Enteral Vancomycin as Primary Prophylaxis Against Clostridioides Difficile Infection in Critically Ill Patients

Overview

The goal of this clinical trial is to determine if oral vancomycin can prevent C.diff infection in adults who are critically ill and are at high risk of C.diff infection due to their medical conditions and being in the hospital. It will also help us learn about the safety of the drug in this setting. The main questions the trial aims to answer are: * Does oral vancomycin lower the rate of C.diff infection in high-risk patients? * Does C.diff carrier status change the C.diff infection rate as well as clearance of carrier status when vancomycin is used as primary prophylaxis? Researchers will compare the oral, active drug vancomycin to a placebo (a look-alike substance that contains no drug) to determine if vancomycin works to prevent C.diff infection in the hospital. Participants will: * Take oral vancomycin or a placebo while they receive systemic antibiotic(s) for up to five days after the last dose of said systemic antibiotic(s). The treatment of said systemic antibiotic(s) is not to exceed 21 days. * When discharged from the hospital, participants will continue to take the study medication in the event he/she did not complete the intended course of the study medication while in the hospital. * Participants will provide stool sample or rectal swabs for to assess their C.diff carrier status as well as any change in stool microbiome status, including VRE (vancomycin resistant Enterococcus) * After completion of the intervention period, participants will be contacted via telephone to assess if they developed diarrhea or any untoward effects of study medication.

Detailed description

Protocol Synopsis

General: Enteral vancomycin has gained attention as a promising strategy for preventing healthcare facility-onset Clostridioides difficile infection (HCFO-CDI) in patients during systemic antibiotic exposure in certain high-risk populations. However, data remain scarce for its use as primary prophylaxis. Our study aims to fill this gap and evaluate whether enteral vancomycin prophylaxis can reduce the incidence of HCFO-CDI in critically ill patients along with other relevant clinical outcomes.

Study Population: Study subjects will include hospitalized subjects with significant risk factors for HCFO-CDI. Inclusion and exclusion criteria are as follows:

Inclusion criteria: Adult patients with at least 72 hours of hospitalization who are on a systemic antibiotic for at least 72 hours presenting with two additional risk factors for the development of HCFO-CDI.

Exclusion criteria: Subjects whose consent cannot be obtained, those with concurrent use of probiotics or metronidazole (except for empiric use), those with an expected course of antibiotic for more than 14 days, those with a prior history of CDI, etc.

Study Intervention: Study subjects will be randomized into two study arms - treatment versus placebo. Those in the treatment arm will receive vancomycin 125 mg solution daily for up to five days after the last dose of systemic antibiotic. Those in the placebo arm will receive a matching placebo solution. A rectal swab will be performed on all subjects prior to randomization and at study termination or discharge to assess C. difficile colonization and the possible development of vancomycin-resistant Enterococcus colonization.

Primary outcome: Incidence of HCFO-CDI, defined as symptoms of ≥ 3 loose stools or diarrhea (in the absence of laxatives or other non-CDI causes) in a 24-hour period in subjects with concurrent positive stool test for C. difficile (polymerase chain reaction \[PCR\] and stool toxin test) \> 72 hours into hospitalization.

Enrollment period and sample size: First dose of enteral vancomycin or matching placebo will be administered within 72 hours of the first dose of systemic antibiotic. Study investigators will monitor the subjects for adherence and possible adverse events every 3 days until hospital discharge. We are planning 1:1 randomization of the study subjects in each group (placebo versus prophylaxis group). Utilizing a 2-sided α of 0.05 and 80% power, an estimated sample size is 176 (88 subject per arm). Sample size was determined by estimating a 0% incidence of HCFO-CDI in the prophylaxis arm and a 10% incidence of HCFO-CDI in the placebo arm based on historical and institutional data. We also anticipate a 20% drop out or attrition rate after randomization.

Interventions

• Drug Vancomycin 125mg
  Vancomycin 125 mg orally daily
• Drug Placebo
  Syrup solution used to mixed with Vancomycin will be used in equal volume to be the placebo comparator.

Primary outcome measures

• Incidence the rate of healthcare facility-onset Clostridioides dificile infection (CDFO-CFI). [Time frame: up to 4 months]

Secondary outcome measures (6)

• Incidence of Vancomycin Resistance Enterococcus (VRE) colonization in stool sample. [Time frame: up to 30 days]
• Rate community onset healthcare facility-associated CDI. [Time frame: up to 90 days]
• Time to Clostridioides difficile infection in symptomatic patients [Time frame: up to 30 days]
• Clostridioides difficile colonization at discharge (PCR and toxin) [Time frame: up to 30 days]
• Hospital length of stay (day) [Time frame: up to 30 days]
• In-hospital Mortality [Time frame: up to 30 days]

Eligibility criteria

Inclusion criteria

• Must meet all 3 criteria:

• Adults aged 18 years and older.
• Receiving ≥ 72 hours of a systemic antibiotic during index hospitalization.
• Admitted ≥ 72 hours into their index hospitalization.
• And must meet 2 additional of the following high-risk criteria

• Age ≥ 65 years
• Previous residence in long-term care facility
• Previous proton pump inhibitor use (chronic or as needed)
• Inflammatory bowel disease
• Immunocompromised state (HIV/AIDS; transplant recipient; receipt of prednisone 20 mg daily for at least one month, immunosuppressants, or chemotherapy)
• End stage renal disease (ESRD)
• Diabetes mellitus
• Receipt of catecholamines (norepinephrine at a rate of ≥ 5 mcg/min)
• Hospitalized ≤ 30 days prior to the index hospitalization.
• Received systemic antibiotics during that prior hospitalization.

Exclusion criteria

• Pregnant or breastfeeding women
• Currently incarcerated individuals
• Individual or legal representative whose informed consent cannot be obtained
• Subject not expected to survive the ICU stay or subject likely to be considered for palliative or hospice care
• Receiving concurrent treatment with metronidazole for any indication
• One-time empiric use of metronidazole is allowed and does not constitute an exclusion criterion
• Receiving concurrent probiotics
• Allergic reaction or had a contraindication for use of enteral vancomycin
• History of prior CDI within the past 90 days of randomization
• Had suspected active CDI prior to inclusion
• Infection requiring more than 14 21 days of systemic antibiotics during index hospitalization

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

United States · 1 center

• Riverside University Health System — Moreno Valley

Publications

• Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol. 2016 Oct;14(10):609-20. doi: 10.1038/nrmicro.2016.108. Epub 2016 Aug 30. PMID 27573580
• Bobo LD, Dubberke ER, Kollef M. Clostridium difficile in the ICU: the struggle continues. Chest. 2011 Dec;140(6):1643-1653. doi: 10.1378/chest.11-0556. PMID 22147824
• Rineh A, Kelso MJ, Vatansever F, Tegos GP, Hamblin MR. Clostridium difficile infection: molecular pathogenesis and novel therapeutics. Expert Rev Anti Infect Ther. 2014 Jan;12(1):131-50. doi: 10.1586/14787210.2014.866515. PMID 24410618
• Zhang S, Palazuelos-Munoz S, Balsells EM, Nair H, Chit A, Kyaw MH. Cost of hospital management of Clostridium difficile infection in United States-a meta-analysis and modelling study. BMC Infect Dis. 2016 Aug 25;16(1):447. doi: 10.1186/s12879-016-1786-6. PMID 27562241
• Vedantam G, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK. Clostridium difficile infection: toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes. 2012 Mar-Apr;3(2):121-34. doi: 10.4161/gmic.19399. Epub 2012 Mar 1. PMID 22555464
• Lemiech-Mirowska E, Michalkiewicz M, Sierocka A, Gaszynska E, Marczak M. The Hospital Environment as a Potential Source for Clostridioides difficile Transmission Based on Spore Detection Surveys Conducted at Paediatric Oncology and Gastroenterology Units. Int J Environ Res Public Health. 2023 Jan 15;20(2):1590. doi: 10.3390/ijerph20021590. PMID 36674344
• Kochan TJ, Foley MH, Shoshiev MS, Somers MJ, Carlson PE, Hanna PC. Updates to Clostridium difficile Spore Germination. J Bacteriol. 2018 Jul 25;200(16):e00218-18. doi: 10.1128/JB.00218-18. Print 2018 Aug 15. PMID 29760211
• Gil F, Lagos-Moraga S, Calderon-Romero P, Pizarro-Guajardo M, Paredes-Sabja D. Updates on Clostridium difficile spore biology. Anaerobe. 2017 Jun;45:3-9. doi: 10.1016/j.anaerobe.2017.02.018. Epub 2017 Feb 22. PMID 28254263

Identifiers

NCT: NCT07221370 · IRBNet #: 2114799-4

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