previous studies that the non-antibiotic policy in acute uncomplicated diverticulitis is safe and applicable in clinical practice, but it also adds evidence that it is safe to discharge patients directly from the emergency department. These findings question the traditional treatment of acute uncomplicated diverticulitis and have the potential to significantly reduce unnecessary admissions as well as allow important cost savings to the health systems [9]. Diverticulitis has become one of the most burdensome pathologies to the health care system, ranking as the sixth most important gastrointestinal disease worldwide [14], with an estimated total cost for treating diverticulitis in a UK hospital to be 5.3 % of the total annual budget for a general surgical clinic [15]. Several studies have also shown that the majority of episodes (80.5 %) of diverticulitis admitted to hospital are uncomplicated [16], and yet the majority of these patients are treated as inpatients [2, 17, 18] resulting in a large, unnecessary cost to the health care system. Some professional guidelines still propose bowel rest and antibiotics [19–22] as the mainstay of treatment, despite no underlying references. Recent studies have, nevertheless, shown that outcomes are not different in patients treated with antibiotics from those treated with only observation in acute uncomplicated diverticulitis [6, 8]. This has now led to a

Patients included in the study

Potentially includible t

n=155

n=66

58±12 54:101 37.1±0.7 10.6±2.8 73±50

60±12.4 25:41 37.4±0.7 10.4±3.4 78±61

Values in parentheses are percentages unless otherwise indicated WBC white blood cell count, CRP C-reactive protein a

Values are means±SD

P value

0.164 0.668 0.003 0.692 0.646

Int J Colorectal Dis (2015) 30:1229–1234

change in the guidelines for antibiotic recommendations in both the Netherlands and Denmark, where routine antibiotic use is no longer recommended in certain cases of acute uncomplicated diverticulitis. Outpatient antibiotic treatment has also been suggested as a safe approach in up to 93–97 % of patients [11, 23–25], but no study has previously evaluated non-antibiotic outpatient management. In this study, none of the patients received antibiotics initially and all were treated as outpatients with a management failure rate of only 2.6 %. The recurrence rate of uncomplicated diverticulitis has been reported to be between 5 and 20 % [26] with most recurrences occurring within the first year [27]. In our study, we had a very acceptable rate of 10.3 % within 1 year. No cost analysis was done in this study, although a recent randomized study [9] showed a saving of 1123.70 Euro per patient treated as an outpatient versus inpatient. In that study, however, all patients received an intravenous (IV) dose of antibiotics prior to discharge and were further treated with oral antibiotics for a total of 10 days. Given the results from our study, the savings per patients would even be greater since no IV or oral antibiotics would be prescribed in the emergency department or on an outpatient basis. Antibiotic resistance has also become a major public health problem, and antibiotic use is being increasingly recognized as the main selective pressure driving this resistance. This further strengthens that routine use of antibiotics in acute uncomplicated diverticulitis should be avoided in common practice. One important limitation of this study is that not all patients that were eligible were included. The main reason for this is the high number of clinicians per hospital, where patients were enrolled at the emergency department after the CT had been performed. Studies performed on patients with an emergency condition commonly encounter a lot of problems in registering all patients and filling in the CRFs. It should also be kept in mind that diverticulitis affects a heterogeneous group of patients that present contraindications for outpatient treatment without antibiotics according to their symptoms, general condition, and associated medical diseases. Our study demonstrates that it is safe and feasible to treat patients with acute uncomplicated diverticulitis as outpatients without antibiotics. The desirable next step in the treatment of patients with known diverticular disease is the development of safe and reliable clinical guidelines eliminating the need for repeated CT investigations. Once this is accomplished, the authors feel that both the burden and the cost to the health care system for diverticulitis will be significantly reduced, as both patients and physicians come to understand the nature and low complication rate of this disease. In conclusion, outpatient, non-antibiotic management in acute uncomplicated diverticulitis is safe, feasible, and effective, with a low complication rate and without compromising

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patient care. We also confirm previous results of low complication rates with the non-antibiotic policy in outpatient management. Acknowledgments The authors wish to thank Dr H. Laurell for including patients from the Mora Hospital. Conflict of interest The authors declare that they have no competing interests. Source of funding This study was supported by a research grant from Uppsala-Örebro Regional Research Fund, Sweden.

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