Biofilms in Ocular Infection: History
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Contributor:
Francesco Petrillo
,
Marica Sinoca
,
Antonio Maria Fea
,
Marilena Galdiero
,
Angela Maione
,
Emilia Galdiero
,
Marco Guida
,
Michele Reibaldi

Fungi represent a very important cause of microbial eye infections, especially in tropical and developing countries, as they could cause sight-threating disease, such as keratitis and ocular candidiasis, resulting in irreversible vision loss. Candida species are among the most frequent microorganisms associated with fungal infection. Although Candida albicans is still the most frequently detected organism among Candida subspecies, an important increase in non-albicans species has been reported. Mycotic infections often represent an important diagnostic-clinical problem due to the difficulties in performing the diagnosis and a therapeutic problem due to the limited availability of commercial drugs and the difficult penetration of antifungals into ocular tissues. The ability to form biofilms is another feature that makes Candida a dangerous pathogen.

  • fungal ocular infection
  • antimicrobial agents
  • Candida albicans
  • fungal biofilms

1. Introduction

Eye infections are one of the most common pathologies in ophthalmology as the eye is excessively exposed to the surrounding environment and comprises intensely vascularized tissues with immunological cellular components that are highly responsive to external stimuli. These infections may affect the external or the internal structures of the eye.
The former is by far the most frequent and results from either the acquisition of a virulent microorganism or the uncontrolled growth of an existing organism due to lowered resistance. The latter is rarer thanks to the defense mechanisms of the eye, which is relatively impermeable to microorganisms; however, they can be caused by trauma, surgery, and blood dissemination [1].

2. Role of Biofilms in Ocular Infection

A strategy commonly used by microorganisms to become resistant to antimicrobials is the ability to form biofilms [2].
Biofilm protects microbes from hostile environmental conditions and at the same time microbes show metabolic cooperation, gain AMR phenotypes, and show altered expression of virulence genes and virulence factors. Microbial biofilms are involved in many diseases, as they represent a favorable environment for the growth of microorganisms and the development of virulence. Biofilms are clusters of microorganisms embedded in a self-produced matrix of extracellular polymeric substances (EPS) [3]. Fungal biofilms are a group of cells immersed in an extracellular matrix (ECM) with the ability to adhere to each other and on different surfaces [4][5][6][7]. Biofilm formation is a feature of Candida spp. and, depending on the species considered, that involves different phases: an initial attachment to a surface, filamentation, cell to cell interactions, biofilm maturation, and dispersal towards new sites helping them to escape from compounds or drugs used for biofilm disruption [8][9]. In the case of eye infections biofilms are usually formed on ocular abiotic surfaces like contact lenses, scleral buckles, intraocular lenses, and sutures. Current studies show that biofilm formation may take place immediately on the biotic surfaces of the eyes, such as mucosal surfaces (e.g., cornea). The first step is very important, and microorganisms must be sufficiently close to the surface to which they must adhere. Both attraction and repulsion forces intervene and depend on the size of the microorganism, the distance from the surface, and the hydrophobicity of the surface itself. For surfaces wetted by fluids, such as conjunctiva or contact lenses, these forces also depend on the presence of solutes within them [10]. Consequently, clinically, biofilm diseases can be extremely difficult to treat because of their resistance to treatments, host immune defenses, and also persistence on mucous surfaces. Biofilm is also observed on medical devices such as catheters, implants, heart valves, intraocular lenses, orthopedic devices and contact lenses [11].
Biofilms can be monomicrobial and polymicrobial. Polymicrobial biofilms are formed by different bacteria, different fungi or by bacteria and fungi together and they are more difficult to treat than monomicrobial biofilms and related planktonic cells [12][13]. The use of contact lenses is an important risk factor for microbial keratitis. Water content, hydrophobicity, and roughness are aspects that influence how different microorganisms interact with different materials. The main factor of virulence is the ability of microorganisms to form biofilms and produce adhesion factors that facilitate their permanence on lenses and containers [14]. Although FK accounts for only 1.5% of all cases of keratitis in contact lens users, the presence of fungi and the subsequent formation of biofilm in contact lenses poses an increasing threat to public health, especially for the ability of fungi to form polymicrobial biofilms, difficult to eradicate [15]. Most of Candida spp. are biofilm producers; this is an important factor associated with virulence and resistance to antifungals. Inappropriate manipulation of contact lenses facilitates the entry of infectious agents into the lenses.
According to the literature, the risk of complications resulting from the use of soft contact lens subtypes is higher than that resulting from the use of rigid contact lenses [16]. It has been discovered that several tear proteins, such as albumin, lysozyme, and fibronectin, increase the adhesion of Candida to contact lenses [17][18]. Some studies have observed the existence of a positive correlation between the adhesion to Candida and the level of water in contact lenses. Both Fusarium and Candida are able of forming biofilms on different types of lenses. The presence of biofilm has decreased the effectiveness of contact lens solutions [19].
Mukherjee et al. have conducted an in vitro study on contact lenses inoculated with keratitis-isolated Fusaria and observed that biofilm capacity is a critical factor for pathogenesis. Furthermore, the biofilm formed by Fusarium isolates showed higher drug resistance in comparison to planktonic cells [20].
Fritsch et al., 2020 [21] studied the formation of biofilms on different types of contact lenses materials by C. albicans and C. krusei and the relative development of preventive or reductive treatment to avoid eye infections among contact lenses users. They found that both C. albicans and C. krusei strains were able to form biofilms on contact lenses, confirming the fact that they are a suitable surface for Candida spp. adhesion and growth and that the formation of biofilms with greater metabolic activity and greater biomass was noted for soft contact lenses by both the species, considering their surface hydrophobicity.
However, current research has shifted the interest to more in vivo and ex vivo examples of fungal biofilm association because there are some limitations associated with the use of in vitro systems for the study of biofilm infections. For example, the microenvironment of the biofilm influences the structure and morphology of the biofilm [22]. Ex vivo studies make use of whole corneas. Due to the limited availability of human corneas, animal corneas are often used, and therefore interspecies variation is a major problem with ex vivo studies [23].
Ranjith et al., in their study, reported that S. aureus and S. epidermidis isolated from patients with endophthalmitis and C. albicans isolated from a patient with keratitis, form polymicrobial biofilms both in vitro using tissues culture plates and ex vivo using human cadaveric cornea as the substratum for biofilm formation. Polymicrobial biofilms showed an increase of several fold resistance to antimicrobial agents than monomicrobial biofilms and planktonic cells.
In conclusion, biofilm formation at the level of intraocular structures or on devices such as contact lenses is the main therapeutic obstacle. Biofilms, especially polymicrobial, being formed by different microorganisms, make the use of conventional antibiotics and antifungals ineffective. Added to this is the fact that when microorganisms acquire, at both genotypic and phenotypic levels, biofilm formation, they also usually acquire new characteristics in terms of resistance to antimicrobial substances.

