Healthy Patients & Effect of Antibiotics

Prospective Study Characterizing Fecal Microbiome Disruptions During and After Receipt of Antimicrobials

The objective of this study is to evaluate the impact of antimicrobial (antibiotic) exposures on the microbiome in healthy adults, specifically during and after usual courses of the antimicrobials used to treat community acquired pneumonia (CAP). Pneumonia is a lung infection, and community-acquired pneumonia is pneumonia that develops outside of a healthcare facility (i.e., in the community). A microbiome is a the community of microorganisms living in a particular location, such as the gut or the mouth. Disruptions to a person's microbiome may reduce his/her "colonization resistance" (resistance to colonization with pathogenic microorganisms) and make him/her more susceptible to multidrug resistant organism (MDRO) colonization and infection.

To study changes in the microbiome, the investigators will recruit 20 healthy adult volunteers and obtain fecal, salivary, skin, and urine specimens at multiple time points before, during, and after administration of antimicrobials. Participants will be randomized to one of 4 antimicrobial regimens, all of which are FDA-approved for treatment of community-acquired pneumonia. Stool specimens will be analyzed via stool culture and genetic sequencing, and all remaining specimens will be frozen and used to create a biospecimen repository for future analysis. The rationale for using healthy volunteers (instead of patients already prescribed antibiotics by their physicians) is because the human microbiome is very complex and can be affected by a variety of medical conditions and other medications. In addition, the presence or absence of patient-specific factors means people with infections may not be prescribed the specific courses of antibiotics the investigators are trying to study. Studying the effect of antibiotics on healthy volunteers will provide baseline data that are more applicable to the population at large.

Study Overview

• Status: Completed
• Conditions: Anti-bacterial Agents; Microbiota
• Intervention / Treatment: Drug: Levofloxacin; Drug: Azithromycin; Drug: Cefpodoxime

Detailed Description

Each year, antimicrobial resistance causes over two million infections and 23,000 deaths in the US alone, representing a critical global public health issue. Some of the most feared multidrug resistant organisms (MDROs) include Clostridium difficile, carbapenem-resistant Enterobacteriaceae (CRE), extended spectrum beta-lactamase producing Enterobacteriaceae (ESBL), MDRO Acinetobacter, and MDRO Pseudomonas aeruginosa; there are few antimicrobials effective against these MDROs, and available antimicrobials often have rate-limiting toxicities. The major risk factor for MDRO colonization and subsequent MDRO infections is exposure to antimicrobials. The use of antimicrobials has been associated with an altered and often less diverse composition of the fecal microbiome, and expansion of the resistome. A "healthy" microbiome provides "colonization resistance" against potentially pathogenic bacteria; antimicrobials disrupt this protective community, providing selective pressure that favors MDRO colonization, persistence, and transmission to others.

Methods to proactively prevent MDRO colonization, rather than reliance on reactive approaches to this problem, are urgently needed. Antimicrobial stewardship is a key component of MDRO prevention efforts; however, there is no method to determine which antimicrobials cause the greatest degree of microbiome disruption. A better understanding of exactly how antimicrobials alter the microbiome is necessary to optimally guide future MDRO prevention efforts and antimicrobial stewardship. The development of microbiome disruption indices (MDIs) would help characterize the risk associated with specific antimicrobials, and can be used during antimicrobial development, patient monitoring while on antimicrobials, and to facilitate infection prevention efforts to contain MDRO spread. Additionally, MDIs can be used as an alert when microbiome disruptions reach a critical level and MDRO colonization is imminent. At that point, interventions to restore the microbiome could be implemented.

Community-acquired pneumonia (CAP) is one of the leading causes of death in the United States, with an estimated >900,000 cases each year in adults age 65 and older. Large amounts of antimicrobials are used in treating patients with CAP because the disease is relatively common. A better understanding of the effect of CAP antimicrobial treatment on the microbiome could result in improved treatment options for patients with CAP and protect CAP patients from colonization or infection with MDROs.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy adults ages 21-60 residing in the St. Louis, Missouri, USA metropolitan area

Exclusion Criteria:

• History of allergic reaction to study antimicrobial(s)
• Contraindication(s) to study antimicrobial(s)
• Inability to provide regular stool samples
• Any non-topical antimicrobial exposure in previous 6 months
• Tube feeds as primary source of nutrition in previous 6 months
• Pregnant or risk of becoming pregnant during study period
• Breastfeeding during study period
• Gastroenteritis in last 3 months
• Any non-elective hospitalization in the previous 12 months
• Incontinent of stool
• Known colonization with an MDRO
• Anticipated change in diet or medications during study period
• Elective surgery during study period
• History of an intestinal disorder
• Inability to provide written, informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levofloxacin; 1 750mg tab of levofloxacin by mouth for 5 days	Drug: Levofloxacin; 5 days of levofloxacin administration; Other Names: Levaquin, Quixin, Iquix
Experimental: Azithromycin; 1 500mg tab by mouth on day 1, then 1 250 mg tab per day by mouth for 4 days (total 5 days)	Drug: Azithromycin; 5 days of azithromycin administration; Other Names: Zithromax, AzaSite, Zmax
Experimental: Cefpodoxime; 200mg tab by mouth twice per day for 5 days	Drug: Cefpodoxime; 5 days of cefpodoxime administration; Other Names: Vantin
Experimental: Azithromycin and cefpodoxime; Azithromycin: 1 500mg tab by mouth on day 1, then 1 250 mg tab per day by mouth for 4 days (total 5 days) Cefpodoxime: 200mg tab by mouth twice per day for 5 days	Drug: Azithromycin; 5 days of azithromycin administration; Other Names: Zithromax, AzaSite, Zmax; Drug: Cefpodoxime; 5 days of cefpodoxime administration; Other Names: Vantin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Degree of Microbial Disruption: Number of Patients With Recovery of Bacterial Species Richness at 185 Days Post-antibiotics	The degree of microbial disruption will be defined by recovery of bacterial species richness (number of species) after antibiotics.	Decrease from baseline (7 days prior to antibiotics) in microbial diversity at 185 days post-antibiotics
Degree of Microbial Disruption: Number of Patients With Increase in Antibiotic Resistance Genes at 185 Days Post-antibiotics	The degree of microbiome disruptions will be defined by an increase in the number of antibiotic resistance genes after antibiotics compared to baseline.	Increase from baseline (7 days prior to antibiotics) in antibiotic resistance genes at 185 days post-antibiotics
Degree of Microbial Disruption: Number of Patients With Continued Microbial Disruption at 185 Days Post-antibiotics	The degree of microbiome disruptions will be defined by continuing microbial disruption, as measured by Bray-Curtis dissimilarity, post-antibiotics compared to baseline.	Persistent disruption from baseline (7 days prior to antibiotics) in microbial composition at 185 days post-antibiotics

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Jennie H. Kwon, DO, MSCI, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): August 30, 2022

Study Registration Dates

• First Submitted: January 11, 2017
• First Submitted That Met QC Criteria: March 27, 2017
• First Posted (Actual): March 31, 2017

Study Record Updates

• Last Update Posted (Actual): November 10, 2022
• Last Update Submitted That Met QC Criteria: October 14, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Azithromycin; Levofloxacin; Ofloxacin; Cefpodoxime; Cefpodoxime proxetil
• Other Study ID Numbers: 201610071

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Summarized metagenomics sequence data will be made available through public repositories at the time of manuscript publication.