Antibiotics Impact on Healthy Subjects

Recruiting at 1 trial location

Overseen By Carla D Williams, R.N.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Antibiotics, Corticosteroids, Immunosuppressants, others

Disqualifiers: Obesity, Hypertension, Diabetes, Asthma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 10

Duration: 1 week

108 Participants Needed

Trial Summary

What is the purpose of this trial?

More than 250 million courses of antibiotics are prescribed annually in the ambulatory care setting in the United States alone, including more than 40 million in children under 18 years of age. The perception that antibiotic use has minimal attendant adverse side effects contributes to the over-utilization of antibiotics in clinical circumstances when they are not strictly indicated. We have learned much about the human microbiome. The emerging view is of profound life-long bi-directional interactions between our microbiota and our cells. Perturbations in the microbiota affect metabolic, immune, and cognitive physiology in experimental animal models. When a person takes an antibiotic, the antibiotic diffuses via the blood into all body compartments, selecting for resistance. We propose to examine the effects of two commonly used antibiotics (the beta-lactam, amoxicillin and the macrolide azithromycin) on human microbial populations and on metabolic and immune physiology, studying healthy human volunteers in a randomized controlled clinical trial at the NIH Clinical Center. Our hypothesis is that in addition to acutely perturbing the human microbiome, these agents will have measurable metabolic and immunologic effects, with residual effects in the weeks that follow. To test this hypothesis, we will assess the effects of a brief therapeutic course of antibiotics on microbiome and metagenome composition. After an initial evaluation period, antibiotics will be given for 7 days or 5 days (depending on the antibiotic), and there will be a post-treatment evaluation. A control group will receive no drug intervention. Specimens will be obtained from multiple sites at each of 10 time points occurring before, during, and after antibiotic administration, and used for estimating bacterial and fungal composition and gene content. We will also assess the effects of the antibiotic course on markers of innate and adaptive immunity as well as markers of metabolic and hormonal physiology. A subgroup of subjects will be studied in the clinical center metabolic chamber to assess 24-hour energy expenditure and its components (sleeping, diet-induced, and activity energy expenditure), as well as macronutrient oxidation rates (carbohydrate, fat, and protein), during 3 of the 10 study visits. In addition to the primary data analyses, we will build a model that integrates the temporal data to begin to understand the complex intertwined physiology between microbiome and host.

Will I have to stop taking my current medications?

The trial requires that participants have not used certain medications, like antibiotics, antifungals, antivirals, corticosteroids, and others, within the last 6 months. If you are currently taking any of these, you would need to stop and wait for the specified period before joining the trial.

What data supports the effectiveness of the drug amoxicillin and azithromycin?

Research shows that azithromycin is highly effective in treating lower respiratory infections, with a success rate of over 93% in some cases. Additionally, both amoxicillin and azithromycin have been effective in treating ear, nose, and throat infections, as well as preventing recurrent ear infections. ^{1 2 3 4 5}

Is it safe for healthy people to take antibiotics like Amoxicillin and Azithromycin?

Antibiotics like Amoxicillin and Azithromycin are generally considered safe, but they can cause side effects such as stomach upset and, in rare cases, more serious issues like allergic reactions or gait disturbances. Most side effects are mild and temporary, but it's important to monitor for any unusual symptoms. ^{6 7 8 9 10}

How does the drug Amoxicillin and Azithromycin differ from other treatments?

Amoxicillin and Azithromycin are antibiotics that may have unique effects on weight gain, as seen in studies where Amoxicillin promoted short-term weight gain in children. Azithromycin is well-tolerated with fewer side effects compared to other antibiotics, but it has been linked to an increased risk of cardiovascular death in some cases. ^{11 12 13 14 15}

Research Team

Christa S Zerbe, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

Healthy adults aged 18-50 who can swallow capsules and comply with study procedures. Participants must be willing to allow storage of their biological samples but cannot have used certain medications or substances in the past months, including systemic antibiotics, steroids, probiotics, antacids, laxatives, and more. Smokers and those with a range of health conditions or recent significant weight changes are excluded.

