1. Management of Clostridium difficile Infections
UC Irvine medical center
Department of internal medicine
4/6/15

2. Objectives
What is Clostridium difficile infection (CDI) and how it’s diagnosed
Major risk factors for CDI
Define the severity of CDI
Treat CDI by degree of severity
Treat recurrent CDI
Examine alternative treatments

3. Case
42 year-old man is evaluated for recurrent diarrhea. Four weeks ago, the patient was diagnosed with a mild Clostridium difficile infection and treated with a 14- day course of metronidazole, 500 mg orally every 8 hours, with resolution of his symptoms. He currently takes no medications. One week after his last dose of metronidazole, he again develops recurrent watery stools without fever or other symptoms. There is no visible blood or mucus in the stools.

4. Case
Physical examination findings are noncontributory. Results of laboratory studies show a leukocyte count of 10,400/µL (10.4 × 109/L) and a normal serum creatinine level. A stool sample tests positive for occult blood, and results of a repeat stool assay are again positive for C. difficile toxin.

5. Case
Which of the following is the most appropriate treatment at this time?
Oral metronidazole for 14 days
Oral metronidazole taper over 42 days
Oral vancomycin for 14 days
Oral vancomycin plus parenteral metronidazole for 14 days
Oral vancomycin taper over 42 days
List the answer choices but do not actually answer the question as it will be answered at the end of the mini-lecture

6. Introduction
C. difficile is a gram positive, spore-forming bacterium that produces disease-causing toxins A&B
PCR test for C. difficile toxin genes has high sensitivity and high specificity
Repeat testing should be discouraged
Testing for cure should not be done
Repeat testing after a negative test increases the likelihood of false positives
Studies have shown that tests for C. diff may remain positive for as long as 30 days in patients with resolution of symptoms
False positive “test of cure” specimens may complicate clinical care and result in additional courses of inappropriate anti-C. diff therapy

7. Major Risk Factors Antibiotic exposure Organism exposure
Certain co-morbidities
GI tract surgery
Gastric acid reduction (e.g. PPI use)
Co-morbid conditions: IBD, chronic liver disease, organ transplant recipients, ongoing malignancy, chronic steroid use, hypogammaglobulinemia, pregnant women, women in the peripartum period

8. CDI Disease Severity

9. Mild-to-Moderate Disease
Watery diarrhea (up to times per day)
Any additional signs or symptoms not meeting severe or complicated criteria

10. Severe Disease
Hypoalbuminemia (serum albumin <3 g/dl) plus ONE of the following:
WBC ≥ 15,000
Abdominal tenderness

11. Complicated Disease Any of the following attributable to CDI:
Admission to ICU
Hypotension with or without required use of vasopressors
Fever ≥ 38.5o C
Ileus or significant abdominal distension
Mental status changes
WBC ≥ 35,000 or <2,000
Lactate > 2.2
End organ failure (mechanical ventilation, renal failure, etc.)

12. Management of CDI Mild-to-moderate disease:
Metronidazole (Flagyl) 500 mg orally 3 times a day for days
If no improvement after 5-7 days, stop metronidazole and switch to vancomycin mg orally 4 times a day for a total of days
Severe disease: vancomycin 125 mg orally 4 times a day for days

13. Management of CDI Complicated disease:
Vancomycin 500 mg orally 4 times a day PLUS
Metronidazole 500 mg IV 3 times a day
CT abdomen recommended
Obtain surgical consult
When oral antibiotics cannot reach a segment of the colon, add vancomycin mg in 500 ml saline via enema 4 times a day until the patient improves
CT can determine the severity and extent of disease and can detect colon wall thickening, ascites, megacolon, ileus, or perforation
Examples of when oral antibiotics may not reach a segment of the colon: ileus, megacolon, Hartman’s pouch, ileostomy, colon diversion

14. Recurrent CDI
1st recurrence can be treated with the same regimen used for the initial episode
If 1st recurrence is severe, vancomycin should be used
2nd recurrence should be treated with a pulsed vancomycin regimen
Standard 10-day course of vancomycin (125 mg QID)
Then 125 mg daily pulsed every 3 days for 10 total doses
For a 3rd recurrence after a pulsed vancomycin regimen, consider fecal microbiota transplant
Despite appropriate initial therapy, CDI recurs in approximately 20% of patients
The choice of therapy for the 1st recurrence does not decrease the probability of a 2nd recurrence
Treatment for the 1st recurrence is determined by the severity of illness in the same way as for the initial presentation

15. Alternative Treatment Considerations

16. Fidaxomicin
Alternative treatment that can be used to for recurrent mild-to-moderate CDI
Dose = 200mg PO BID x 10 days
Demonstrated non-inferiority to vancomycin in 2 randomized control trials
Drawbacks:
Significantly more expensive than vancomycin
Limited data on long-term efficacy
Cost difference for a 10-day regimen: $2800 for fidaxomicin vs. $100-$400 for vancomycin
Drawback: surveillance testing in one of the fidaxomicin efficacy trials has already revealed the evolution of a C. diff strain with an elevated minimal inhibitory concentration to fidaxomicin due to a mutation in RNA polymerase B

17. Probiotic Use
Saccharomyces boulardii did result in fewer recurrences in a group of patients with recurrent CDI
Caution:
Problems with study design
Limited use
Risk of bacteremia or fungemia
Use not recommended by guidelines
Small trials of Lactobacillus use have failed to show efficacy in treating recurrent CDI
The study had inadequate randomization by the type of adjunct CDI antibiotic
Efficacy limited to subgroup of patients treated only with high doses of vancomycin
Use not recommended due to lack of efficacy data, potential harm, high costs, and lack of biological plausibility for these non-human micro-organisms to confer colonization resistance

18. Now back to our case…

19. Case
In summary, 42 year-old male with a 1st recurrence of CDI. He has mild-to-moderate disease.

20. Case
Which of the following is the most appropriate treatment at this time?
Oral metronidazole for 14 days
Oral metronidazole taper over 42 days
Oral vancomycin for 14 days
Oral vancomycin plus parenteral metronidazole for 14 days
Oral vancomycin taper over 42 days

21. Case
Which of the following is the most appropriate treatment at this time?
Oral metronidazole for 14 days
Oral metronidazole taper over 42 days
Oral vancomycin for 14 days
Oral vancomycin plus parenteral metronidazole for 14 days
Oral vancomycin taper over 42 days
This recurrent mild-to-moderate CDI requires a repeat course of PO metronidazole for 14 days

22. Key Points CDI is commonly encountered in the hospital
Treatment is based on severity of infection (mild-moderate, severe, complicated)
For mild-moderate CDI, if no improvement after 5-7 days of metronidazole, stop and switch to oral vancomycin
For complicated CDI, add rectal vancomycin when oral antibiotics may not reach the colon
Treat 1st recurrence with same regimen as initial infection
Treat 2nd recurrence with pulsed vancomycin
Treat 3rd recurrence with fecal transplant
Currently probiotic use is not recommended by guidelines

23. The End

24. References
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108:478. Kelly, Ciaran P., MD, and J. Thomas Lamont, MD. "Clostridium Difficile in Adults: Treatment." Clostridium Difficile in Adults: Treatment. Ed. Stephen B. Calderwood and Elinor L. Baron. N.p., 31 Mar < search=clostridium%2Bdifficile&selectedTitle=1~150#H10>.