Prevention of Clostridium Difficile-associated Diarrhea by Daily Intake of Kefir
Prevention of Clostridium Difficile-associated Diarrhea by Daily Intake of Kefir
This study is being conducted to investigate the potential benefits of probiotic intake for
 preventing antibiotic associated diarrhea and Clostridium difficile infection in patients
 undergoing a systemic antibiotic treatment. The primary research question is: can daily
 intake of kefir, a yogurt-like food containing probiotics, reduce the incidence of diarrhea
 and Clostridium difficile infection in patients during antibiotic treatment?
Background and Significance

 Clostridium difficile infections are of great concern for hospitals nationwide and C.
 difficile remains the most common nosocomial infection in North America. The majority of
 patients with C. difficile infection respond to orally administered metronidazole or
 vancomycin, but 5-30% of patients go on to develop recurrent infection and diarrhea, despite
 antibiotic treatments. The idea that gut microbiota influence susceptibility and recovery
 from disease is becoming more widely reported. Disruption of normal bacterial flora in the
 gut during systemic antibiotic use has been attributed to the uncontrolled growth of bacteria
 that are otherwise suppressed such as C. difficile. Even after an antibiotic regimen has
 concluded, restoration of the normal gut microbiota is thought to be paramount to
 interrupting the cycle of C. difficile infection. The idea of reintroducing normal microbial
 flora to patients with recurrent C. difficile infections has been the foundation upon which
 the use of probiotic agents, including fecal transplants, has been introduced. The use of
 probiotics to treat antibiotic-associated diarrhea, and specifically C. difficile infections,
 has been studied and successes have been reported, and in particular by our group. The
 emerging idea, however, is that probiotic consumption can be used to prevent the onset of a
 C. difficile infection, which requires further study. Meta-analyses have been conducted on
 previously reported data and ultimately conclude that the use of probiotics is safe and
 effective. However, there remains a need for a focused and controlled study assessing the
 efficacy of kefir consumption on the incidence of C. difficile infections at St. Luke's
 Hospital in Duluth, MN, and CHI Creighton University Medical Center in Omaha, NE. The data
 collected from this study have the potential to change clinical practice at not only our
 institutions, but at any hospital or institution that has a population of patients undergoing
 systemic antibiotic treatment.

 Risk factors for persistent C. difficile infection include age greater than 65 years, poor
 nutritional status, recent abdominal surgery, prolonged hospitalization and recent stay in
 the ICU. The purpose of this study is to determine if administering a daily regimen of kefir
 to at-risk patients can reduce the incidence of C. difficile infections. Because treatment
 for C. difficile infections is difficult and expensive, and recurrent infections are common,
 a way to prevent these infections is of great interest. A preventive measure that reduces the
 incidence of diarrhea and C. difficile infections will clearly improve patient health, and
 will have a multi-fold impact on how patients are cared for while in the hospital as well as
 post-discharge. There is potential for cost-saving, as well, in the form of the direct cost
 of antibiotic treatments and prolonged hospital stays. Additionally, the cost in time and
 effort to prevent the spread of these infections will be reduced, as well, all of which
 ultimately improve patient care.

 Preliminary Studies

 Many studies have been published indicating a potential for probiotics as a prophylaxis
 against diarrhea associated with antibiotic use in humans. Additionally, a recent report in a
 rodent model suggests that kefir consumption concomitantly with antibiotic treatment may
 prevent the development of C. difficile-associated diarrhea. However, to our knowledge there
 have not been any studies published that have investigated the preventive effects of kefir
 consumption specifically related C. difficile infection in human patients. This protocol will
 serve as an initial study for a subset of at-risk patients and the data collected will
 provide guidance for future studies to include a more broad range of at-risk patients.

 Research Design and Methods

 Subjects

 The study will include patients who have been prescribed a systemic antibiotic of any kind
 (administered by oral or parenteral route), but have not yet begun the treatment regimen.
 There will be three study groups:

 -  Group A: Patients receive antibiotics and receive no kefir

 -  Group B: Patients receive antibiotics and receive kefir during their hospital stay only

 -  Group C: Patients receive antibiotics and receive kefir following discharge for the
 duration of their antibiotic regimen, for a maximum of 30 days

 All patients will receive a journal to track their kefir intake (if in Group C) and any loose
 stools or diarrhea for 30 days after their hospital stay. Additionally, all patients will
 receive a follow-up phone call 3-5 days after discharge from the hospital, and weekly
 thereafter for 30 days, to determine if diarrhea has occurred. All patients will be
 instructed to call their physician if symptoms of diarrhea occur. The aims of this study are
 to determine the incidence of antibiotic-associated diarrhea in each of the study groups as
 well as the presence of C. difficile in the stool of those patients that report having
 diarrhea.

 Data Collection and Accrual Methods

 Patients who meet inclusion criteria and consent to be part of the study will be assigned to
 one of the three study groups at random.

 During the standard admissions interview, patients are asked about any allergies, including
 milk protein allergy. This type of allergy will exclude patients from participating in the
 study. Because kefir is 99% lactose free, lactose intolerance will not exclude individuals
 from participating. Per standard of care, a physical exam will be performed and a
 symptom-directed exam will be performed at any follow-up appointments, typically one month
 after discharge from the hospital.

 Patients in study groups consuming kefir will receive an information card that includes the
 nutrition facts for a 4-ounce serving of kefir. Lifeway brand Kefir® will be used as it is
 widely available and comes in several palatable flavors. The probiotic content of Lifeway
 Kefir remains constant, regardless of flavor.

 Patients in Group A will receive their prescribed antibiotics during their hospital stay and
 will not receive kefir. These patients will be instructed to not consume any yogurt, kefir,
 or other probiotic products during their hospital stay and for 30 days post-discharge.

 Patients in Groups B and C will begin receiving kefir on the same day that their prescribed
 antibiotic regimen begins. Four ounces of kefir will be administered 3 times a day to
 patients enrolled on this study. A 4 oz. glass of kefir will be provided with every mealtray,
 and nursing staff at each of the participating institutions will administer the kefir to the
 patients. The amount of kefir consumed by the patient will be recorded by the nursing staff
 and entered in the electronic medical record. Four ounces is a standard serving of yogurt and
 is well-tolerated by patients. This serving size will help maintain ongoing live probiotic
 cultures in the individuals receiving kefir.

 For patients in Group B, administration of kefir by the nursing staff will continue for the
 duration of the patients' hospital stay only. For patients in Group C, kefir will be
 prescribed at the same dose as given during their hospital stay (at least 4 ounces of kefir 3
 times each day, not to exceed 12 ounces per day).

 All patients will be given a journal in which they can record any symptoms of a C. difficile
 infection (i.e., diarrhea). Additionally, patients in Group C will record their kefir
 consumption on a daily basis. All patients will receive a follow-up phone call 3 days after
 their hospital discharge and weekly thereafter for 30 days (a total of 4 phone calls).
 Patients will be asked if they have had any incidence of diarrhea in order for nursing staff
 and physicians to assess if C. difficile infection has occurred.

 All patients will be asked to contact their physician if they experience diarrhea after their
 hospital stay. These patients will be offered a fecal C. difficile test, as per standard of
 care. Any patient that has 3 or more watery stools in a 24 hour period and a positive C.
 difficile stool test will be considered as having a C. difficile infection. Stool collection
 and testing will be carried out per treatment guidelines. No further typing of C. difficile
 isolates will be performed on samples obtained as it is beyond the scope of this study.

 Patients who develop a C. difficile infection during the study will be immediately treated
 per standard of care and will be considered treatment failures. However, these patients will
 be contacted for follow-up information pertinent to the study (i.e., duration of symptoms,
 and efficacy of standard treatment). Follow up contacts will be made via telephone; an
 initial call will be made 3 days post discharge from the hospital and patients will be
 contacted weekly thereafter for 30 days. During these phone calls, patients will be asked if
 they have any concerns or symptoms, specifically related to diarrhea.

 If at any point during the hospitalization or during the follow-up timeframe a patient
 receiving kefir displays signs or symptoms of an invasive bacterial, yeast, or fungal
 infection, blood cultures and other cultures as deemed clinically appropriate (urine culture,
 sputum culture, wound culture, etc.) will be obtained. Signs and symptoms of an invasive
 infection include, but are not limited to, the following: fever, chills, elevated WBC
 concentration, elevated serum C-reactive protein (CRP) and/or procalcitonin levels, and
 hypotension.

 If a suspected invasive infection occurs during the course of kefir administration, the
 following empiric treatment regimen will be considered:

 • Intravenous administration of vancomycin plus piperacillin/tazobactam plus fluconazole

 -  Intravenous daptomycin will be used for patients with a previously documented vancomycin
 allergy

 -  An intravenous fluoroquinolone (ciprofloxacin or moxifloxacin) will be used for patients
 with a documented penicillin allergy

 -  Intravenous micafungin will be used for patients with a documented fluconazole allergy

 Initial intake screening for inclusion in the kefir research study will include an evaluation
 of known allergies. Antibiotic therapy will be adjusted in accordance with identification of
 the causative organism(s) and corresponding antibiotic susceptibilities. Treatment duration
 will be determined based on standards of care for the clinical situation and the causative
 organism.

 Data Analysis

 The three treatment groups will be compared using logistic regression with covariates of
 study location, age, gender, antibiotic type and doses, hypoalbuminemia, and compromised
 immune system. Model selection based on the Akaike Information Criterion will be used to
 select covariates in final models. The treatment groups will also be compared without
 covariate adjustment. As needed, missing data will be handled using multiple imputation after
 assessment of missing at random considerations. Dependent and independent variables in
 planned analyses will be included in imputations along with any auxiliary variables thought
 to be potentially related to predicting the missing data. In addition, in order to include
 other auxiliary covariates in the imputations that are potentially related to missingness,
 logistic regression will be performed with the dependent variable missing/not missing. Only
 imputed values of independent variables will be used in the analyses. Multiple imputation
 will be performed with the R package mi.

 The data being collected from the patient journals are to be used to monitor compliance with
 antibiotic use, kefir consumption, and any symptoms of C. diff infection. These data will be
 particularly useful in the event that there is no difference seen in C. diff infection rates
 among the study groups. From the self-reported patient data, compliance can be monitored and
 exclusion from the study may be warranted in the case of non-compliance.
Inclusion Criteria:

 Patients who have:

 -  Been admitted to the medical unit on 7 West at St. Luke's Hospital (Duluth, MN)

 -  Been prescribed a systemic antibiotic of any kind (administered by oral or parenteral
 route), but have not yet started the regimen

 -  Consented to be randomized and take part in the study and are adults greater than 19
 years of age

 Exclusion Criteria:

 Patients who are/have:

 -  Tube feeding

 -  Undergoing dialysis and other renal treatment

 -  An existing C. difficile infection

 -  A recent history of C. difficile infection (within the last 3 months)

 -  A recent history of antibiotic use (within the last 3 months)

 -  Inflammatory bowel disease, Crohn's disease, or other chronic gastrointestinal
 syndrome

 -  A history of acquired of genetic immunodeficiencies; active, acute or chronic serious
 infections (i.e., viral hepatitis, HIV/AIDS), or autoimmune disorders

 -  Undergoing gastrointestinal surgery, radiation, or cytotoxic chemotherapy

 -  Allergy to milk protein