Inclusion Criteria

I am between 18 and 50, healthy, and okay with giving samples and taking capsules for a study.

Exclusion Criteria

I have certain skin conditions.

I cannot attend all the required study visits.

Any condition contraindicating study participation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either amoxicillin for 7 days or azithromycin for 5 days, with a control group receiving no drug intervention

1 week

10 visits (in-person)

Post-treatment Evaluation

Participants are evaluated for changes in microbiome, immune, and metabolic parameters after antibiotic administration

2-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Amoxicillin
• Azithromycin
• Control

Trial Overview The MIME Study is testing how two common antibiotics—amoxicillin and azithromycin—affect the human microbiome as well as metabolic and immune physiology in healthy volunteers. It's a randomized controlled trial where one group receives amoxicillin for 7 days, another azithromycin for 5 days, while a control group gets no drug intervention.

Participant Groups

Group I: Group C Experimental Treatment 1 Intervention

Azithromycin

Group II: Group B Experimental Treatment 1 Intervention

Amoxicillin

Group III: Group A Experimental Treatment 1 Intervention

Control

Amoxicillin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections
• Ear, nose and throat infections

Approved in United States as Amoxicillin for:

• Infections of the ear, nose, throat, genitourinary tract, skin and skin structure, and lower respiratory tract

Approved in Canada as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

In a study analyzing 102 medical files, 71% of amoxicillin-clavulanic acid prescriptions were found to be appropriate according to hospital guidelines, indicating a generally good adherence to antibiotic prescribing standards.

However, 15% of prescriptions were deemed unacceptable, often made by junior doctors, highlighting the need for improved training and oversight to optimize antibiotic use, especially for acute pulmonary infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evaluation of amoxicillin-clavulanic acid prescriptions in a teaching hospital of Parisian suburb]. Dupont, C., Massé, C., Auvert, B., et al.[2019]

In a study of 71 children with recurrent acute otitis media, both azithromycin and amoxicillin were found to be effective in reducing the number of AOM episodes, with clinical response rates of 80.6% and 89.5%, respectively.

The safety profiles of both treatments were similar, indicating that azithromycin can be considered a viable alternative to amoxicillin for preventing recurrent AOM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of amoxicillin and azithromycin in the prevention of recurrent acute otitis media. De Diego, JI., Prim, MP., Alfonso, C., et al.[2019]

In a study of 153 patients with lower respiratory tract infections, azithromycin demonstrated high clinical effectiveness, achieving a 93.6% success rate in treating community-acquired pneumonia (CAP) and 94.9% in acute exacerbation of chronic bronchitis (AECB).

Azithromycin provided symptom relief within three days for 88.6% of CAP patients and 77.2% of AECB patients, with only a small incidence of adverse events (9.1%), primarily gastrointestinal issues like abdominal pain and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SAFETY AND EFFECTIVENESS OF AZITHROMYCIN IN THE TREATMENT OF LOWER RESPIRATORY INFECTIONS: AN INTERNATIONAL, MULTICENTER, NON-COMPARATIVE STUDY. Gašparić, M., Penezić, A., Kolumbić-Lakoš, A., et al.[2018]

In a study involving 109 patients with chronic obstructive pulmonary disease, azithromycin and amoxicillin showed similar efficacy in treating infectious exacerbations, with cure or improvement rates of 85% for azithromycin and 78% for amoxicillin at day ten.

Both antibiotics demonstrated comparable safety and tolerability, with no significant differences in adverse effects or secondary symptoms like cough and dyspnea, suggesting that either medication can be effectively used for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison between azithromycin and amoxicillin in the treatment of infectious exacerbation of chronic obstructive pulmonary disease. Andre-Alves, MR., Jardim, JR., Frare e Silva, R., et al.[2019]

In a study of 100 patients with ENT diseases, roxithromycin (300 mg once daily) showed a satisfactory clinical response in 82% of patients, comparable to 78% for amoxicillin/clavulanic acid (875+125 mg twice daily), indicating similar efficacy in treating these conditions.

