Clinical trial NCT02951702
Conditions: Clostridium Difficile Infection Prophylaxis Vancomycin
Sponsor: St. Luke's Hospital, Chesterfield, Missouri
Start date: 2016-11-01; Completion date: 2017-07-01
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if oral vancomycin used as primary Clostridium difficile prophylaxis can reduce the incidence of this infection in high-risk patients.

Detailed description:
Clostridium difficile infection is a common healthcare-associated infection and one that is associated with significant morbidity as well as a risk for mortality. Current practice throughout the United States is targeted at infection prevention measures such as hand washing and isolation. Despite these measures, incidence of Clostridium difficile infections continue to rise as some institutions, including our own. Recently, a study published in Clinical Infectious Diseases found oral vancomycin for secondary prophylaxis to reduce the incidence of recurrence. No studies to date have evaluated primary prophylaxis with oral vancomycin. This will be a single center, prospective study to evaluate oral vancomycin use as primary Clostridium difficile prophylaxis. Patients treated by infectious disease physicians will be identified as "high risk" and after pager notification the ID physician will have the option to start oral vancomycin 125 mg by mouth daily if they determine it to be appropriate. Risk factors include age older than 65 years, taking gastric acid suppression medication, and receiving select broad-spectrum antibiotics. Oral vancomycin will be continued until de-escalation of antibiotics or hospital discharge and patients will be evaluated for Clostridium difficile infection development from the current hospital admission up to 4 weeks following antibiotic discontinuation.

Arms: arm 1: This will be the historical arm that has not received oral vancomycin but match criteria for "high risk" arm 2: This arm will receive oral vancomycin 125 mg daily if "high risk" and determined to be appropriate by an ID physician Intervention type: drug, vancomycin 125 mg daily
Interventions: intervention 1: Vancomycin Oral
Intervention descriptions: intervention 1: This arm will receive oral vancomycin 125 mg daily if "high risk" and determined to be appropriate by an ID physician

Protocol documents:
Prot_SAP_000.pdf: 
Oral Vancomyin for Primary Clostridium Difficile Infection  
Prophylaxis in Patients Receiving High-Risk Antibiotics 
Ryan Medas, Pharm.D. 
St. Luke’s Hospital 
232 Woods Mill Road 
Chesterfield, MO 63107 
ryan.medas@stlukes-stl.com  
Phone: 314-205-6100 x4062 
Fax: 314-205-6791 
 
Introduction 
Clostridium difficile infection (CDI) occurred in over 500,000 patients in 2011, and was found to 
account for 14,000 deaths in the United States in 2007.1 CDI provides a burden of 
approximately $3.2 billion annually in the United States.2 Transmission of Clostridium difficile 
from one patient to others can easily occur, and CDI outbreaks have been reported across the 
country. Additionally, once a patient has an initial episode, the rate of recurrence is 
approximately 20%.3 Rates of CDI have increased over the past couple decades across the 
country and St. Luke’s Hospital has also seen a rise in CDI incidence. 
 
A variety of risk factors have been identified for CDI: antibiotic use, number and duration of 
antibiotics, duration of hospitalization, age greater than 65 years, gastrointestinal (GI) acid 
suppression, GI surgery and tube feeds, and immunosuppression such as chemotherapy and 
HIV.3-5 The largest contributor to CDI risk is the use of antibiotics. Fluoroquinolones, 
clindamycin, and 3rd generation cephalosporins have been identified as carrying the highest 
risk.4,6 Additionally, broad-spectrum penicillins have been found to convey a higher risk of 
CDI.4,6 Hospitalized patients on antibiotics are particularly vulnerable because often additional 
risk factors are present such as simply being in the hospital and receipt of gastrointestinal (GI) 
acid suppression therapy with a proton-pump inhibitor (PPI) or histamine-2 receptor antagonist 
(H2RA).  
 
