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Ocular mycoses: infection of the eye by fungi.

Ocular mycoses are being reported with increasing frequency as a consequence of new and improved diagnostic techniques. In addition, there has been an increase in the number of immunosuppressed patients in the population eg those who are HIV positive or receiving radiation treatment or chemotherapy, who may be increasingly susceptible to ocular mycoses. (4)

Fungal cells

Fungi are eukaryotic organisms, ie they are characterised by the presence of a cell membrane, which encloses the organelle. The genome is located in the nucleus and mitochondria are responsible for energy production, while vesicles and golgi apparatus package and transport cellular constituents. Carbohydrates, such as trehalose, are stored within fungal cells and the cell wall itself is composed of unique components such as chitin. Hence, although sometimes classified with plants, fungi are a unique and distinct group of organisms.

Growth and reproduction

Fungal growth and infection frequently begins with the spore. Spore size and method of dispersal vary widely with species. Some spores are actively motile while those associated with eye infections are often relatively small (<5 m in diameter) and are dispersed passively by the wind. Individuals can potentially be exposed to great numbers of fungal spores in the normal course of their lives. Hence, the incidence of fungal infection is often correlated with frequency of spore exposure. Composting material, eg poorly stored animal fodder, may contain up to 170,000 fungal spores from potential pathogens per gram of material. Bird droppings can also be rich sources of both spores and living cells of fungal pathogens. Germination of fungal spores, including those associated with eye infection, will occur within 24 hours after deposition if temperature and moisture conditions are favourable. Subsequent fungal growth may take a number of forms, eg unicellular, as in the yeast Candida (Figure 1), or filamentous, as associated with most fungal species (Figure 2). Associated with filamentous growth is the production of many enzymes, eg amylases, cellulases, esterases, lipases, proteinases, and oxidases. These compounds are associated with the ability of fungi to penetrate and macerate many substrates, including the materials of contact lenses. These enzymes also enable fungi to overcome some of the host defences, including mucous-covered or keratin-containing barriers, to break down components of the immune system, and to disrupt potential microbial competitors.

[FIGURE 1 OMITTED]

Types of fungi in eye infection

Many thousands of fungal species have been described and the majority can be classified into four major groups: basidiomycetes, ascomycetes, phycomycetes, and fungi imperfecti. Estimates of the number of fungi implicated in eye infections range from 60 species representing 30 genera (8) to 105 species representing 35 genera. (9) Members of all the major groups are involved. The unicellular yeast Cryptococcus, for example, is a basidiomycete and a pathogen characteristic of immunocompromised patients. By contrast, the majority of yeast-like fungi, such as Candida albicans (Figure 1) are members of ascomycetes. Also classified within the ascomycetes is the common eye-associated fungus genus Aspergillus (Figure 2), which is abundant in many environments worldwide, including hospitals. Species of Aspergillus produce enormous numbers of spores and are an important cause of allergies and lung infection. Some of the simplest fungi, eg species of Mucor, are classified within phycomycetes. Members of this group have high growth rates and produce enormous numbers of aerial spores which can cause eye infections. By contrast with the other groups, they possess a limited number of enzymes, which restricts them to simple substrates; as such they are often termed 'sugar fungi'. Another group of fungi associated with the eye are the 'dematiaceous' fungi. This group includes a number of genera characterised by dark pigmentation of the hyphae. At least 20 species from 11 genera are implicated including Bipolaris, Curvularia, and Exophiala. Finally, organisms of uncertain classification, such as the common fungal-like aquatic organism Pythium insidiosum, may also be involved in eye infection.

Diagnosis of ocular mycoses

Diagnosis of a fungal eye infection involves there cognition of typical clinical features, followed by direct microscopic observation of fungi in scrapes or biopsy samples. Any fungi isolated by these methods can then be cultured and identified. Further histopathology, immunohistochemistry, and DNA-based tests may be necessary to confirm a diagnosis of a specific fungal infection.

Normal ocular mycoflora

There have been few studies investigating fungal infection of the eye. One study (10) recorded the presence of fungi on the surface of the eye in 2.9% of healthy individuals, incidence being higher in older people. Most of the species recorded were non-pathogenic and likely to have been transmitted by aerial contamination, but some pathogenic species were also found; Penicillium species was the most commonly isolated. In areas of the world with lower socioeconomic status and poorer hygiene, fungi are found more frequently in association with the eye, especially in agricultural communities. In Ahvaz, Iran, 11 of 172 swabs taken from patients attending hospital were positive for pathogenic fungi, Cladosporium being the commonest genus recorded, followed by Drechselera, Alternaria, Fusarium, Epicoccum and three yeasts, viz., Cryptococcus, Candida albicans, and Rhodotorula rubra. (11)

[FIGURE 2 OMITTED]

Ocular mycoses

The major eye infections caused by fungi and summarised in Table 1 and described in the sections below.