Roxithromycin was found to be safe, with only 2 patients experiencing side effects, and its once-daily dosing may improve patient compliance compared to the twice-daily regimen of amoxicillin/clavulanic acid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter study on the clinical efficacy and safety of roxithromycin in the treatment of ear-nose-throat infections: comparison with amoxycillin/clavulanic acid. Mira, E., Benazzo, M.[2013]

A study analyzing adverse drug events related to antibiotics in Brazil from December 2018 to December 2021 identified 294 safety signals, with azithromycin leading in the number of signals (49), highlighting the importance of monitoring antibiotic safety.

Serious adverse events were linked to ceftazidime and avibactam, a new drug, and unexpected issues like suicide attempts were associated with amoxicillin/clavulanate, indicating the need for careful evaluation of antibiotic safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential safety signals for antibacterial agents from the Brazilian national pharmacovigilance database (Vigimed/VigiFlow). Barbosa, LHLA., Silva, ARO., Carvalho-Assef, APD., et al.[2022]

In a study of 3229 adult patients with respiratory infections, azithromycin was found to have a similar incidence of treatment-related adverse events (10.3%) compared to standard antibiotics (11.5%).

Azithromycin resulted in significantly fewer patient withdrawals due to adverse effects (0.4% vs. 2.1%), indicating it is well tolerated and a safe option for treating bacterial infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of azithromycin in the treatment of adults with community-acquired respiratory tract infections. Treadway, G., Pontani, D., Reisman, A.[2022]

A total of 252 adverse drug reaction reports related to antimicrobial resistance were submitted to The Netherlands Pharmacovigilance Centre from 1998 to January 2019, with the most common antibiotics involved being tobramycin and colistin.

The study highlighted that over half of the reports were associated with 'Watch' antibiotics, indicating a significant concern regarding off-label use and drug ineffectiveness, suggesting the need for improved monitoring and stewardship strategies in antibiotic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre. Habarugira, JMV., Härmark, L., Figueras, A.[2021]

Antibiotics, while generally safe for target species, can cause a range of adverse effects in animals, including allergic reactions, gastrointestinal issues, and more severe conditions like hepatic toxicity and anaphylaxis.

There is a significant lack of published safety data on antibiotics used in food animals, highlighting the need for further research to better understand their potential toxic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of antibiotic drugs in food animals: comparison of findings from preapproval studies and postapproval experience in the United States with safety information in published literature. Modric, T., Modric, S., Murphy, MJ., et al.[2013]

Newer antibiotics have improved safety profiles and therapeutic effectiveness compared to older agents, leading to their increased use even in uncertain bacterial infection cases.

Despite their perceived safety, some newer antibiotics have documented side effects, and a few have been withdrawn from the market shortly after introduction, highlighting the importance of understanding their potential adverse effects and interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Separating fact from fiction: the data behind allergies and side effects caused by penicillins, cephalosporins, and carbapenem antibiotics. Leviton, I.[2019]

A large study involving over 7.8 million antibiotic prescriptions found that azithromycin is associated with a significantly increased risk of cardiovascular death (hazard ratio of 1.82) compared to amoxicillin, particularly within 5 days of exposure.

Azithromycin was also linked to a higher risk of noncardiovascular death and all-cause mortality, indicating potential safety concerns with its use, especially in patients with pre-existing cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Azithromycin Use With Cardiovascular Mortality. Zaroff, JG., Cheetham, TC., Palmetto, N., et al.[2021]

In a study of 3,995 patients aged 2-94, azithromycin demonstrated a favorable safety profile, with only 12.0% of patients experiencing side effects, which is significantly lower than the 14.2% seen with other standard antibiotics.

