Antibiotics versus No Antibiotics for the Treatment of Acute Uncomplicated Diverticulitis: Review of the Evidence and Future Directions

Abstract

Background:

Acute diverticulitis occurs in 25% of individuals with diverticular disease and is associated with significant morbidity and mortality rates. Disease severity is classified as uncomplicated or complicated, with the latter including perforation, fistula, obstruction, or distant abscess. Uncomplicated diverticulitis often improves without surgery or invasive therapies. Administration of antibiotics is a standard of care for treatment of acute uncomplicated diverticulitis. However, recent data suggest antibiotics do not influence outcomes significantly. To address these conflicting approaches, the Surgical Infection Society hosted an Update Symposium at its 37^th Annual Meeting examining the role of antibiotics in the treatment of acute uncomplicated diverticulitis. Here, we provide a synopsis of the symposium's findings and a brief review of recent prospective and randomized clinical trials on the topic.

Methods:

A search of Embase, MEDLINE, and the Cochrane Library was performed for prospective series and randomized clinical trials published between January 1, 2010, and January 1, 2018, comparing outcomes of antibiotic versus no antibiotic therapy for acute uncomplicated diverticulitis.

Results:

We identified two single-center prospective series and two randomized clinical trials comparing outcomes for patients with acute uncomplicated diverticulitis treated with antibiotics versus no antibiotics.

Conclusion:

Current evidence does not support administration of antibiotics to improve outcomes in carefully selected healthy patients with acute uncomplicated left-sided diverticulitis. Further studies should help identify specific subpopulations of patients who would derive benefit from antibiotic therapy and help define appropriate antibiotic regimens and treatment durations that minimize cost, adverse effects, and risk of anti-microbial resistance.

Diverticular disease is among the most common gastrointestinal disorders in the Western world, and its prevalence has increased significantly since the early 20^th Century [1]. Most cases are diagnosed in individuals above the age of 60 years [2]. Left-sided disease involving the sigmoid colon occurs in most cases [3]. Acute diverticulitis afflicts as many as 25% of patients, consisting of localized diverticular inflammation precipitated by obstruction, stasis, alterations in colonic microflora, or ischemia [4]. Disease-related morbidity and mortality rates are substantial, as are treatment costs, which exceed $3 billion annually [5].

Acute diverticulitis typically presents with left lower-quadrant abdominal pain and tenderness associated with diarrhea or constipation, fever, and leukocytosis. The gold standard imaging study to confirm the diagnosis is a contrast-enhanced computed tomography (CT) scan [6]. Disease severity is then classified using the Hinchey or modified Hinchey classification system [7]. Acute uncomplicated diverticulitis includes stage I disease limited to colonic wall thickening, pericolic inflammation, or small (<5 cm) pericolic abscess, whereas complicated diverticulitis includes stages II or greater (distant intraperitoneal or pelvic abscess or peritonitis, respectively). In addition to hospitalization, complete bowel rest, and administration of intravenous fluids and broad-spectrum antibiotics, patients with complicated disease more often require invasive therapies including percutaneous abscess drainage via interventional radiology procedures or surgery for diffuse peritonitis [8].

The majority of patients with acute uncomplicated diverticulitis improve with medical management alone [9]. Treatment consists of restricted oral intake ± intravenous (IV) fluids, close observation, pain medication, and antibiotics. Although prospective data fail to show improved outcomes, antibiotic administration is strongly supported by expert opinion and remains a standard of care [10,11]. Moreover, there is no consensus regarding optimal antibiotic choice, route of administration, or duration of administration. In our current environment of improved anti-microbial stewardship aimed at optimizing clinical outcomes, minimizing toxicity, reducing costs, and curtailing anti-microbial resistance, the Surgical Infection Society hosted an Update Symposium at its 37^th Annual Meeting to define the role for antibiotics better in the treatment of acute uncomplicated diverticulitis. Here, we review recent prospective and randomized clinical trials on the subject and summarize the meeting's findings and recommendations.

