Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.1.1. Phase 1: The Assessment of the Microbial Contamination of In-Use Eye Drop Content and Dropper Tip and Inner Cap Surfaces
- This study was conducted collaboratively between the Ophthalmology Services and the Pharmacy Unit (PU)—UPSO2.
- The storage temperature of collected eye drops was between +2 and +8 °C for a maximum of 48 h before analysis.
- The information recorded for each eye drop included the collection date, active ingredient, batch number, source, packaging type, storage conditions during use, indication, and duration of treatment.
Validating the Assay Conditions
- The selection of microbial contaminants
- Gram-positive cocci: Staphylococcus aureus (NCTC 10788);
- Gram-negative bacilli: Pseudomonas aeruginosa (NCTC 12924);
- Fungi: Candida albicans (NCPF 3179).
- b.
- Establishing the number of microorganisms necessary for contamination
- c.
- Microbial contamination of the dropper tip and inner cap of sterile eye drops
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- Volumes of 0.2 mL of the selected dilution, 10−4, were deposited on the inner surface of eye drop caps.
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- The eye drop bottles were positioned upside down to bring the eye drop tips into contact with the suspension by immersion.
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- The eye drop bottles were then repositioned upright to evenly distribute the suspension over the entire surface of the tips and caps.
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- Finally, the eye drop bottles were placed horizontally and rolled on the bench.
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- The eye drop bottles were incubated upright for 24 h at room temperature.
- Inoculated (0.1 mL) at H0 onto blood agar plates. These were incubated for 24 h at 37 °C for S. aureus and P. aeruginosa and for 48 h for C. albicans, and they were then analyzed to enumerate the microorganisms (MO) in the dilution of interest.
- Incubated for 24 h at room temperature and then inoculated (0.1 mL) onto blood agar plates. These were in turn incubated for 24 h at 37 °C for S. aureus and P. aeruginosa and for 48 h for C. albicans, and they were then analyzed to enumerate the MOs in the dilution of interest after 24 to 48 h in 0.9% NaCl.
- d.
- Sampling and culturing the eye drop tips and inner caps
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- The excess solution in the caps was removed after 24 h of contact with the indicated microorganism.
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- The eye drop tips and inner caps were swabbed separately using eSwab® (Deltalab, Spain).
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- The agar plates were inoculated by direct inoculation from the swab, which was spread over the entire surface; then, the swab was turned by 90° and spread a second time by turning the Petri dish 90°.
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- The blood agar plates were incubated for three days at 37 °C for S. aureus and P. aeruginosa and at 30 °C for C. albicans.
Collection and Culture of In-Use Specimens
- Identification of Microorganisms by MALDI-TOF-MS
- b.
- Evaluation of Residual Content Contamination
2.1.2. Phase 2: Evaluation of the Practical and Antimicrobial Properties of the Pylote SAS Antimicrobial Technology
Validation of the Practical Application of Activated Rispharm™
- -
- Activated Rispharm™ Eye Drops: Practical Evaluation
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- The Production of a Batch of Eye Drops in an Isolator: For the production of eye drops in the isolator, the operators had to evaluate the following:
- The adaptability of the bottleneck to the filling process.
- The attachment of the dropper tip to the eye drop container.
- The capping procedure.
- -
- Inspection and Packaging: For the inspection and control of organoleptic characteristics, operators were asked to verify that the bottles were transparent enough to allow the detection of any non-conformities (clarity, absence of particles, color, volume).
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- Concerning labeling and packaging, they had to ensure the absence of significant malfunctions on the labeling lines and verify the suitability of the eye drop bottle size for the size of the eye drop boxes used by UPSO2 for secondary packaging.
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- Practical Use: A drop was extracted from the eye drops every hour for several consecutive hours to replicate patient use. This administration pattern corresponds to enhanced antibiotic eye drop treatments that must be administered every hour for an average of 2 to 3 days or longer, depending on the severity of the infection.
- -
- Other evaluated aspects included the flexibility of the bottle during manipulation, the consistency of delivered drops, and changes in or issues with the eye drops during use.
