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

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

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.

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.

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

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

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

CDI Disease Severity

Mild-to-Moderate Disease Watery diarrhea (up to 10-15 times per day) Any additional signs or symptoms not meeting severe or complicated criteria

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

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.)

Management of CDI Mild-to-moderate disease: Metronidazole (Flagyl) 500 mg orally 3 times a day for 10-14 days If no improvement after 5-7 days, stop metronidazole and switch to vancomycin 125 mg orally 4 times a day for a total of 10-14 days Severe disease: vancomycin 125 mg orally 4 times a day for 10-14 days

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 500 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

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

Alternative Treatment Considerations

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

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

Now back to our case…

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

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

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

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

The End

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. 2015. <http://www.uptodate.com/contents/clostridium-difficile-in-adults-treatment?source=search_result& search=clostridium%2Bdifficile&selectedTitle=1~150#H10>.