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics12081277

References

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  2. Vert, M.; Doi, Y.; Hellwich, K.-H.; Hess, M.; Hodge, P.; Kubisa, P.; Rinaudo, M.; Schué, F. Terminology for biorelated polymers and applications (IUPAC Recommendations 2012). Pure Appl. Chem. 2012, 84, 377–410.
  3. Chandra, J.; Kuhn, D.M.; Mukherjee, P.K.; Hoyer, L.L.; McCormick, T.; Ghannoum, M.A. Biofilm formation by the fungal pathogen Candida albicans: Development, architecture, and drug resistance. J. Bacteriol. 2001, 183, 5385–5394.
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  10. Willcox, M.D. Pseudomonas aeruginosa infection and inflammation during contact lens wear: A review. Optom. Vis. Sci. 2007, 84, 273–278.
  11. Anju, V.; Busi, S.; Imchen, M.; Kumavath, R.; Mohan, M.S.; Salim, S.A.; Subhaswaraj, P.; Dyavaiah, M. Polymicrobial Infections and Biofilms: Clinical Significance and Eradication Strategies. Antibiotics 2022, 11, 1731.
  12. Kulshrestha, A.; Gupta, P. Polymicrobial interaction in biofilm: Mechanistic insights. Pathog. Dis. 2022, 80, ftac010.
  13. Mendonca, J.R.; Dantas, L.R.; Tuon, F.F. Activity of multipurpose contact lens solutions against Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens and Candida albicans biofilms. Ophthalmic Physiol. Opt. 2023; online ahead of print.
  14. de Oliveira, P.R.; Resende, S.M.; de Oliveira, F.C.; de Oliveira, A.C. Fungal keratitis. Arq. Bras. Oftalmol. 2001, 64, 75–79.
  15. Fritsch, L.N.; Dias, A.L.T.; Silva, N.C.; Fernandes, G.J.M.; Ribeiro, F.B.d.A.O. Comparative analysis of biofilm formation by Candida albicans and Candida krusei in different types of contact lenses. Arq. Bras. Oftalmol. 2021, 85, 235–239.
  16. Ahn, J.; Choi, M. The Ionization of Polymeric Materials Accelerates Protein Deposition on Hydrogel Contact Lens Material. Materials 2023, 16, 2119.
  17. Dutta, D.; Cole, N.; Willcox, M. Factors influencing bacterial adhesion to contact lenses. Mol. Vis. 2012, 18, 14–21.
  18. Campolo, A.; Pifer, R.; Shannon, P.; Crary, M. Microbial Adherence to Contact Lenses and Pseudomonas aeruginosa as a Model Organism for Microbial Keratitis. Pathogens 2022, 11, 1383.
  19. Mukherjee, P.K.; Chandra, J.; Yu, C.; Sun, Y.; Pearlman, E.; Ghannoum, M.A. Characterization of Fusarium keratitis outbreak isolates: Contribution of biofilms to antimicrobial resistance and pathogenesis. Investig. Ophthalmol. Vis. Sci. 2012, 53, 4450–4457.
  20. Roberts, A.E.; Kragh, K.N.; Bjarnsholt, T.; Diggle, S.P. The limitations of in vitro experimentation in understanding biofilms and chronic infection. J. Mol. Biol. 2015, 427, 3646–3661.
  21. Fritsch, L.N.; Dias, A.L.T.; Silva, N.C.; Fernandes, G.J.M.; Ribeiro, F.B.d.A.O. Análise comparativa da formação de biofilmes, por Candida albicans e Candida krusei, em diferentes tipos de lentes de contato. Arq. Bras. Oftalmol. 2022, 85, 235–239.
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