Clinical Outcomes

We identified four studies within the search period comparing patient outcomes for acute uncomplicated diverticulitis treated with or without antibiotics (Table 1). Isacson et al. conducted a single-center prospective observational study evaluating outpatient management without antibiotics of CT-verified, acute uncomplicated diverticulitis in 155 patients (35% male; mean age 57) [12]. Additional inclusion criteria included age over 18 years, lower-abdominal pain or tenderness within three days, and elevated C-reactive protein or white blood cell count. Exclusion criteria included high fever, peritonitis, septicemia, dehydration or need for IV fluid administration, pain requiring IV/subcutaneous morphine, pregnancy, immunosuppression, dementia, and ongoing antibiotic therapy. Over a three-month follow-up period, the authors found that 97.4% of patients managed without antibiotics did not require hospital admission or experience complications. Four patients (2.6%) required hospital admission within 14 days. Three experienced complications, and one had progression of disease. All were treated successfully as inpatients without surgery. Although disease recurred in five patients, all were treated as outpatients without antibiotics. The authors concluded that outpatient management of CT-verified acute uncomplicated diverticulitis without antibiotics is both feasible and safe with a low complication rate.

Table 1.

Studies Comparing Patient Outcomes for Acute Uncomplicated Diverticulitis Treated with or without Antibiotics

Series	Type	Inclusion criteria	Exclusion criteria	Study arms	Follow-up period	Primary outcomes	Secondary outcomes
Isacson et al. (2015) [12]	Prospective cohort	CT-confirmed left-sided AUD	Complicated diverticulitis, pregnancy, dementia, immunocompromised, pain requiring narcotics, dehydration requiring IV fluid, ongoing abx therapy, peritonitis or septicemia	Analgesic only	3 mos	Readmission within 1 mo, complication (abscess, fistula, obstruction, perforation), recurrence	N/A
Mali et al. (2016) [13]	Prospective cohort	CT-confirmed AUD	Age <18 or >90 y, pregnancy, peritonitis, organ failure, other infection requiring abx, ongoing abx therapy, immunocompromised (diabetes, steroid use, liver disease)	Analgesic only	30 d	Incidence of complicated diverticulitis	Length of stay, readmission, antibiotic treatment, complications of diverticulosis, death
Chabok et al. (2012) [14]	Multicenter, randomized	CT-confirmed left-sided AUD	Complicated diverticulitis, pregnancy, high fever, peritonitis, sepsis, ongoing abx therapy, immunocompromised	Broad spectrum abx + IVF vs. IVF alone	12 mos	Complications, need for surgery, hospital stay, abdominal pain and tenderness, fever	Recurrence, need for surgery, changes in bowel habits, abdominal pain, results of colorectal examinations
Daniels et al. (2017) [16]	Multicenter, randomized	CT-confirmed primary left-sided AUD	Previous diverticulitis, IBD, pregnancy, sepsis, immunocompromised, ASA > III, suspicion of colon cancer, Hinchey stage >1b, abx use within 4 wks of study	Abx vs. observation	12 mos	Time to full recovery	Days spent outside hospital, readmission rate, occurrence of complicated diverticulitis, need for surgery, recurrence, adverse events, antibiotic side effects, death

abx = antibiotics; ASA = American Anesthesiologists Society; AUD = acute uncomplicated diverticulitis; CT = computed tomography; IBD = inflammatory bowel disease; IVF = intravenous fluids; N/A = not available.

In 2016, Mali et al. conducted a similar single-arm, prospective observational study at a single academic medical center, reviewing non-antibiotic treatment for CT-verified acute uncomplicated diverticulitis [13]. Patients with pericolic air on CT were included in the study, whereas patients with ongoing antibiotic therapy, immunosuppression, organ dysfunction, pregnancy, other infections, or suspicion of peritonitis were excluded. Of note, the only intervention over the 30-day follow-up period was administration of nonsteroidal anti-inflammatory drugs or paracetamol for pain. The primary outcome was the incidence of complicated diverticulitis. Among the 161 patients included in the study, 153 (95%) completed the follow-up, whereas four patients were excluded after initial CT imaging revealed complicated diverticulitis. Fourteen patients (9%) had pericolic air. In this cohort, 140 patients (87%) were managed successfully as outpatients, but 3% required hospital admission because of worsening symptoms. Antibiotics were administered to 14 patients (9%). None of the patients developed complicated diverticulitis or required surgical intervention. The authors concluded that non-antibiotic treatment of uncomplicated diverticulitis is safe and effective.