Validation of the Antimicrobial Properties of Activated Rispharm™
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- Group 1: 3 standard packaging vs. 3 Activated Rispharm™ packaging contaminated with 105 CFU of S. aureus.
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- Group 2: 3 standard packaging vs. 3 Activated Rispharm™ packaging contaminated with 105 CFU of P. aeruginosa.
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- Group 3: 3 standard packaging vs. 3 Activated Rispharm™ packaging contaminated with 103 CFU of C. albicans.
3. Results
3.1. Phase 1: Assessment of Microbiological Contamination In-Use Eye Drops
3.1.1. Validation of Sampling and Culture Methods
3.1.2. Collection and Culture of In-Use Specimens
Contamination Rate and Characteristics of Contaminated Bottles
Number of Microorganisms Recovered from Eye Drop Tip and Inner Cap
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- The three contaminated eye drop tips and inner caps used during hospitalization had a microbial load of less than 10 CFU.
Isolated Microorganisms
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- The identified microorganisms included commensal germs from the environment and human skin flora. The used eye drops collected from the hospital and patients showed microbial contamination of the eye drop tips and caps with Staphylococcus epidermidis and Stenotrophomonas maltophilia. All other detected microorganisms originated only from patients using eye drops. The most frequently detected microorganisms from used eye drop tips and caps were Gram-positive bacteria (GPB), such as Micrococcus luteus (n = 14) and other GPB considered part of the skin flora, including Staphylococcus hominis (n = 5), Staphylococcus capitis (n = 4), Kocuria species (n = 6), Staphylococcus aureus (n = 3), Staphylococcus haemolyticus (n = 3), Staphylococcus warneri (n = 2), Staphylococcus saprophyticus (n = 2), Staphylococcus auricularis (n = 1), Staphylococcus pasteuri (n = 1), Corynebacterium species (n = 2), Microbacterium aurum (n = 2), Aerococcus viridans (n = 1), and Dolosigranulum pigrum (n = 1). Isolated GPB found in the environment included Bacillus cereus (n = 2), Bacillus thuringiensis (n = 1), Bacillus licheniformis (n = 1), Janibacter hoylei (n = 2), Lysinibacillus spp. (n = 1), and Streptomyces violaceoruber (n = 1). Gram-negative bacteria (GNB) contaminants included Stenotrophomonas maltophilia (n = 3), Moraxella osloensis (n = 2), Pseudomonas oryzihabitans (n = 1), Acinetobacter lwoffii (n = 1), and Roseomonas mucosa (n = 4). Sterility tests showed only one positive result (in-use eye drop bottle collected from a patient) involving the eye drop tip and inner cap contaminated with Candida parapsilosis (n = 1). The residual content’s microbial contaminants were Candida parapsilosis and Lysinibacillus spp. (n = 1).
3.2. Phase 2: Evaluation of the Practical and Antimicrobial Properties of Pylote SAS Antimicrobial Technology
3.2.1. Validation of the Practical Application of Activated Rispharm™
- -
- Use of Activated Rispharm™: Minor discrepancies were noted compared to the bottles routinely used. There were no significant differences in the bottleneck size or its adaptability to the filling process. Operators unanimously acknowledged the challenge of inserting the dropper tip. The operators recommended the implementation of a more robust capping procedure to ensure secure bottle closure, with a particular focus on addressing any vacuum occurrence before the final screwing movement.
- -
- Three different operators were involved in evaluating (1) the organoleptic characteristics, (2) labeling, and (3) packaging with Activated Rispharm™ packaging. One operator raised concerns about the space between the cap ring and the bottle body, which may affect the proper closure of the bottles. All operators faced labeling issues because of the width of the Activated Rispharm™ bottles and the parameters of the labeling machine. There were no difficulties with the secondary packaging.
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- Three pharmacists were assigned to simulate the administration of compounded eye drops. They all agreed on the flexibility of the Activated Rispharm™ bottles and the dispensing of drops. The Activated Rispharm™ bottles were described as flexible, providing a good grip and allowing the formation of drops with a reproducible volume and controlled administration frequency. The bottle shape during use demonstrated no changes, such as observed deformities, after emptying the bottle.