The most common side effects were mild to moderate gastrointestinal issues, and only 0.7% of patients discontinued treatment due to side effects, indicating that azithromycin is well tolerated even among patients with various concurrent illnesses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical toleration and safety of azithromycin. Hopkins, S.[2022]

In a study of 1012 healthy adolescents with acne who were prescribed long-term antibiotics, it was found that their weight-for-age Z-scores (WAZs) actually decreased post-antibiotics, indicating no weight gain associated with antibiotic use.

The results showed that 26% of adolescents experienced a decrease in WAZ of ≥0.2 Z-scores after antibiotic treatment, while only 18% had an increase, suggesting that antibiotics do not promote weight gain in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of long-term antibiotic use on weight in adolescents with acne. Contopoulos-Ioannidis, DG., Ley, C., Wang, W., et al.[2018]

In a study involving 248 preschool children in rural Burkina Faso, a 5-day course of amoxicillin significantly improved weight gain compared to placebo, with an average increase of 317 grams.

Neither azithromycin nor cotrimoxazole showed any significant effect on weight or height gain, indicating that amoxicillin may have unique short-term growth-promoting effects in healthy children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Antibiotics on Short-Term Growth among Children in Burkina Faso: A Randomized Trial. Sié, A., Dah, C., Ouermi, L., et al.[2022]

In a study involving 12 healthy male volunteers, azithromycin was found to remain in the bloodstream for an extended period, with measurable levels lasting between 7 to 17 days after a standard treatment regimen of 500 mg over three days.

The long elimination half-life of azithromycin (averaging 76 hours) suggests that it could maintain effective concentrations in tissues for up to 30 days, raising questions about the implications of prolonged exposure to subinhibitory levels in patients with respiratory infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Determination of Azithromycin in Plasma during a 6-Week Period in Normal Volunteers after a Standard Dose of 500mg Once Daily for 3 Days. Crokaert, F., Hubloux, A., Cauchie, P.[2021]

References

1. France pubmed.ncbi.nlm.nih.gov

[Evaluation of amoxicillin-clavulanic acid prescriptions in a teaching hospital of Parisian suburb]. [2019]

2. Ireland pubmed.ncbi.nlm.nih.gov

Comparison of amoxicillin and azithromycin in the prevention of recurrent acute otitis media. [2019]

3. Croatia pubmed.ncbi.nlm.nih.gov

SAFETY AND EFFECTIVENESS OF AZITHROMYCIN IN THE TREATMENT OF LOWER RESPIRATORY INFECTIONS: AN INTERNATIONAL, MULTICENTER, NON-COMPARATIVE STUDY. [2018]

4. Brazil pubmed.ncbi.nlm.nih.gov

Comparison between azithromycin and amoxicillin in the treatment of infectious exacerbation of chronic obstructive pulmonary disease. [2019]

5. England pubmed.ncbi.nlm.nih.gov

A multicenter study on the clinical efficacy and safety of roxithromycin in the treatment of ear-nose-throat infections: comparison with amoxycillin/clavulanic acid. [2013]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Potential safety signals for antibacterial agents from the Brazilian national pharmacovigilance database (Vigimed/VigiFlow). [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The safety of azithromycin in the treatment of adults with community-acquired respiratory tract infections. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Safety of antibiotic drugs in food animals: comparison of findings from preapproval studies and postapproval experience in the United States with safety information in published literature. [2013]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Separating fact from fiction: the data behind allergies and side effects caused by penicillins, cephalosporins, and carbapenem antibiotics. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Association of Azithromycin Use With Cardiovascular Mortality. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Clinical toleration and safety of azithromycin. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Effect of long-term antibiotic use on weight in adolescents with acne. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Effect of Antibiotics on Short-Term Growth among Children in Burkina Faso: A Randomized Trial. [2022]

15. New Zealand pubmed.ncbi.nlm.nih.gov

A Phase I Determination of Azithromycin in Plasma during a 6-Week Period in Normal Volunteers after a Standard Dose of 500mg Once Daily for 3 Days. [2021]