We identified two randomized trials comparing patient outcomes for acute uncomplicated diverticulitis treated with or without antibiotics (Table 2). Chabok et al. published the first open multi-center randomized trial from 10 hospitals in Sweden and one in Iceland comparing antibiotics + IV fluids with IV fluids alone in the treatment of CT-verified acute uncomplicated left-sided diverticulitis [14]. Patients with an abscess, fistula, sepsis, or free air on CT were excluded. A total of 623 eligible patients (403 women) were randomized into two groups: 314 received IV cefuroxime or cefotaxime and metronidazole, or a carbapenem, or piperacillin/tazobactam, followed by oral ciprofloxacin or cefadroxil with metronidazole, for a total of at least seven days, whereas 309 received no antibiotics. The median age was 58 (range 23–88) years. There were no significant differences between the study groups in demographics, clinical characteristic or presentation, or inflammatory features. Previous diverticulitis, which is associated with a lower complication rate, was significantly more common in the non-antibiotic group (p = 0.002). An intention-to-treat analysis was performed. The primary analysis included short-term results comparing occurrence of complications, need for surgery, hospital stay, fever, and abdominal pain and tenderness. The follow-up analysis at 12 months included recurrence, need for surgery, changes in bowel habits, abdominal pain, and results of colorectal examinations.

Table 2.

Randomized Prospective Studies Comparing Antibiotic Treatment with No Antibiotics for Acute Uncomplicated Diverticulitis

Series	Study arms	Complication rate (%)	Recurrence (%)	Need for surgery (%)	Length of hospital stay (d)	Time to recovery (d)	Morbidity rate (%)	Mortality rate (%)
Chabok et al. (2012) [14]	Broad spectrum abx + IVF vs. IVF alone	1.00 vs. 1.9 (p = 0.302)	15.8 vs. 16.2 (p = 0.881)	1.6 vs. 2.3 (p = 0.541)	2.9 vs. 2.9 (p = 0.717)	N/A	N/A	N/A
Daniels et al. (2017) [16]	Abx vs. observation	2.6 vs. 3.8 (p = 0.377)	3.0 vs. 3.4 (p = 0.494)	2.3 vs. 3.8 (p = 0.323)	3 vs. 2 (p = 0.006)	12 vs. 14 (p = 0.151)	54.5 vs. 48.5 (p = 0.221)	0.4 vs. 1.1 (p = 0.432)

NA = not available.

The authors found no significant difference between groups in median hospital stay, temperatures, or subjective reports of abdominal pain as measured by visual analog scale (VAS) score, but significantly less abdominal tenderness on the second day in the antibiotic group (p = 0.041). Complications occurred in nine patients (1.4%), but there was no difference between groups. Six patients (1.9%) in the no-antibiotics group developed perforations or intra-abdominal abscesses compared with three patients (1%) in the antibiotic group. There was no significant difference in recurrent diverticulitis or need for surgery between treatment groups. Ten patients (3.2%) initially in the no-antibiotic group received antibiotics because of worsening disease. A total of 41 patients were lost to follow-up. On the basis of these results, the authors concluded that antibiotic administration does not prevent recurrence or surgical complications.

The second multi-center randomized clinical trial investigating antibiotic usage in acute uncomplicated appendicitis (DIABOLO trial) was published by Daniels et al. in 2017 [16]. The authors included 528 patients with CT-verified primary, left-sided, stage 1a and 1b disease according to the modified Hinchey/Ambrosetti criteria. Patients from 22 clinical sites in The Netherlands were randomized into two groups, either a conservative strategy including hospital admission, supportive measures, and at least 48 hours of IV antibiotics followed by oral antibiotics for a 10-day total duration of treatment, or a liberal strategy without antibiotics, admission based on clinical grounds, and supportive measures only. The primary endpoint was time to full recovery, defined as hospital discharge with return to pre-illness activities and VAS pain score below 4 without daily pain medication. Secondary endpoints included morbidity, costs, readmission rate, health-related quality of life, recurrence rate, and the proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention. A non-inferiority design was utilized, and intention-to-treat and per-protocol analyses were performed.

There were no statistical differences between groups. For the primary endpoint, there was no difference in median time to recovery between antibiotics vs. no antibiotics (12 days vs. 14 days; p = 0.151). Over the six-month follow-up period, no significant differences between the antibiotic and non-antibiotics groups were found for the secondary endpoints of progression to complicated diverticulitis (2.6% vs. 3.8%; p = 0.377), ongoing diverticulitis (4.1% vs. 7.3%; p = 0.183), recurrent diverticulitis (3% vs. 3.4%; p = 0.494), surgical resection (2.3% vs. 3.8%; p = 0.323), readmission rate (12% vs. 17.6%; p = 0.148), adverse events (54.5% vs. 48.5%; p = 0.221), or death (0.4% vs.1.1%; p = 0.423). Hospital stay was significantly shorter in the non-antibiotic group (2 vs. 3 days; p = 0.006). The authors concluded that observational treatment without antibiotics does not prolong recovery and is appropriate in patients with uncomplicated diverticulitis.

