Healthy Patients & Effect of Antibiotics
Condition: Microbiota; Anti-bacterial Agents
Study type: Interventional

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.
    

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.
    

Intervention name(s): Levofloxacin; Azithromycin; Cefpodoxime
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 5 days of levofloxacin administration; 5 days of azithromycin administration; 5 days of cefpodoxime administration
Other intervention name(s): Levaquin, Quixin, Iquix; Zithromax, AzaSite, Zmax; Vantin
Intervention MeSH terms: Azithromycin; Levofloxacin; Cefpodoxime; Cefpodoxime proxetil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other