C.Diff treatment

Clinical Scenario and PICO question

You see a familiar name on the Picis tracking board- a 67 year old man you obs-admitted for pyelonephritis and mild dehydration 2 weeks ago. Today he presents with fever, abdominal pain, and diarrhea. These symptoms started 3 days ago and have become progressively worse.


PE: 118         116/64          20      38.8    98% on RA

Gen: awake and alert, appears uncomfortable

HEENT: tacky mucous membranes

Lungs: CTA Bilat

CV: tachycardia, no m/r/g, regular

Abd: mild diffuse tenderness, hypoactive BS, no masses, rebound

Rectal: watery, heme neg stool


WBC 26,000                      Na 146         

Hgb 11                             K 4    

Hct 33                              Cl 111

Plt 180                              HCO3 18

Neut 88%                         BUN  40

Cr  2.2

Glc  220

 You order oral metronidazole, IVF, a c.diff toxin assay, and arrange for re-admission (with C.diff isolation- thank you bed board). While waiting for a bed, your patient’s blood pressure decreases to 90/48. Because you have been nagged repeatedly by the PROCESS team, you add a lactate which comes back at 5.6.

 Besides excellent supportive care, are there alternative treatment options for your patient?

 P:  Ill patient with suspected C. diff infection and clinical deterioration

I:   Vancomycin, IV metronidazole, colectomy, fecal transplant

C:  Oral metronidazole

O:  Resolution of infection, ICU admission, death



Avoiding a Code 44 during your next Code Brown:  Updates in the Treatment of Clostridium difficile Colitis 

Thanks to Ted and Lisa Toerne for hosting a fabulous evening with Smoque BBQ and a lively discussion led by resident presenters Chris Yenter, Drew Dean, Abbi Balger, Shannon Lovett, Vijay Menon and Danielle Riccardi. 

By means of background, in 2010 the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) published updated clinical practice guidelines forClostridium difficile infection (Infect Control Hosp Epidemiol 2010;31:431-455).  The epidemiology of C. difficile has changed:  it is no longer a nosocomial infection restricted to hospitalized patients and nursing home residents.  Instead, it is also being identified in healthy adults and children in the community, sometimes without any recent antecedent antibiotic use.  There is also a new C. difficilestrain associated with fluoroquinolone use and commonly identified as NAP1/BI/027, which causes outbreaks of unusually severe and recurrent disease (ring a MRSA bell, anyone?).

Attempts have been made to identify optimal treatment strategies in this new age of killer C. difficile.  The three articles reviewed during JC are all referenced in the 2010 SHEA/IDSA guidelines.  None of the articles are of extremely high quality, yet they all helped shape national recommendations on the treatment of Clostridium difficile infection.  An EBM take-home point for the night is that clinical guidelines are not always based on high quality data, and parts of the guidelines may be derived solely from consensus opinion.  In the manuscript, guidelines should always identify both the strength of specific recommendations and the quality of supporting evidence. 

1.  Zar FA, Bakkanagari SR et al.  A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile Associated Diarrhea, Stratified by Disease Severity.  Clin Infect Dis 2007;45:302-7.

This prospective double-blind RCT compared treatment with oral vancomycin (125 mg qid) versus metronidazole (250 mg qid) for 10 days in 150 patients with Clostridium difficile associated diarrhea (CDAD).  Overall cure rates were 84% in the metronidazole group and 97% in the vancomycin group (p= .006).  In patients with mild CDAD clinical cure rates between the groups were not statistically different (90% metronidazole, 98% vancomycin, p= .36).  However, in patients with severe CDAD, clinical cure with metronidazole was significantly less than cure with vancomycin (76% versus 97%, p= .02).  Recurrence rates were similar in the 2 groups.  Their conclusion was that although vanco and metronidazole are equally effective for the treatment of mild CDAD, vancomycin is superior in cases of severe CDAD.

Problems with this study:  the authors developed their own non-validated severity score to rank patients as having mild or severe CDAD (high age, high fever, high WBC, low albumin, ICU, pseudomembranous colitis).  Yenter mentioned that they didn’t look at IV metronidazole, limiting the ability to compare the 2 drugs.   Drew Dean highlighted the difference between an intention to treat  (ITT) analysis (preferred) and a per-protocol analysis.  This study performed a per-protocol analysis, and tossed out patients who withdrew or died during the study.  By not including those patients in the analysis of the results, there is a potential to derive misleading and inaccurate conclusions.  An example from Wikipedia: if people who have a more refractory or serious problem tend to drop out of a study at a higher rate, even a completely ineffective treatment may appear to be provide benefit if one compares outcomes before and after the treatment for only those who finish the treatment.  For the purposes of ITT analysis, everyone who begins the treatment is considered to be part of the trial, whether they finish the treatment/trial or not. 