Critical Appraisal of Trials

There are important limitations to consider regarding the aforementioned studies. Both Isacson et al. and Mali et al. are observational in design and thus subject to inherent biases compared with randomized controlled studies [12,13]. These also are single-arm studies with no comparison groups or blinding, and Mali et al. recruited subjects from only a single site. The follow-up times are relatively short for both studies at three months and 30 days. Both studies confirmed the diagnosis of uncomplicated diverticulitis with CT scanning, which is advantageous in terms of homogeneity between subjects but may limit the applicability of the results as some patients begin treatment as outpatients on the basis of a clinical diagnosis alone. The criteria for uncomplicated disease differed between studies. Isacson et al. excluded patients with CT signs of abscess, fistula, or colonic obstruction, but Mali et al. included subjects with pericolic air. The studies also instituted other important exclusion criteria, including age <18, ongoing antibiotic therapy, or the presence of another infection requiring antibiotics, pregnancy, diabetes, immunosuppression (corticosteroids, chemotherapy, and chronic liver disease), high fever, dehydration and vomiting mandating IV therapy, pain requiring narcotics, dementia, organ dysfunction, and suspicion of peritonitis or sepsis. Collectively, only relatively healthy subjects without significant co-morbidities were included for analysis, which again limits broad applicability to the general population.

In 2012, a Cochrane review analyzed the effects of antibiotics on outcomes of CT-confirmed left-sided uncomplicated diverticulitis [16]. Only one of the three trials compared antibiotics with no antibiotics [14]. One trial [15] compared single-compound (cefoxitin) antibiotic therapy with combination therapy (gentamicin–clindamycin) in 77 patients with a radiographic diagnosis of acute uncomplicated diverticulitis. There were no significant differences in the cure rate (p = 0.48) or failure rate (p = 0.48) between treatment groups. The third trial (Ribas 2010) compared short (24–48 hour) IV antibiotic administration with longer (seven-day) treatment in 50 patients with CT-verified uncomplicated diverticulitis. There was no significant difference in treatment failure between the two groups. The authors of the Cochrane review concluded that the evidence suggests antibiotics have no effect on complications, emergency surgery, or recurrence in acute uncomplicated diverticulitis. Notwithstanding, the authors stated that more confirmation is needed before clinical guidelines can be changed safely.

An evaluation of the randomized clinical trial by Chabok et al. found adequate descriptions of the allocation method and concealment, attrition, and exclusion of patients after randomization, defined primary and secondary outcomes, and power calculations for the group sizes [14]. The study did not perform blinding of patients, health care providers, or data assessors, which can result in performance or detection bias. The authors found previous episodes of diverticulitis were less frequent in the antibiotic treatment group. With other studies suggesting that perforation is less frequent in subsequent attacks, this may afford the antibiotic group a treatment advantage, although CT scanning should have excluded these individuals. Nevertheless, only 60% of subjects had primary diverticulitis, which may limit the clinical applicability of the results. The study definitely is limited by a failure to register all eligible patients at participating centers, and there is no standardized antibiotic treatment regimen. The study was powered to detect a 5% difference in the complication rate between treatment groups. The observed difference was only 0.9%, which would have necessitated enrolling at least 5,500 patients to achieve statistical significance. Lastly, the external validity of the findings may be limited by differences in host patient demographics, disease virulence, or other unrecognized treatment variables in Sweden and Iceland versus in the United States.

In comparison, the multicenter, randomized, placebo-controlled study by Daniels et al. enrolled only primary diverticulitis cases, although patients who had previous bouts of abdominal pain not definitely diagnosed radiologically were not excluded. The treatment regimen was standardized to IV followed by oral amoxicillin–clavulanic acid therapy. This approach mandated hospital admission for all patients in the antibiotic group, whereas subjects in the observational group could enter out-patient treatment directly. It is unclear what, if any, untoward effects the inpatient environment had on primary or secondary outcome measures. As discussed above, there were no statistically significant differences between groups for the outcome measures, although the rates of all secondary complications were higher for the observation group with the obvious exception of antibiotic-related morbidity. This trend toward worse outcomes in the observational group is compounded by a lack of power to detect differences within Hinchey classes (1a vs. 1b). Considering patients may undergo percutaneous drainage of abscesses as large as 5 cm, observation or antibiotics alone may not constitute acceptable approaches in this patient population.