As the CDI incidence has been on the rise, a variety of preventative measures have been 
utilized and are supported by guidelines from the Infectious Diseases Society of 
America/Society of Healthcare Epidemiology of America (IDSA/SHEA).3 These 
recommendations include use of gloves and gowns upon entry into patient rooms who have 
CDI, hand hygiene with soap and water, patient isolation, and antimicrobial use restrictions.3 
Despite these implementations in hospitals throughout the country and at St. Luke’s Hospital, 
CDI still remains an issue. Van Hise and colleagues found that prophylactic oral vancomycin in 
patients with a history of CDI and treated actively with antibiotics at the time of inclusion had a 
reduction in CDI recurrence up to 4 weeks following the discontinuation of antibiotics. This is 
one retrospective, single-center study and thus further studies are needed to uniformly adopt 
this practice, but it may be a promising lead in reducing CDI recurrence if results can be 
replicated.7  
 


The study by Van Hise and colleagues reviewed secondary prophylaxis. St. Luke’s Hospital and 
hospitals throughout the country have adopted preventive strategies recommended by the IDSA 
guidelines, and yet CDI incidence continues to increase. As a result, further preventative 
measures need to be explored to prevent the first episode of CDI. Currently there is no literature 
regarding the use of oral vancomycin for primary CDI prophylaxis in high-risk patients for 
infection. The purpose of the study is to evaluate the efficacy of primary oral vancomycin 
prophylaxis in patients deemed high risk for CDI.  
 
 
Objectives 
 
The primary outcome of this study is CDI occurrence 4 weeks following the completion of 
antibiotic therapy or hospital discharge, whichever occurs first.  
 
Secondary outcomes include time to CDI occurrence and CDI severity which will be based on 
the IDSA/SHEA criteria for mild to moderate, defined as white-cell count less than 15,000 
cells/µL or increase in serum creatinine (SCr) by <1.5 times the baseline; severe, defined as 
white-cell count greater than 15,000 cells/µL or increase in SCr by >1.5 times the baseline; and 
fulminant, defined as the criteria above for severe with shock, hypotension, ileus, or megacolon.  
 
Methods 
This will be a pre-post intervention cohort study of patients treated for infection with the below 
listed risk factors for CDI in addition to antibiotic therapy. This study will be limited to the 
infectious diseases physicians at St. Luke’s Hospital. This will allow for expert review and 
decision-making regarding prophylaxis for each patient. The CDI prophylaxis intervention will be 
vancomycin 125 by mouth daily.  
 
The intervention will be the identification of “high risk” patients and subsequent clinical decision 
to start prophylaxis based on collaboration with the consulted infectious disease physician on 
the case. Oral vancomycin 125 mg by mouth daily was selected for inclusion since oral 
vancomycin is known to concentrate in the colon with stool concentrations exceeding 800 mcg/g 
in patients receiving treatment doses (vancomycin 125 mg PO every 6 hours), and minimal 
inhibitory concentrations (MICs) for Clostridium difficile are typically 1 to 2 mcg/mL.8-10 
Additionally, we hypothesize that vancomycin 125 mg daily may minimize disruption of normal 
flora and allow for increased vancomycin dose and interval if overt infection develops.11  
 
Infectious diseases providers will be notified through daily pager notification of potential patients 
on whom they are consulted that meet inclusion criteria and the decision is left to the infectious 
disease physician to start oral vancomycin or to withhold from prophylaxis. If therapy will be 
started, consent will be obtained. The discontinuation of oral vancomycin prophylaxis will be left 
to the discretion of the infectious disease provider. 
 
Patients at high risk must be 65 years of age or older, on GI acid suppression with an H2RA or 
PPI, and receiving pre-specified antibiotics. Age and GI acid suppression have been identified  


in the literature as risk factors for CDI in addition to antibiotic risk factors. Patients must receive 
a select group of antibiotics for greater than 24 hours. The antibiotics considered for inclusion 
are a fluoroquinolone (ciprofloxacin, levofloxacin), clindamycin, a 3rd or 4th generation 
cephalosporin, a broad-spectrum aminopenicillin (ampicillin-sulbactam, piperacillin-tazobactam), 
or a carbapenem. These antibiotics were chosen due to their association with a higher risk of 
CDI occurrence. Patients will be excluded if they do not meet all three requirements for “high 
risk” (age, acid suppression, and antibiotic) or if they have a vancomycin allergy that precludes 
its use. Additionally, patients who had active CDI prior to antibiotic initiation, who were on 
prophylactic vancomycin prior to antibiotic therapy, or who received medications that cover CDI 
as part of the primary antibiotic treatment will be excluded (metronidazole, rifaximin, 
fidaxomicin). Patients will be excluded if they are pregnant or breastfeeding. 
 
CDI will be defined as documentation of loose stools or diarrhea with a positive C. diff toxin and 
glutamate dehydrogenase (GDH) or positive polymerase chain reaction (PCR). The diagnosis of 
CDI at St. Luke’s Hospital begins with a toxin and GDH. If both are positive, then the patient is 
determined to have CDI, if both are negative, then the patient does not have CDI. If the results 
are discordant (i.e. one positive and one negative) then a PCR is run to determine the presence 
of CDI. Thus a patient can be diagnosed with CDI by either a positive toxin and GDH or by a 
positive PCR.  
 
Baseline patient information will also be gathered including age, race, sex, antibiotic indication, 
antibiotics used, antibiotic duration, probiotic use, H2RA, or PPI use prior to or during 
hospitalization, oral vancomycin duration, severity of disease parameters (white blood cell 
count, SCr, hypotension, shock, ileus, megacolon).  
 
Data collection will occur for patients admitted to St. Luke’s Hospital from May 1, 2014 to May 1, 
2017. The pre-intervention arm will be patients treated at St. Luke’s Hospital between May 1, 
2014 and August 1, 2016. Pre-intervention patients will be identified based upon a report that 
identifies patients older than 65 years of age and receiving the antibiotics outlined above. If 
patients meet all three “high risk” criteria, they will be matched according to antibiotic received 
with the post-intervention arm. The post-intervention arm will be included through April 1, 2016 
and evaluated from November 1, 2016 through May 1, 2016. All patients meeting criteria and 
consenting to treatment will be included. The study will target a total of 100 patients in each 
arm.  
 
Statistics 
The difference in the primary outcome will be assessed using chi-square and Fisher’s exact, as 
appropriate. CDI severity (mild-moderate, severe, fulminant) will be assessed using chi-square 
and time to CDI occurrence will be analyzed using a Kaplan-Meier curve.  
 
Data Handling and Record Keeping 
Data will be stored on a password-locked computer. The computer is located in the clinical 
pharmacy office which is locked and requires a key for access during off hours. Patient data will 


be collected from electronic records that require a username and password for access. Patient 
identifiers will be removed when sharing information with others.  
 
 
 
 
References 
1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United 
States. N Engl J Med. 2015;372:825-834. 
2. O’Brien JA, Lahue BJ, Caro JJ, et al. The emerging infectious challenge of Clostridium 
difficile–associated disease in Massachusetts hospitals: clinical and economic consequences. 
Infect Control Hosp Epidemiol. 2007;28:1219–1227. 
 
3. 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(5):431-455.  
 
4. Owens Jr RC, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial risk factors for 
Clostridium difficile infection. Clin Infect Dis. 2008;46:S19-31. 
 
5. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of healthcare-
associated infections. N Engl J Med. 2014;370(13):1198-1208. 
 
6. Marra F, Ng K. Controversies around epidemiology, diagnosis, and treatment of Clostridium 
difficile infection. Drugs. 2015;74:1095-1118. 
 
7. Van Hise NW, Bryan AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of 
oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with 
systemic antimicrobial agents. Clin Infect Dis. 2016 published ahead of print. 
 
8. Keighley MR, Burdon DW, Arabi Y, et al. Randomised controlled trial of vancomycin for 
pseudomembranous colitis and postoperative diarrhoea. BMJ 1978;2:1667–1669. 
 
9. Wong SS, Woo PC, Luk WK, et al. Susceptibility testing of Clostridium difficile against 
metronidazole and vancomycin by disk diffusion and E-test. Diagn Microbiol Infect Dis. 
1999;34:1–6. 
 
10. Freeman J, Stott J, Baines SD, et al. Surveillance for resistance to metronidazole and 
vancomycin in genotypically distinct and UK epidemic Clostridium difficile isolates in a large 
teaching hospital. J Antimicrob Chemother. 2005;56:988–989. 
 
11. Johnson S. Potential risks and rewards with prophylaxis for Clostridium difficile infection. 
Clin Infect Dis. 2016. Editorial Commentary:1-2.