3.2.2. Validation of the Antimicrobial Properties of Pylote SAS Antimicrobial Technology
- -
- For S. aureus, the standard packaging showed CFU counts higher than the detection limit (3.3 × 103 CFU) 24 h after the cap and insert inoculation. In the same conditions, the agar plates from Pylote packaging showed a countable average of 2.1 × 102 CFU. A difference in the reduction of above 1.2 log in favor of Pylote packaging was observed compared to standard packaging.
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- For P. aeruginosa, standard packaging also showed CFU counts higher than the detection limit (3.3 × 103 CFU) 24 h after the cap and insert inoculation. Agar plate counts from PyloteTM showed 3.2 × 102 CFU on average, leading to a reduction higher than 1 log.
- -
- For C. albicans, both packaging types showed similar microbial loads: 3.0 × 102 CFU for standard packaging and 2.4 × 102 CFU for PyloteTM packaging.
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
S. aureus | P. aeruginosa | C. albicans | ||||
---|---|---|---|---|---|---|
Inoculated number at 0 h | Detected number after 24 h contact time | Inoculated number at 0 h | Detected number after 24 h contact time | Inoculated number at 0 h | Detected number after 24 h contact time | |
Bottle 1 | 103 CFU | 6.5 × 102 CFU | 103 CFU | 1.1 × 102 CFU | 102 CFU | 1.7 × 101 CFU |
Bottle 2 | 4.6 × 102 CFU | 3.6 × 102 CFU | 2.2 × 101 CFU | |||
Bottle 3 | 5.6 × 102 CFU | 2.0 × 102 CFU | 1.6 × 101 CFU | |||
Mean ± SD | 5.6 × 102 CFU ± 9.55 × 101 CFU | 2.2 × 102 CFU ± 1.3 × 102 CFU | 1.8 × 101 CFU ± 0.3 × 101 CFU |
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Microbial Load (CFU) | Staphylococcus aureus | Pseudomonas aeruginosa | Candida albicans |
---|---|---|---|
At C0/mL) | 5.2 × 105 | 1.7 × 105 | 2.4 × 103 |
After C24 h in 0.9% NaCl (/mL) | 4.3 × 103 | 8.0 × 101 | 2.2 × 103 |
After A24h contact with standard eye drop packaging (cap + tip) | >3.3 × 103 | >3.3 × 103 | 3.0 × 102 ± 0.4 × 102 CFU |
After 24 h contact with Activated RispharmTM eye drop packaging (cap + tip) | 2.1 × 102 ± 7.0 × 101 | 3.2 × 102 ± 9.0 × 101 | 2.4 ×102 ± 6.0 × 101 |
Log reduction Pylote TM vs. standard eye drop packaging | >1.2 | >1.1 | 0 * |
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Roquefeuil, L.; Iskandar, K.; Roques, C.; Marchin, L.; Guittard, M.; Poupet, H.; Brandely-Piat, M.-L.; Jobard, M. Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study. Pharmaceutics 2024, 16, 933. https://doi.org/10.3390/pharmaceutics16070933
Roquefeuil L, Iskandar K, Roques C, Marchin L, Guittard M, Poupet H, Brandely-Piat M-L, Jobard M. Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study. Pharmaceutics. 2024; 16(7):933. https://doi.org/10.3390/pharmaceutics16070933
Chicago/Turabian StyleRoquefeuil, Léa, Katia Iskandar, Christine Roques, Loïc Marchin, Mylène Guittard, Hélène Poupet, Marie-Laure Brandely-Piat, and Marion Jobard. 2024. "Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study" Pharmaceutics 16, no. 7: 933. https://doi.org/10.3390/pharmaceutics16070933
APA StyleRoquefeuil, L., Iskandar, K., Roques, C., Marchin, L., Guittard, M., Poupet, H., Brandely-Piat, M.-L., & Jobard, M. (2024). Evaluating and Managing the Microbial Contamination of Eye Drops: A Two-Phase Hospital-Based Study. Pharmaceutics, 16(7), 933. https://doi.org/10.3390/pharmaceutics16070933