Even given the significant methodologic problems of this study, Erik pointed out that the large effect size supports the validity of the results.

2.  Lamontagne F, Labbe E et al.   Impact of Emergency Colectomy on Survival of Patients with Fulminant Clostridium difficile Colitis during an Epidemic Caused by a Hypervirulent Strain.  Ann Surg 2007;245:267-272.

These authors sought to determine if emergency colectomy for fulminant CDAD provides a mortality benefit.  In this retrospective observational cohort study, 161 patients with 165 cases of CDAD requiring ICU admission or prolonged ICU stay for severe CDAD were included, and the primary outcome was mortality within 30 days of ICU admission.  There was an overall 53% mortality rate, with almost half of the deaths occurring within 2 days of ICU admission.  Independent predictors of 30 day mortality were WBC >/= 50 K, lactate >/= 5, age >/= 75, immunosupression, and vasopressor dependent shock.  Adjusting for these confounders, colectomy reduced the odds of death by 78% (adjusted odds ration 0.22, 95% CI 0.07-0.67, p=0.008).  The authors attempted to use subgroup analysis to identify patients more likely to benefit from colectomy (age >/= 65, immunocompetent, WBC >/= 20, or lactate between 2.2 and 4.9), however as Sam pointed out, the subgroups are small, and subgroup analysis should only be used to generate future hypotheses.  Dan stressed the authors’ finding that without a colectomy, 94% of patients with a WBC >/= 50K or with lactate >/= 5 died within 30 days of admission to the ICU, or as Shannon said, “think about involving surgery earlier than when the patient is in the unit with a lactate of 12”.

As Shannon pointed out, no timeline was provided on when the colectomy was performed.  In addition, the decision to operate was based on individual surgeon preference.  As Abbi mentioned, this study was performed during an epidemic caused by a hypervirulent strain, and limited to 2 hospitals in Quebec, which limits its external validity.  Ted brought up the question of whether or not patients are receiving EGDT/optimal medical care, which would influence outcomes. 

Although there are significant limitations to this study, the results are similar to the only other colectomy study referenced in the SHEA/IDSA guidelines.

3.  Aas J, Gessert CE, et al.  Recurrent Clostridium difficile Colitis:  Case Series Involving 18 Patients Treated with Donor Stool Administered via a Nasogastric Tube.  Clin Infect Dis 2003;36:580-5.

This case series examined the results of treating recurrent CDAD with a stool transplant.  Relapse rates after treated CDAD are around 20%, and may be higher with new more virulent strains.  Relapse begets relapse, and patients end up receiving multiple courses of antibiotics.  Administering donor stool, either by NG or per rectum, has been attempted to restore the normal healthy colonic bacterial flora.  In this single institution study, of 18 patients with documented recurrent CDAD, 2 patients died of unrelated illnesses, 1 patient had an isolated recurrence of CDAD, but the other 15 had no relapses at 90 day follow-up.  The protocol to prepare the stool (usually donated from healthy family members or less commonly from healthy donors) is outlined.  All you need is a household blender and a paper coffee filter…really.  Donors were screened for blood born and enteric pathogens.  The authors stress that the patients were uniformly receptive to the idea of stool transplantation, likely reflecting the significant disability and frustration associated with recurrent CDAD infection.  This is limited case series data from a single institution, but the idea of restoring bacterial homeostasis is appealing, or per Ted Toerne, “Bring on the filtered stool”!

Three Bottom lines: 

#1:  Article 1 is referenced in the 2010 CDAD clinical guidelines from SHEA/IDSA, and their treatment recommendations are provided in the table below.  Importantly, elevated WBC or creatinine, and shock or ileus/megacolon should prompt more aggressive therapy, either with vancomycin or with vanco + IV metronidazole.

#2:  Consider involving surgery early in cases where pressors are needed, or if toxic megacolon, perforation, high WBC, or lack of response to medical therapy (Harwood).

#3:….and although we’ll never order a stool transplant in the ED, Ben Harris is ready to donate if needed.


Background articles
1) Clostridium difficile--more difficult than ever. Kelly CP, LaMont JT. N Engl J Med. 2008 Oct 30;359(18):1932-40. Review. No abstract available. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.
2)  Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection.  Dial S, Kezouh A, Dascal A, Barkun A, Suissa S. CMAJ. 2008 Oct 7;179(8):767-72.