Impact of Oral Antibiotic Treatment on C. Difficile

Background and Significance:

C. difficile has emerged as one of the most important pathogens that threaten the health and
quality of life for many populations. Data from different studies clearly indicate that
shedding of viable spores and subsequent contamination of environmental surfaces play an
important role in the transmission of C. difficile. We aim to perform an analysis of the
impact of different oral antibiotic therapy on microbiologic kinetics in patients with C.
difficile diarrhea, such as: shedding, colonization and environmental contamination. We
believe data from this study can inform whether drug therapies may be used to interrupt
disease transmission and to improve the infection control of C. difficile.

Purpose of the Study:

The purposes of this study are to 1) determine the impact of oral fidaxomicin, oral
metronidazole and oral vancomycin on the baseline and the temporal variation of C. difficile
isolated from specific body sites of a patient with microbiology-proven CDAD and 2) determine
the impact of oral fidaxomicin, oral metronidazole and oral vancomycin on the baseline and
the temporal variation of C. difficile isolated from targeted surfaces in a hospital room. ,
More specifically, we will establish the extent and quantity of C. difficile shedding,
colonization and environmental contamination in patients who received oral fidaxomicin, oral
metronidazole, or vancomycin and the duration that stool remains positive for C. difficile.

This study will prospectively study the role of the environment in Healthcare Associated
Infections (HAIs) in the modern healthcare setting and will specifically address many
limitations of previous studies. The study will use modern diagnostic and molecular methods
to describe the microbiologic characteristics and concordance of cultures from the
environment and from patient, describe temporal variation and relationship in the
microbiologic profiles of cultures obtained from the environment and from the patient, assess
confounders such as hand hygiene and quality of cleaning, and provide longitudinal follow up
for subsequent outcomes.

This study will utilize microbiologic and molecular techniques to critically and
prospectively examine the impact of the environmental bioburden on the risk of colonization
and infection of hospitalized patients. Data from this study will provide novel, important
information regarding the true impact of the hospital environment on the acquisition and
spread of HAIs and Multi-Drug Resistant (MDR)-pathogens in hospitalized patients over time.
As such, data collected in this study may provide important information about the mechanisms
and relative frequency of how and when environmental sources of bacteria lead to colonization
and infection in hospitalized patients. These data may in turn stimulate or justify the
future development of novel preventive interventions.

Design and Procedures/Study Interventions:

This is a randomized, controlled study of patients with documented CDAD, defined as having
polymerase chain reaction for C. difficile in a patient with more than 3 loose stools within
24 hours. Eligible patients for enrollment will be identified by microbiology-driven alerts
or by orders for contact isolation for C. difficile. Study team will be alerted to approach
the patient to provide information about the study and to obtain informed consent.

This study will obtain microbiological cultures from 2 sources: 1) environmental surfaces in
the room and 2) body surfaces of the patient at predefined intervals starting the day of
enrol1ment. Cultures will be obtained on Day 1 (day of enrol1ment), Day 3 and Day 7 following
admission to the room, at the end of each subsequent week (Day 14, Day 21, etc.), and on the
day of discharge from the hospital room. Microbiological cultures will be obtained from the
following body sites: perianal and stool specimens. Microbiological cultures will be obtained
from 5 high-touch environmental surfaces as outlined in the protocol.

Selection of Subjects:

A total of 30 patients are anticipated to be enrolled in this study, 10 in each of the three
treatment arms. Patients will be block-randomized to receive one of the three antibiotic
treatments for CDAD described above. The study will enroll 10 patients receiving
metronidazole therapy, 10 patients receiving oral vancomycin therapy and 10 patients
receiving oral fidaxomicin therapy.

As soon as the PI or study coordinator finds that a patient has a positive C. difficile
result, the primary care provider (PCP) in hospital will be contacted to discuss the patient.
If the PCP agrees to allow potential enrollment, the PCP will introduce the study to the
patient. If the patient indicates willingness to participate, the PI or study coordinator
will be introduced by the PCP or another caregiver known to the patient. The informed consent
process will take place if the patient is interested in participating. The patient will be
enrolled as a study subject if all eligibility criteria are met. The PCP will formally
prescribe fidaxomicin, metronidazole or vancomycin following randomization. Fidaxomicin will
be supplied by the study sponsor. Metronidazole and vancomycin will not be supplied by the
sponsor. If the subject is randomized to receive fidaxomicin, the PI or study coordinator
will notify the Duke Investigational Drug Service (IDS) that a subject is enrolling and will
order this drug through the IDS. As soon as the 10th subject who is prescribed fidaxomicin
enrolls, then enrollment will be closed to patients prescribed fidaxomicin. Enrollment will
be closed to subjects taking metronidazole and vancomycin as soon as the 10th subject in each
group is enrolled. The subject will begin treatment with the medication prescribed by the PCP
in hospital.

No compensation is being offered for participation in this study.

Consent Process:

The consent process will be conducted by a study coordinator or the principal investigator.
This will typically occur in the patient's hospital room..

Subject's Capacity to Give Legally Effective Consent:

Subjects will need to be able to give consent to participate in this study.

Risk/Benefit Assessment:

The risks are minimal for this study. First, patients may experience adverse effects from the
antibiotics that they consent to receive. Each of three agents is recommended for the
treatment of CDAD. Second, the microbiological samples that will be taken may cause some
discomfort and minor bleeding which will be discussed with the patient during the consenting
process. Declining to participate in the study will not affect the clinical care of the
patient. Results of study specimens will not be analyzed in real-time and will not be sent
back to clinicians.

SAEs are not anticipated for this study. Any standard SAE events that may occur will be
reported to the manufacturer and to the IRB.

There is no direct benefit to the patient in the study. The sponsor will supply Fidaxomicin
if this is prescribed for a patient enrolled in the study. The data from this study may
prompt future studies that examine the use oral antibiotics to reduce the transmissibility of
C. difficile.

Data Analysis and Statistical Considerations:

Descriptive statistics will be used to correlate culture results from the environment and the
patient.

Data and Safety Monitoring:

PI will review and sign off on all adverse events or problems as they occur and will submit
reports of such events to the IRB in accordance with HRPP policies and to the sponsor in
accordance with the protocol.

Privacy, Data Storage and Confidentiality:

Privacy during swabbing shall be maintained by swabbing the patient in the patient's room
with the door closed as would be appropriate for other patient care, using Universal
Precautions. To ensure privacy the patient and environmental samples will use an
automatically generated ID and room number in place of name, MRN or other personal
identifiers.

Data collected by the study will be entered into secure Access databases. All connections to
the system, both external and internal, occur over encrypted channels. Access to components
of the system is role-based and can only be granted by administrators of the system. All
collected information is stored on a server hosted by Duke Medicine.

Inclusion Criteria:

- adult patients with microbiology-proven CDAD

- provides informed consent

- eligible to receive oral antibiotic therapy

Exclusion Criteria:

- prisoners

- pregnant women

- children <18 years

- patients who have contra-indications for perianal swabs, those who has medical
conditions that would invalidate the results of the swabs

- patients requiring intravenous therapy for treatment of CDAD

- patients who do not consent and those who withdraw consent