Anti-Microbial Stewardship

Anti-microbial drug use can result in direct effects on the patient (i.e., adverse drug effects, Clostridiodes difficile infection [CDI], and dysbiosis) and promote resistance in the patient and general population [18]. Strategies that limit anti-microbial drug exposure may reduce both individual risks and overall resistance pattern within the general population. For example, traditional treatment regimens for acute diverticulitis employ fluoroquinolones (FQs) [19,20]. Heightened awareness now surrounds the utilization of this anti-microbial class because of the increasing number of adverse effects associated with their administration [21]. As seen in the DIABOLO trial, even when non-FQ anti-microbials are utilized, approximately 8% experienced an antibiotic-related side effect, with 1% discontinuing therapy because of the adverse event [16].

Anti-bacterial agents constitute a major risk factor for CDI, and FQs have the propensity to select hypervirulent strains [22,23]. Fortunately, of the subjects tested because of symptoms in the DIABOLO trial, no subjects tested positive for CDI [16]. This may have resulted from the lower propensity of amoxicillin/clavulanate, the predominant anti-microbial drug administered, to cause CDI [24]. Further investigation is required to determine if antibiotics with higher CDI risk (i.e., third-generation cephalosporins and FQs) increase the incidence of CDI in patients treated for uncomplicated acute diverticulitis [24].

The microbiology of diverticulitis, particularly when associated with intra-abdominal abscesses, includes members of Enterobacteriaceae, notably Escherichia coli [25]. Anti-microbial resistance continues to increase within this group of organisms [26]. A recent report by Cocconlini et al. demonstrated low rates of resistance (approximately 7%) in patients with complicated diverticulitis [27]. In contrast, new models suggest that by 2030, at least 70% of all E. coli isolates will demonstrate multi-drug resistance via expression of extended-spectrum beta-lactamases [28]. An antibiotic-free strategy could prove beneficial by exerting less selective pressure and thus reduced resistance rates within the community.

As reflected by the two randomized controlled trials discussed here, the duration of anti-microbial therapy for diverticulitis traditionally includes a 7–10-day course of therapy [14, 16]. The Surgical Infection Society Intra-abdominal Infection guidelines recommend 5–7 days for patients with no source control [20]. This may be extrapolated to uncomplicated diverticulitis, as these patients rarely need or undergo source control [29]. Moreover, a recent trial demonstrated four days of anti-microbial therapy for diverticulitis is as effective as seven days [30]. Shortening treatment durations (e.g., 4–5 days) or basing them on clinical response would reduce anti-microbial drug exposure.

Considering the potential damage associated with anti-microbial utilization, a careful risk–benefit analysis should help determine whether to administer such drugs to patients with uncomplicated diverticulitis. A decrease in unnecessary anti-microbial drug use could prevent future resistance both in individual patients and in the community as a whole. This approach may allow infections that require anti-microbial therapy to remain treatable with narrow-spectrum and oral anti-microbials.

Future Directions

Multiple unresolved areas regarding acute uncomplicated diverticulitis treatment require additional studies. These include management of right-sided or recurrent disease, patients with significant co-morbidities, and patients with higher severity of disease. More accurate stratification of disease severity may require combining traditional classification systems (Hinchey) with newer approaches, such as the Neff or modified Neff radiologic classification system based on CT findings. Geographic differences between patient populations and disease pathogenesis deserve further investigation. With a heightened awareness of the risks of antibiotic therapy, a cost–benefit analysis can define their utility better. Improved tracking of adverse drug events, anti-microbial resistance, and dysbiosis may help as well.

Conclusions

Administration of antibiotics has been the standard of care for the treatment of acute uncomplicated diverticulitis. In view of the evidence presented at the Surgical Infection Society Update Symposium discussed here, healthy patient populations with no significant co-morbidities derive no benefits from this approach. We recommend against the use of antibiotics in these select cases. For patient populations not fitting this description, antibiotics should remain an integral component of acute uncomplicated diverticulitis therapy until additional studies are performed.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Jaung

, Robertson

, Vather

, et al. Changes in the approach to acute diverticulitis. ANZ J Surg, 2015; 85:715–719.

Jacobs

DO.

Clinical practice: Diverticulitis. N Engl J Med, 2007; 357:2057–2066.

Weizman

, Nguyen

. Diverticular disease: Epidemiology and management 2011. Can J Gastroenterol; 25:385–389.

Strate

, Modi

, Cohen

, Spiegel

. Diverticular disease as a chronic illness: Evolving epidemiologic and clinical insights. Am J Gastroenterol, 2012; 107:1486–1493.