Eyelids and associated structures

The most important fungi to affect the eyelids are Trichophyton and Microsporum, which cause flaking skin lesions that become inflamed. Particularly notable is T. schoenleini, which develops as a raised, crusted area around the eyelashes. The tear glands and associated canals may be infected by Aspergillus fumigatus or A. flavus ('dacryocystitus') causing obstruction of the nasolacrimal duct. Patients exhibit epiphora (running over of tears) and a black discoid elevated area on the lower lid. The species of Leptothrix, Sporotrichum, and Rhinospiridium are also known to invade the lacrimal sac.

Conjunctiva

Fungal infection of the conjunctiva is relatively rare. In children and young adults, however, infection by Leptothrix may cause a unilateral conjunctivitis, characterised by yellow or grey areas under the epithelium. This condition does not usually lead to ulceration, although there may be considerable infiltration by blood cells. Conjunctivitis can also be caused by the fungus Sporotrichum resulting in the formation of small, yellow, and sometimes ulcerating, nodules on the conjunctiva, while in Rhinosporidium infection, yellow to pink nodules are formed, which may develop into tumours. Candida, Aspergillus and Trichophyton species can also cause conjunctivitis, with or without involvement of adjacent areas of skin.

Cornea

Common precipitating events for fungal infection of the cornea (keratomycosis or fungal keratitis) include surgical trauma, contaminated contact lenses and alterations in lacrimal secretion. (12) This condition constitutes one of the more serious eye infections. Keratomycosis is a chronic condition, beginning as a grey-coloured, superficial necrosis of the cornea with a dull dry surface and surrounded by a sharp yellow line. The condition may be accompanied by pain, corneal infiltrates, pus in the anterior chamber and iritis. Perforation of the cornea is rare, but if it occurs, the fungus may invade the uvea, vitreous body, and retina. The most common species involved in keratomycosis is Aspergillus fumigatus, followed by members of the Mucoraceae. (13) Fusarium may also be an important cause, with this being the most common cause of infectious fungal keratitis in elderly patients in Brazil (14) and in China. (15) Pythium insidiosum can also cause keratitis in tropical and temperate regions. (16,17) Fungal keratitis is relatively rare among contact lens wearers but in a recent outbreak of Fusarium keratitis in the USA, 283 out of 695 identified cases were contact lens wearers. (18) In the UK, the British Ophthalmologic Surveillance Unit identified 0.32 cases of fungal keratitis per year and in 56% of these cases, Candida was the only fungus isolated. (19,20) However, filamentous fungi are more common, especially in males following trauma. Recent studies also suggest that species of Alternaria and Paecilomyces can cause keratitis in patients wearing frequent replacement contact lenses and who use a multipurpose cleaning solution. (21) If corneal infiltrates are observed, especially in contact lens wearers, mycological assessment should always be performed. (22) Fungal keratitis responds well to treatment, especially with azoles and surgery should only be necessary in advanced cases.

Sclera

The sclera is rarely affected by fungal infection. However, scleral ulceration caused by Cryptococcus has been reported in HIV positive individuals. (23) In addition, the first case of 'sclerokeratitis' ie scleral necrosis adjacent to an area of corneal infiltrate, caused by the fungus Metarrhyium anisopliae, has been reported in Australia. (24)

Uvea

Infection of the iris, ciliary body and choroid by fungi, causing uveitis, is relatively rare. The most frequent organisms involved are Aspergillus fumigatus and Candida, although Coccidiodes may also be implicated. An endogenous chronic uveitis can also be caused by fungi, especially Candida.

A more general infection of the anterior structures of the eye is often referred to as 'endophthalmitis'. Recently, a case of a 70-year-old male was reported with anterior endophthalmitis following intraocular lens implantation. A 'fluffy fungal-like growth' was observed, which was ultimately identified as the fungus Paecilomyces variotii. (25) Species of Cephalosporium have been occasionally reported as a cause of endophthalmitis.26

Vitreous body

Inflammatory reactions within the vitreous can result in liquefaction, opacification and shrinkage, the tissue ultimately becoming necrotic. (4) A fungal infection of the vitreous progresses more slowly than a bacterial infection and is more likely to remain localised. The most common organisms involved are the species of Aspergillus, Cephalosporium, Fusarium, and Candida.

Retina

Retinitis attributable to Candida may occur in patients with a debilitating systemic disease, especially if they are also receiving chemotherapy or immunosuppressant drugs. Localised lesions caused by Cryptococcus may also occur.

Optic disc and nerve

The optic nerve can be affected by infections spreading from the eye, orbit or brain, resulting in optic neuritis. Optic neuritis can be caused by members of the Phycomycetes and the yeast Cryptococcus.

Orbit

Fungal infections of the orbit comprise a small minority of orbital infections ('orbital cellulitis') but can have a devastating effect on ocular function. (27) Fine needle aspiration cytology can help to make an early definitive diagnosis of this condition.

