Taking A Dive Into Diverticulitis

You are treating a 43-year-old male with two days of left lower quadrant abdominal pain, a documented fever of 38.4 and malaise. He has no urinary or bowel symptoms. His past medical history is unremarkable. He looks well by ED standards. After a focused history and physical examination, you narrow the differential to diverticulitis. You order analgesia, blood work, intravenous fluids, and you get a CT scan of his abdomen and pelvis. The report confirms acute uncomplicated diverticulitis.

As an ED physician how would you manage this patient? Do you consult general surgery? Would you empirically give antibiotics? Would you discharge home with symptom management and outpatient referral?

If you presented to a Canadian Emergency Department today and diagnosed with acute uncomplicated diverticulitis, chances are you would be placed on antibiotics and managed by General Surgery as an inpatient or outpatient. Yet over the last decade, there has been an emerging paradigm shift with several European, American, and French guidelines recommending selective rather than routine antibiotics when managing immunocompetent patients with acute uncomplicated diverticulitis (Figure 1).

Table 1: Guidelines Recommending against routine Antibiotics in Diverticulitis 

• The American Academy of Family Physicians (AAFP) 2022
• The American Gastroenterological Association (AGA) 2021
• The American College of Physicians (ACP) 2021
• The Canadian Family Physician (CFP) 2021
• The American Society of Colon and Rectal Surgeons (ASCRS) 2020
• European Society of Coloproctology (ESOC) 2020
• The World Society of Emergency Surgery (WSES) 2020
• The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 2018
• The European Association of Endoscopic Surgery (EAES) 2018
• La Haute Autorité de santé (HAS) 2017

Despite these societal recommendations and supporting research, the management of these patients remains entrenched in this antibiotic dogma. Given that most of these patients are assessed, treated, and likely discharged from our ED it is important that we own these patients and be at the vanguard of this antibiotic stewardship.

Take Home Point 1:

Diverticulitis is now believed to be as much an inflammatory as an infectious process.

For the ED doctor, diverticulitis is the appendicitis of the left lower quadrant. It results from periodic inflammation of protrusions in the colonic wall called diverticula. The cause of diverticulosis is still widely debated and likely a complex interplay between age, diet, genetic factors, colonic motility, changes in colonic structure, and the gut microbiome^1-6. Our understanding of this disease process is evolving, and it is now believed that diverticulitis is as much an inflammatory process as an infectious one.

This association comes from an overlap with other diseases thought to be caused by chronic inflammation (i.e., cardiovascular disease, diabetes mellitus) and the correlation with risk factors for elevated inflammatory markers such as sedentary behaviour, obesity, smoking, westernized diets high in red meats, refined grains, and fat.^7-11  It’s this shift in pathogenesis that has led us to question whether antibiotics are truly necessary in all patients.

Take Home Point 2:

Routine antibiotic use in low-risk immunocompetent patients with uncomplicated diverticulitis has not been shown to accelerate recovery nor improve outcomes.

Several high impact societal guidelines, including CJEM and CMAJ 2022, recommend outpatient management without antibiotics in patients with uncomplicated diverticulitis (Table 1).^3,12

The first major study to show this was in 2012 called the AVOD trial. This RCT demonstrated that patients treated or not treated with antibiotics had a low overall complication rate with perforation and abscess formation in only 1.4% of patients. There were no differences found between the groups in the frequency of in-hospital or follow-up surgeries, length of hospital stays; recurrence, or chronic symptoms including abdominal pain or changes in bowel habit after 12 months of follow-up.

RCT1: Chabok, et al 2012. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. British Journal of Surgery

• Clinical Question: Is it necessary to prescribe antibiotics to all patients undergoing management for mild left-sided diverticulitis as identified on CT scan?
• Methods: Open Labelled, Multicenter, Randomized Control trial between 2003-2010 involving 10 surgical departments in Sweden and Iceland
  • Experimental Group n= 314:
    • Cefuroxime/Cefotaxime + Flagyl OR Meropenum/Ertapenum/Imipenem OR Piperacillin-tazobactam
    • Followed by PO Ciprofloxacin/Cefadroxil + Flagyl on the ward/ discharge
      • Altogether minimal antibiotic duration = 7 days
    • Control Group n=309: IV Fluids
  • 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
  • Outcomes:
    • Primary Outcome: 
      • Recovery without complications after 12 months of follow-up
    • Results
      • Complications P = 0.30
      • In-hospital Surgery P = 0.32
      • Follow up Surgery P = 0.15
      • Length of Hospital Stay P = 0.72
      • Recurrence P = 0.88

In 2017, a second randomized control trial, from the ‘Dutch Diverticular Disease Collaborative’ added to this literature by performing, ‘the DIABOLO’ trial (DIverticulitis: AntiBiotics Or cLose Observation?).  They concluded that there was no significant difference in time to recovery, rates of ongoing, complicated, or recurrent diverticulitis, rates of readmission, adverse events, sigmoid resection, or mortality after 12 months of follow-up.

RCT2: Daniels et al 2017. Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. British Journal of Surgery

• Clinical Question: Is it necessary to prescribe antibiotics to all patients undergoing inpatient or outpatient management for mild left-sided diverticulitis as identified on CT scan?
• Methods: Multicentered, Open Label, Pragmatic, Randomized Control Trial in 22 sites of the Netherlands
  • Experimental Group n= 287:
    • Amoxicillin/Clavulanic Acid 1.2g IV QID x 48 hrs then Amoxicillin/Clavulanic Acid PO 625 TID
    • PCN Allergy = Cipro + Flagyl
  • Control Group n=283:
    • Inpatient or Outpatient analgesia: Tylenol
    • Antibiotics; deterioration, proven subsequent complicated diverticulitis, Temp >39, positive blood cultures or sepsis
  • Outcomes:
    • Primary Outcome: 
      • Time to Recovery during 6 months of follow up
    • Results
      • Median time to recovery P =0⋅15
      • Complicated Diverticulitis P =0⋅38
      • Ongoing Diverticulitis P =0⋅18
      • Recurrent Diverticulitis P =0⋅49
      • Sigmoid resection P =0⋅32
      • Readmission P = 0⋅15
      • Adverse events P =0⋅22
      • Mortality P =0⋅43
      • Hospital stay was significantly shorter in the antibiotic group 2 vs 3 days P =0⋅01

Of note, patients treated with antibiotics did have a shorter hospital stay of 2 vs 3 days; however, bacterial resistance was also noted twice in this same group, one patient to penicillin and clindamycin, and another to Flagyl.

Since their initial debut, both AVOD and DIABOLO have published longitudinal follow up trials.

A 2 year follow up of almost 90% of patients in the DIABOLO study showed no difference in recurrence rates of complicated or uncomplicated diverticular disease, readmission or need for surgical resection. At a mean follow-up of 11 years in the AVOD trial, there continued to be no difference in recurrent diverticulitis, complications, need for surgery due to diverticular disease, or reported quality of life.

• DIABLO van Dijk et al 2018:
  • 24 month Follow Up
    • Recurrences P = 0.89
    • Complications P = 0.40
    • Surgery for Diverticulitis P = 0.08

• AVOD Isacson et al 2019:
  • 11 Year Follow Up
    • Recurrences P =0⋅99
    • Complications P =0⋅74
    • Surgery for diverticulitis P =0⋅72
    • Quality of life nonsignificant in any of the measured dimensions

In 2021 Jaung et al completed the STAND trial (Selective Treatment with Antibiotics for Non-complicated Diverticulitis). Again, they found no difference in median time of hospital stay, adverse events, readmission to hospital or pain scores.

RCT3: Jaung et al 2021. Antibiotics Do Not Reduce Length of Hospital Stay for Uncomplicated Diverticulitis in a Pragmatic Double-Blind Randomized Trial. Clinical Gastroenterology and Hepatology

• Clinical Question: Is it necessary to prescribe antibiotics to all patients undergoing management for mild left-sided diverticulitis as identified on CT scan?
• Methods: International, Multicenter, Non-Inferior Double Blinded Randomized Control Trial
• Experimental Group n=85:
  • Standardized Protocol for analgesia, antiemetic therapy, dietary modification and discharge Criteria
  • IV Cefuroxime 750 mg q4hrs and PO Flagyl 400 mg TID
  • OR PO Amoxicillin/Clavulanic Acid 625mg TID
• Control Group n =95:
  • Standardized Protocol for analgesia, antiemetic therapy, dietary modification and discharge Criteria
  • Placebo
• Outcomes:
  • Primary Outcome: Length of Hospital Stay
  • Secondary Outcome(s):
    • Occurrence of adverse events, readmission to the hospital, procedural intervention, change in serum markers of inflammation, and patient-reported pain scores at 12 and 24hrs
  • Results
    • Median time of hospital stay (P =0.2).
    • Adverse events (P = 1.0)
    • Readmission to the hospital within 1 week (P = 0.1)
    • Readmission to the hospital within 30 days (P = 0.3)
    • Mean pain score at 24 hours (P = 0.9)

Mora-Lopez et al from Barcelona Spain more recently published a fourth study specifically addressing the question if outpatient non-antibiotic therapy is safe in this patient population.  This DINAMO study showed no statistically significant difference in hospitalizations, return visits to the ED, pain control nor emergency surgery. This is the 4^th RCT adding to the growing evidence that non-antibiotic treatment is non inferior to our current standard treatment, and the second study to support that outpatient management without antibiotics is safe.

RCT4: Mora-López et al. (2021). Efficacy and Safety of Nonantibiotic Outpatient Treatment in Mild Acute Diverticulitis (DINAMO-study): A Multicentre, Randomised, Open-label, Noninferiority Trial. Annals of Surgery

• Clinical Question: Is it necessary to prescribe antibiotics to all patients undergoing outpatient management for mild left-sided diverticulitis as identified on CT scan?
• Methods: Prospective multicenter, open label, non-inferiority randomized control trial of 15 colorectal surgery units
  • Experimental Group n=242: Ibuprofen 600 mg PO Q8H + Acetaminophen 1g PO Q8H
  • Control Group n=238:
    • Amoxicillin/Clavulanic Acid 875/125 PO TID +
    • Ibuprofen 600 mg PO Q8H + Acetaminophen 1g PO Q8H
  • Outcomes:
    • Primary Outcome: Hospital Admission
    • Secondary Outcome(s):
      • Repeat visits to ED, Need for Emergency surgery, Pain control
    • Results
      • Hospitalization rates P = 0.19
      • Revisits P=0.98
      • Need for Emergency Surgery P= 0.51
      • Poor pain control at 2 days follow up P=0.31

The safety of outpatient management is also supported by a number of observational studies, systematic reviews and metanalyses, with one study of over 2500 patients including 2 randomized trials, 2 prospective cohort studies and 5 retrospective analyses finding no differences in efficacy of treatment with and without antibiotics in rates of treatment failure (P = 0.28), recurrence of diverticulitis (P= 0.21), complications (P = 0.67–0.91), readmission rate(P = 0.26), or need for surgery (P = 0.34).¹³

A 2020 Cochrane review also found no significant differences in outcomes but acknowledge the high risk of bias given only one was a double-blinded and that more research was needed given the wide confidence intervals. However, despite this quality of evidence they still concluded that antibiotics have not been shown to be superior to management without.¹⁴

This strategy may not just apply to left sided diverticulitis but to right sided uncomplicated diverticulitis as well with a 2016 single-center study again showing no significant difference between antibiotic and no antibiotic groups regarding treatment failure (P=0.62), length of hospital stays (P=0.98), or cost (0.04).

Right-Sided Diverticulitis: Kim, J. Y., et al. (2019). Prospective randomized clinical trial of uncomplicated right-sided colonic diverticulitis: antibiotics versus no antibiotics. International Journal of Colorectal Disease

• Clinical Question: Is it necessary to prescribe antibiotics to all patients undergoing management for mild right-sided diverticulitis as identified on CT scan?
• Methods: Single Center, open label, prospective randomized control trial
  • Experimental Group n=64:
    • No antibiotics, IVF, bowel rest 3-5 days
  • Control Group n =61:
    • Ceftriaxone 2g IV OD + Flagyl 500mg IV TID
    • Followed by Cefpodoxime 100mg BID + Flagyl 250mg TID x 10 days
      • Cipro + Flagyl if PCN allergy
    • Results:
      • Primary Outcome: Treatment failure Rate of the initial treatment
      • Secondary Outcome(s): length of hospital stay and total admission costs.
      • Results
      • Rates of Treatment Failure P = 0.62
      • Length of Hospital Stay P = 0.98
      • Total admission costs lower in the no antibiotics group
        • US $1004.70 vs US $1112.40, respectively, P = 0.04

Some of the major strengths of AVOD, DIABALO, STAND, and DINAMO trials was the well-matched demographics of the experimental and control groups and the similarity to our own ED population. Additionally, each RCT individually included different aspects of different patient variables that are of interest to us in the Emergency Department. For example, 40% of AVOD patients had recurrent diverticulitis, a population we regularly see. The DIABOLO investigated only index presentations. STAND and DINAMO looked at outpatient management success without antibiotics. AVOD included only patients with temperatures >38, a vital sign many Emergency Physicians would report as an indication for antibiotics in this patient population. All studies looked at negative treatment reactions.