Mayl

, Marchenko

, Frierson

Management of acute uncomplicated diverticulitis may exclude antibiotic therapy Cureus. 2017; 9:e1250.

DeStigter

, Keating

. Imaging update: Acute colonic diverticulitis, 2009:22:147–155.

Klarenbeek

, de Korte

, van der Peet

, Cuesta

. Review of current classifications for diverticular disease and a translation into clinical practice. Int J Colorectal Dis, 2012; 27:207–214.

Schaffzin

, Wong

. Nonoperative management of complicated diverticular disease. Clin Colon Rectal Surg, 2004; 17:169–176.

Horesh

, Wasserberg

, Zbar

, et al. Changing paradigms in the management of diverticulitis. Int J Surg, 2016; 33:146–150.

10.

Vennix

, Morton

, Hahnloser

, et al.; Research Committee of the European Society of Coloproctology. Systematic review of evidence and consensus on diverticulitis: An analysis of national and international guidelines. Colorectal Dis, 2014; 16:866–878.

11.

Andersen

, Bundgaard

, Elbrond

, et al. Danish national guidelines for treatment of diverticular disease. Dan Med J, 2012; 59:C4453.

12.

Isacson

, Thorisson

, Andreasson

, et al. Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: A prospective study. Int J Colorectal Dis, 2015; 30:1229–1234.

13.

Mali

, Mentula

, Leppaniemi

, Sallinen

. Symptomatic treatment for uncomplicated acute diverticulitis: A prospective cohort study. Dis Colon Rectum, 2016; 59:529–534.

14.

Chabok

, Pahlman

, Hjern

, et al. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. Br J Surg, 2012; 99:532–539.

15.

Kellum

, Sugerman

, Coppa

, et al. Randomized, prospective comparison of cefoxitin and gentamicin–clindamycin in the treatment of acute colonic diverticulitis. Clin Ther, 1992; 14:387–384.

16.

Daniels

, Unlu

, de Korte

, et al. A randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis. Br J Surg, 2017; 104:52–61.

17.

Shabanzadeh

, Wille-Jorgensen

. Antibiotics for uncomplicated diverticulitis. Cochrane Database Syst Rev, 2012; 11:CD009092.

18.

Dellit

, Owens

, McGowan

Jr , et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis, 2007; 44:159–177.

19.

Byrnes

, Mazuski

. Antimicrobial therapy for acute colonic diverticulitis. Surg Infect, 2009; 10:143–154.

20.

Mazuski

, Tessier

, May

, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect, 2017; 18:1–76.

21.

Food and Drug Administration. Updates: Warnings for oral and injectable fluroquinolone antibiotics due to disabling side effects. FDA. Bethesda, Md.

22.

Pepin

, Saheb

, Coulombe

, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: A cohort study during an epidemic in Quebec. Clin Infect Dis, 2005; 41:1254–1260.

23.

McDonald

, Gerding

, Johnson

, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis, 2018; 66:987–994.

24.

Vardakas

, Trigkidis

, Boukouvala

, Falagas

. Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: A systematic review and meta-analysis. Int J Antimicrob Agents, 2016; 48:1–10.

25.

Brook

, Frazier

. Aerobic and anaerobic microbiology in intra-abdominal infections associated with diverticulitis. J Med Microbiol, 2000; 49:827–830.

26.

Hawkey

, Warren

, Livermore

, et al. Treatment of infections caused by multidrug-resistant gram-negative bacteria: Report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother, 2018; 73(suppl_3):iii2–iii78.

27.

Coccolini

, Trevisan

, Montori

, et al. Mortality rate and antibiotic resistance in complicated diverticulitis: Report of 272 consecutive patients worldwide: A prospective cohort study. Surg Infect , 2017;Jul 21 (Epub ahead of print).

28.

Alvarez-Uria

, Gandra

, Mandal

, Laxminarayan

. Global forecast of antimicrobial resistance in invasive isolates of Escherichia coli and Klebsiella pneumoniae. Int J Infect Dis, 2018; 68:50–53.

29.

Ellison

DL.

Acute diverticulitis management. Crit Care Nurs Clin North Am, 2018; 30:67–74.

30.

Schug-Pass

, Geers

, Hugel

, et al. Prospective randomized trial comparing short-term antibiotic therapy versus standard therapy for acute uncomplicated sigmoid diverticulitis. Int J Colorectal Dis, 2010; 25:751–759.