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Healthy Patients & Effect of Antibiotics

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ClinicalTrials.gov Identifier: NCT03098485
Recruitment Status : Active, not recruiting
First Posted : March 31, 2017
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Microbiota Anti-bacterial Agents Drug: Levofloxacin Drug: Azithromycin Drug: Cefpodoxime Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Other
Official Title: Prospective Study Characterizing Fecal Microbiome Disruptions During and After Receipt of Antimicrobials
Study Start Date : January 2017
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Experimental: Levofloxacin
1 750mg tab of levofloxacin by mouth for 5 days
Drug: Levofloxacin
5 days of levofloxacin administration
Other Name: 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 Name: Zithromax, AzaSite, Zmax

Experimental: Cefpodoxime
200mg tab by mouth twice per day for 5 days
Drug: Cefpodoxime
5 days of cefpodoxime administration
Other Name: 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 Name: Zithromax, AzaSite, Zmax

Drug: Cefpodoxime
5 days of cefpodoxime administration
Other Name: Vantin




Primary Outcome Measures :
  1. Degree of microbial disruption: changes in bacterial microbial diversity [ Time Frame: Change from baseline (7 days prior to antibiotics) in microbial diversity at 7, 30, and 60 days post-antibiotics ]
    The degree of microbial disruption will be defined by changes in bacterial microbial diversity before and after antibiotics

  2. Degree of microbial disruption: changes in number of antibiotic resistance genes [ Time Frame: Change from baseline (7 days prior to antibiotics) in antibiotic resistance genes at 7, 30, and 60 days post-antibiotics ]
    The degree of microbiome disruptions will be defined by the changes in number of antibiotic resistance genes before and after antibiotics

  3. Degree of microbial disruption: duration of microbial disruption [ Time Frame: Change from baseline (7 days prior to antibiotics) in microbial stability at 7, 30, and 60 days post-antibiotics ]
    The degree of microbiome disruptions will be defined by the duration of microbial disruption after antibiotics.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03098485


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Jennie H. Kwon, DO, MSCI Washington University School of Medicine

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03098485     History of Changes
Other Study ID Numbers: 201610071
First Posted: March 31, 2017    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Summarized metagenomics sequence data will be made available through public repositories at the time of manuscript publication.
Additional relevant MeSH terms:
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Levofloxacin
Ofloxacin
Cefpodoxime
Cefpodoxime proxetil
Ceftizoxime
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors