TOX NEG Trial: Clostridium Difficile Diagnosis and Treatment
TOX NEG Trial: Clostridium Difficile Diagnosis and Treatment
The purpose of this study is to determine the risks and benefits of antibiotic treatment for
 Clostridium difficile infection (CDI) among patients whose stool samples are nucleic acid
 amplification test (NAAT) positive and enzyme immunoassay (EIA) negative for C. difficile.

 Currently, healthcare facilities use a wide variety of tests and strategies for identifying
 patients with CDI; both EIA and NAAT are widely used. There is no clear gold standard for
 identifying CDI. At WUSM and BJH, patients are only treated for CDI if they have a positive
 EIA. However, at many other healthcare facilities, the standard of care is to treat for CDI
 if the patient is NAAT positive. Some patients who are NAAT-positive may not have true CDI;
 while this treatment is standard of care at many facilities, the risk and benefits of
 treating these patients for CDI is unknown.

 We propose to perform a double blinded, randomized controlled non-inferiority trial of
 antimicrobial of patients who are EIA negative, NAAT positive to determine the risks and
 benefits of CDI treatment in this population.
Study Purpose:

 The purpose of this study is to determine the risks and benefits of antibiotic treatment for
 Clostridium difficile infection (CDI) among patients whose stool samples are nucleic acid
 amplification test (NAAT) positive and enzyme immunoassay (EIA) negative for C. difficile.

 Background:

 Clostridium difficile infection (CDI) is the most common cause of healthcare-associated
 diarrhea. There is no gold standard diagnostic test for (CDI). Commercially available assays
 detect C. difficile or its toxins in stool. Nucleic acid amplification tests (NAAT) are much
 more sensitive than toxin enzyme immunoassays (EIA). However, clinical correlation is needed
 to determine who has CDI. Most US clinical microbiology laboratories have adopted NAATs for
 C. difficile under the presumption the enhanced analytical sensitivity was beneficial.
 Although some patients with NAAT-positive/toxin-negative stool have CDI and a false-negative
 toxin EIA, subsequent studies indicate most patients with NAAT-positive / toxin-negative
 stool do not have CDI. Rather, they are asymptomatic C. difficile carriers who have diarrhea
 for other reasons. Most of these studies also have limitations and considerable controversy
 remains for whether NAATs or toxin EIAs should be used when CDI is suspected.

 Treatment of asymptomatic C. difficile carriers is not beneficial, and may result in harm. At
 hospitals that utilize NAATs, most patients with NAAT-positive / toxin-negative stool receive
 treatment for CDI. The most common treatments for CDI, metronidazole and oral vancomycin, are
 highly disruptive of the intestinal microbiome. These antimicrobials create selective
 pressures that promote the acquisition and proliferation of antimicrobial resistance and
 multidrug resistant organisms (MDRO), including public health threats such as MDRO
 Enterobacteriaceae like carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum
 beta-lactamase (ESBL) producing organisms, vancomycin-resistant Enterococcus (VRE), and the
 latest emerging threat Candida auris. This leads to MDRO infections and MDRO spread to
 others. Paradoxically, unnecessary treatment for CDI may increase risk for CDI once treatment
 is stopped contributing to CDI-related adverse events and C. difficile spread to others.
 Unnecessary CDI treatment potentially harms both that patient and other people. Whether the
 benefit of treating patients with NAAT-positive/toxin-negative stool that are missed cases of
 CDI outweighs the risk of treating patients with NAAT-positive/toxin-negative stool that are
 asymptomatic C. difficile carriers remains unknown.

 This study is a double-blinded randomized controlled trial of CDI treatment for patients with
 NAAT-positive / toxin-negative stool. Such a trial is necessary to understand the
 risk-benefit of treating these patients for CDI. Patients with NAAT-positive / toxin-negative
 stool who consent to participate will be randomized to 10 days of oral vancomycin or placebo.
 Stool and environmental specimens will be obtained at regular time points and interrogated
 with culturomic and metagenomic methods. Patients will be followed until eight weeks after
 discontinuation of study drug. These data and specimens will be used to determine the impact
 of oral vancomycin versus placebo on the microbiome, C. difficile and MDRO colonization,
 environmental contamination, duration of diarrhea, CDI-related adverse events, and death.

 Specific aims and hypotheses:

 Specific Aim 1: Determine if there are differences in microbiome disruption and acquisition /
 persistence of C. difficile and other MDRO carriage in stool among patients with
 NAAT-positive / toxin-negative stool who are randomized to a 10-day course of oral vancomycin
 versus placebo.

 Hypotheses: Study participants who receive oral vancomycin will have greater disruption of
 the taxonomic and functional metabolic profiles of the fecal microbiome, increases in
 antimicrobial resistance genes, acquire more MDRO, and will have greater persistence and
 abundance of MDRO in stool compared to participants who receive placebo. Participants who
 receive oral vancomycin will not have detectable C. difficile in stool after completion of
 study drug, but will be more likely to have C. difficile in stool at week 8 after completion
 of study drug compared to participants who receive placebo.

 Specific Aim 2: Determine if there are differences in C. difficile and other MDRO
 environmental contamination between treatment groups.

 Hypothesis: Study participants who receive oral vancomycin will have less environmental C.
 difficile contamination but more MDRO contamination compared to participants who receive
 placebo while receiving study drug. After study drug is completed, those who receive oral
 vancomycin will have more environmental contamination due to both C. difficile and other
 MDROs.

 Specific Aim 3: Determine if there are differences in CDI-related outcomes between groups.

 Hypothesis: There will be no difference in time to resolution of diarrhea or CDI-related
 outcomes between treatment groups.
Inclusion Criteria:

 -  Stool submitted to the BJH microbiology laboratory for C. difficile testing that tests
 negative for C. difficile toxins (C. difficile Tox A/B II, Alere, Waltham, MA) as part
 of routine clinical care and positive by NAAT (Xpert C. difficile, Cepheid, Sunnyvale,
 CA)

 -  Clinically significant diarrhea (≥3 diarrheal bowel movements per day or ≥1 diarrheal
 bowel movement plus abdominal pain)

 -  ≥18 years of age.

 Exclusion Criteria:

 -  The presence of a condition associated with persistent / prolonged / recurrent
 diarrhea, including, but not limited to:

 -  Upcoming chemotherapy

 -  Previous or upcoming bone marrow/hematopoietic stem cell transplant,

 -  Leukemia: new, not in remission, or receiving chemotherapy

 -  Inflammatory bowel disease

 -  Crohn's disease

 -  Ulcerative colitis

 -  Microscopic colitis

 -  Previous total colectomy

 -  Previous partial colectomy without return to formed bowel movement or previous
 resection of colon

 -  Colostomy or ileostomy

 -  Unable to follow study procedures

 -  Not expected to survive until study follow-up is complete

 -  Allergy or intolerance to oral vancomycin

 -  A history of CDI in the past 3 months

 -  Alternate infectious etiology for diarrhea

 -  Receipt of CDI antibiotic treatment (excluding empiric treatment given while pending
 EIA results)

 -  Does not provide consent will exclude a patient from participating in the trial.