Clostridium Difficile colitis- more virulent than ever ECHO- February 18, 2016 Charles Krasner, M.D. UNR School of Medicine Sierra NV Veterans Affairs Hospital

Growing problem of pseudomembranous colitis MMWR- “…incidence, deaths, and excess health care costs are at historic highs” +/- 1 billion dollars/yr 3x increase in decade- now 500,000 infections and 29,000 deaths per year. More deaths than even MRSA infections. #1 cause of increase- over use of antibiotics #2 cause – appearance of a more virulent C.diff strain associated with risk of greater mortality #3 cause- increased relapse rate – 20% of cases have at least one relapse- difficult to treat #4 cause- overdiagnosis???

Asymptomatic C. diff Carriers 60% of stool carriers in one study also had it on their skin and their surrounding environment Spores on the skin of these carriers were easily transferred to others Non-poopers are important sources of potential infection to others- everyone should wash with soap and water!

Hospitals started seeing very severe cases of C.diff colitis with high mortality

The C. difficile had now become resistant to common antibiotics and flourished in the hospital

NAP-1 C. diff strain- nasty super bug now seen throughout Nevada and USA. Approx. 1/2 of all cases in NV are NAP-1 positive!!! resistant to common antibiotics overused in hospital, particularly fluoroquinolones A genetic mutation allows 10 to 20x more toxin A and B to be secreted, plus it has its own unique binary toxin More likely to progress to fulminant disease and death Increased rate of spore germination to active disease increases likelihood of relapse If your micro lab does a PCR test, they are already testing for NAP-1, but you may need to request results

C. Diff Lab Diagnosis Direct culture- not used - $$$/slow turn around time ELISA- Is the C. diff producing toxin? – detect toxin A +/- toxin B. Detects the toxin, but misses some cases – about 70% sensitive. Is that important? C. diff PCR- positive test tells you C. difficile carrying the toxin gene is present in the stool. 100% sensitive, but DOES NOT differentiate between asymptomatic carriers and toxin producers. Do not order as a test of cure!

Date of download: 2/17/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era JAMA Intern Med. 2015;175(11): doi: /jamainternmed Kaplan-Meier Curves of Time to Resolution of Diarrhea by Clostridium difficile Test GroupThe median duration of diarrhea for patients with at least 1 day was 3 days (interquartile range, 1-6 days) for Tox+/PCR+ (121 of 131), 2 days (interquartile range, 1-4 days) for Tox−/PCR+, and 2 days (interquartile range, 1-3 days) for Tox−/PCR− (927 of 1123) (P <.001). Log-rank P values are P <.001 for all groups, P =.003 for Tox+/PCR+ vs Tox−/PCR+, (143 of 162) P <.001 for Tox+/PCR+ vs Tox−/PCR−, and P <.001 for Tox−/PCR+ vs Tox−/PCR−. Tox+/PCR+ indicates C difficile toxin immunoassay positive and polymerase chain reaction positive; Tox−/PCR+, C difficile toxin immunoassay negative and polymerase chain reaction positive; Tox−/PCR−, C difficile toxin immunoassay negative and polymerase chain reaction negative. Figure Legend:

Are we over-diagnosing C. diff infection? Careful patient selection is vital Up to 50% of tested patients don’t have significant diarrhea Up to 40% are on a laxative regimen when tested The PCR test may be 100% sensitive, but only a 45% positive predictive value for CDI There is no difference in length of diarrhea or mortality in toxin-/PCR+ or toxin -/pcr- patients !

Negative consequences of over-treating CDI Contact precautions adversely effect the patient- anxiety, depression, isolation Receive unnecessary antibiotics that can paradoxically increase risk of actual CDI and select for VRE etc Expense of isolation, need for single room Adversely effect hospital infection incidence rate

Human beings as ecosystems- not just an individual, but a collaborative effort between commensal bacteria and their host

Original Article Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile Els van Nood, M.D., Anne Vrieze, M.D., Max Nieuwdorp, M.D., Ph.D., Susana Fuentes, Ph.D., Erwin G. Zoetendal, Ph.D., Willem M. de Vos, Ph.D., Caroline E. Visser, M.D., Ph.D., Ed J. Kuijper, M.D., Ph.D., Joep F.W.M. Bartelsman, M.D., Jan G.P. Tijssen, Ph.D., Peter Speelman, M.D., Ph.D., Marcel G.W. Dijkgraaf, Ph.D., and Josbert J. Keller, M.D., Ph.D. N Engl J Med Volume 368(5): January 31, 2013

Rates of Cure without Relapse for Recurrent Clostridium difficile Infection. van Nood E et al. N Engl J Med 2013;368:

Some new C. diff Developments The Beagle “Sniff” test as a near perfect diagnostic test Tigecycline looks to be an effective antibiotic in fulminant C.diff combined with oral vanco and iv metronidazole Enthusiasm for stool transplant, now available in (Jelly Belly Diarrhea Flavored ?) gelatin capsules!

New surgical approach for fulminant colitis- less invasive, better mortality Traditional – total colectomy Double-barrel ileostomy – preserves colon, much lower mortality

Test time!

I. Which fact is incorrect about C. diff? Causes 500,000 cases per year Severity of illness has increased last few years Majority of C. diff cases are community acquired Relapses are major problem with C. diff and may respond to stool transplant

II. Which of the following is incorrect regarding medical management of C. diff? Oral metronidazole is recommended for mild C. diff Oral vancomycin is preferred for moderate or severe C.diff Patients with fulminant C. diff with ileus should receive intravenous vancomycin

III. Manifestations of fulminant C. diff include all the following except: Severe abd pain and worsening diarrhea Hypotension requiring vasopressors Dropping WBCs Respiratory failure requiring intubation Elevated lactate levels Renal failure

IV. Increased virulence of NAP-1 strain is a result of which of the following ? Lower rates of germination Higher resistance to anti-fungal agents Gene mutation leading to reduced toxin production Ability to produce large amounts of toxin A and B that overwhelm treatment attempts

V. New approaches to C. diff infection include all of the following except: PCR testing for quicker and more sensitive diagnosis – but may result in over-treatment of a carrier state Stool transplant for recurrent disease Less invasive surgical techniques to improve outcome and allow for earlier intervention Fidaxomicin as an inexpensive and effective oral therapy for NAP-1 strain infections