The major limitation to all these studies is their relative small sample size. Although AVOD and DIABALO indicated that antibiotics do not prevent complications these studies were superiority trials and were not powered to detect subgroup differences. This is important because although not statistically significant the observed complication rate in the AVOD trial was 1.9% vs 1% in the antibiotic group suggesting a possible trend.¹⁵ There was a similar non-significant trend towards more cases of complicated diverticulitis and elective sigmoid resections in the DIABALO trial however this may be explained by their inclusion of a higher risk population. AVOD, DIABALO and DINAMO were all non-blinded studies and only STAND performed a doubled blinded RCT.

Although there was no significant difference, there is still a possibility for reporting, selection, and confirmation bias^14,16. Another universal critique to all these studies was the strict inclusion/exclusion criteria producing a younger, healthier participant sample which some would argue limits the generalizability of the results.^6-9,14,16 Although the exclusion criteria (refer below) in all studies was robust, I don’t think it’s a strong enough reason to discredit these recommendations as it is unlikely many of us as ED physicians would deem an older, sicker, immunosuppressed, pregnant, or a complicated comorbid patient as straight forward and safe for discharge without consideration for antibiotics or surgical opinion.

• Exclusion Criteria:
  • >2 criteria for SIRS syndrome upon presentation to hospital
    • (temperature <36 C or >38 C, heart rate >90 beats/min, respiratory rate >20 breaths/min or PaCO3 <32mmHg, white cell count <4 or >12   109/L),
  • Previous drug reactions to the antibiotics used or had a lactose allergy,
  • Administered regular immunomodulators or biologics within the 6 months prior to presentation,
  • Used regular nonsteroidal anti-inflammatory drugs for greater than a week prior to
  • presentation,
  • Used steroids for >5 days prior to presentation,
  • Administered >1 dose of intravenous or >2 doses of oral antibiotics prior to illness
  • Pregnant
  • ASA >3/4
  • CT evidence of complicated acute diverticulitis

Another major challenge for the ED is the close follow up achieved in these RCTs with some being as early as within 2 days, something we currently do not have universally in our system^6-9.

I want to emphasize that the recommendations by these guidelines are not saying “no antibiotics ever”, as there are several situations and patients who should receive antibiotics^3,17:

1. Uncomplicated diverticulitis with risk factors:
   • Immunosuppressed: HIV, transplanted organs, renal failure on dialysis
   • Pregnant/breastfeeding
   • Comorbidities or Frail (ASA>3)
   • Refractory symptoms or vomiting
   • CRP >140 mg/L
   • WBC > 15x 10⁹ cells/L
   • Failed conservative treatment

1. Uncomplicated Diverticulitis and hemodynamic instability

2. Complicated diverticulitis (defined as radiologic evidence of perforation or intra- abdominal abscess) or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan

When antibiotic management is necessary, Amoxicillin-Clavulanic acid is your first line choice to reduce risks associated with fluoroquinolones, such as C.Difficile. Ciprofloxacin combined with Flagyl can be reserved for patients with PCN allergies. The duration of treatment is usually 5 days-7 but is physician dependent^3,17-19:

• Outpatient x5-7 days:
  • Amoxicillin-clavulanic acid 875 mg PO BID or 500 mg PO TID
  • PCN Allergy:
    • Ciprofloxacin 500-750 mg PO BID AND Metronidazole 500 mg PO BID
  • Inpatient:
    • Ceftriaxone 1 g IV q24h AND Metronidazole 500 mg IV q12h
    • PCN Allergy:
      • Ciprofloxacin 400 mg IV q12h AND Metronidazole 500 mg IV q12h

Nevertheless, the use of selective rather than routine antibiotics has significant health implications for our patients and society in the long run. Our potentially inappropriate use of antibiotics is contributing to antimicrobial resistance rendering some infections impossible to treat.

TAKE HOME POINTS

1. Diverticulitis is as much an inflammatory as an infectious process
2. Routine antibiotic use in low risk immunocompetent patients with uncomplicated diverticulitis has not been shown to accelerate recovery nor improve outcomes
3. Evidence exists that outpatient management of uncomplicated diverticulitis without antibiotics is safe.

We are in the middle of a paradigm shift and there is enough evidence and support from the current guidelines and local hospital recommendation to change our practice in the ED today. An “antibiotics for all” approach in managing acute diverticulitis – especially in patients who are appropriate for outpatient management – is not necessary.