The Effect of Antibiotic Eye Drops on the Nasal Microbiome in Healthy Subjects

Study Overview
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Brief Summary
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Ophthalmic topical antibiotics are commonly prescribed in clinical practice for several indications such as bacterial conjunctivitis, keratitis, blepharitis, dacryocystitis and also as prophylaxis. Aminoglycosides (i.e. gentamicin) and fluoroquinolones (i.e. ciprofloxacin) are among the most frequently used substance classes. There is evidence that topical non-antibiotic eye drops might have an effect on the nasopharyngeal mucosal flora. This seems logical due to the anatomical connection through the nasolacrimal duct and the fact that up to 80% of topically administered drug diffuse into the systemic circulation through the highly vascularized nasopharyngeal mucosa. However, in the literature no data on the effect of antibiotic eye drops on the nasal or pharyngeal microbiome are currently available. Recently, new, non-culture based techniques for assessment of the bacterial microbiome have been developed, so-called next-generation sequencing (NGS). NGS utilizes universal primers targeting the 16S rRNA gene, which is ubiquitous across most bacteria. With this technique, it is possible to gain information about a wide range of the bacterial microbiome and not only on pre-selected species. In the present study, NGS will be used to investigate the effect of antibiotic eye drops on the nasal and pharyngeal microbiome. For this purpose, healthy subjects will be randomized to either receive eye drops containing gentamicin, ciprofloxacin or topical lubricants as control. As secondary outcome, prevalence of bacterial resistance genes, as well as signs and symptoms of ocular surface damage will be assessed. The study will be carried out in 2 parts. Since both formulations of topical antibiotics contain benzalkonium chloride which also has a potential effect on the nasal and pharyngeal mucosal flora, it is unknown how much benzalkonium chloride would contribute to changes in the nasal microbiome after administration of topical antibiotics. To overcome this problem, first a pilot study in 20 subjects will be performed in which subjects will be randomized to receive either eye drops containing gentamicin, ciprofloxacin, preservative-containing topical lubricants or preservative-free topical lubricants. Based on the results of this pilot study, the control for the main part of the study will be chosen, depending on the effect on the bacterial microbiome. The results of the pilot study could also provide useful data to adjust the sample size for the main study part. In the main study, 60 subjects will be randomized to receive gentamicin, ciprofloxacin or lubricant eye drops. The same examinations as described above will be performed after 1 week treatment as well as 1 week and 3 months after treatment.

Official Title
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The Effect of Antibiotic Eye Drops on the Nasal Microbiome in Healthy Subjects, a Phase II Study

Conditions
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Nasal and Pharyngeal Microbiome

Intervention / Treatment
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* Drug: Gentamicin Ophthalmic
* Drug: Ciprofloxacin Ophthalmic
* Drug: Povidone Ophthalmic
* Drug: Povidone and Benzalkonium Chloride Ophthalmic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged between 18 and 45 years Normal ophthalmic findings Tear Break Up Time >10 seconds Schirmer I Test > 10mm/5min Ametropia ≤ 6 diopters No use of topical eye or nasal drops in the last 3 months Exclusion Criteria: Regular use of medication, abuse of alcoholic beverages or drugs Participation in a clinical trial in the 3 weeks preceding the study Treatment in the previous 3 weeks with any drug (except intake of hormonal contraceptives) Treatment with topical or systemic antibiotics within 8 weeks before inclusion Symptoms of a clinically relevant illness in the 3 weeks before the first study day History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with distribution, metabolism or excretion of study drugs Known hypersensitivity to any of the components of the IMP under investigation or other study medication Pregnant or breast-feeding women Women of childbearing potential (neither menopausal, nor hysterectomized, nor sterilized) not using effective contraception (i.e. oral contraceptives, intra-uterine device, contraceptive implant or condoms)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gentamicin eye drops<br>4 drops daily in both eyes for 7 ± 1 days | Drug: Gentamicin Ophthalmic<br>* 4 drops daily in both eyes for 7 ± 1 days<br>|
| Experimental: Ciprofloxacin eye drops<br>4 drops daily in both eyes for 7 ± 1 days | Drug: Ciprofloxacin Ophthalmic<br>* 4 drops daily in both eyes for 7 ± 1 days<br>|
| Active Comparator: Povidone eye drops unpreserved<br>4 drops daily in both eyes for 7 ± 1 days | Drug: Povidone Ophthalmic<br>* 4 drops daily in both eyes for 7 ± 1 days<br>|
| Active Comparator: Povidone eye drops preserved<br>4 drops daily in both eyes for 7 ± 1 days | Drug: Povidone and Benzalkonium Chloride Ophthalmic<br>* 4 drops daily in both eyes for 7 ± 1 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nasal bacterial microbiome | 16S rRNA gene sequencing | change after 1 week treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharyngeal bacterial microbiome | 16S rRNA gene sequencing | change after 1 week treatment | 
| Antibiotic resistance gene prevalence |  | change after 1 week treatment | 
| Minimum inhibitory concentrations for gentamicin and ciprofloxacin |  | change after 1 week treatment | 
| Tear film thickness |  | change after 1 week treatment |