Most fungal invaders of the orbit are opportunistic saprophytes. In some patients infected with HIV, an invasive infection, caused by Aspergillus, may occur. (28) Sinonasal 'aspergillosis' with extension to the orbit often exhibits a relentless progression and can lead to total loss of vision. (27) In addition, infection of the orbit by Mucor ('Mucormycosis') may be associated with diabetic ketoacidosis.29 This condition occurs most commonly in immunosuppressed children and the patient may present with blurred vision, orbital pain, and eye movement problems (ophthalmoplegia). In addition, two aggressive cases of orbital cellulitis have occurred in the USA, associated with Pythium insidiosum. (30) Chronic inflammation of the orbit, possibly associated with fungi, can also be observed in a few cases and is usually of unknown cause.

[FIGURE 3 OMITTED]

Fungal contamination

The ubiquitous nature of fungi means that they frequently contaminate cosmetics, skin lotions, and ocular medical materials. For example, fungi were present in approximately 10% of tested cosmetic products shared by the public. (31) Of these, 3.9% contained fungal or opportunistic pathogens. Contamination of contact lenses by fungi (Figure 3) is usually regarded as negligible, but is being increasingly observed. Whereas the bacterium Haemophilus influenzae can be isolated in large numbers from patients wearing disposable lenses on a six-night extended wear schedule, fungi were present in much smaller numbers. (32) In addition, in a separate study of hydrogel contact lenses (33) bacteria were isolated from 38% of lenses tested, but no fungi were found. However, background infections of the cornea are a complication of photorefractive keratectomy. (34) Some of these cases can be traced to the wearing of a disposable contact lens worn post-operatively overnight. The fungus involved was believed to be a species of Aspergillus (most probably A. fumigatus). Ocular problems may also occur in patients fed intravenously through feeding lines; (35) 24% of such patients developed Candida infection of the eye (most probably caused by C. albicans, C. parapsilosis, C. glabrata, or C. guillermondi). The result may be a uveitis and endophthalmitis, which can lead to blindness. Contamination of donor corneas preserved by organ culture may also be a potential problem. In one study, three out of 1,134 culture media from donor corneas were contaminated by fungi. However, treatment of donor eyes with 10% betadine (1% povidine-iodine) solution significantly reduced microbial growth and especially the

fungus Candida. (36)

Treatment of ocular fungal infections

Antifungal agents are classified into two major groups, viz., polyenes (eg amphotericin-B) and azoles (eg econazole and fluconazole) (Table 2). The mode of action of polyenes and azoles are markedly different, although both disrupt membrane function.

Polyenes

Polyenes bind directly to the unique fungal sterol ergosterol and compromise membrane function. Amphotericin-B is effective against Candida but may penetrate ocular tissues poorly. (37) This substance and its solubilising agent can actually be toxic to the eye. Natamycin is better tolerated and actually penetrates the cornea quite effectively after topical application. The range of activity of natamycin is controversial, but it is often the treatment of choice in many countries, especially for filamentous fungal keratitis. Although natamycin is too toxic to be used intravenously, amphotericin-B can be used by this method for orbital infections and for endophthalmitis.

Azoles

Azoles bind to cytochrome P-450 fungal enzyme, resulting in a decrease in synthesis of ergosterol and an increase in permeability of the membrane. All azoles, with the exception of fluconazole, depress the activity of the immune system. Several compounds have been used including thiabendazole, itraconazole, clotrimazole, miconazole, ketoconazole, fluconazole and econazole. (38) Several new azoles are also becoming available eg isavaconazole, ravaconazole and altaconazole. Most are effective against Candida, although econazole is more effective against filamentous fungi. Azoles are widely used in the form of drops since they exhibit good penetration of ocular tissues. They are well tolerated, although econazole, miconazole and ketoconazole have been reported to irritate eyes in some cases. (39,40) Itraconazole, thiabendazole, ketoconazole and fluconazole are absorbed significantly by ocular tissue following oral administration.

Econazole and miconazole have also been used intravenously, but absorbed levels are usually too low for treatment of systemic mycoses.

Fluconazole is probably the azole of choice for intravenous use, achieving high levels of penetration of ocular tissues within a few hours of a single dose. (41) Posaconazole, a structural analogue of itraconazole, was approved for use in USA in 2006. (42) It can be applied as an oral suspension and can be administered even if the patient has poor renal function. It is therefore, useful in high-risk patients, with rare or resistant fungi, or if the patient cannot tolerate other antifungals.

In some cases, combination therapy (topical amphotericin B eye drops and sub-conjuctival injection of fluconazole) may be more efficient at treating keratomycosis compared with eye drops alone. (43) Resistance to anti-fungal agents has been growing in recent years, especially to azoles. Several mechanisms of resistance have been identified including modification of sterol synthesis pathways by the fungus, modification of enzymes to reduce the binding of azoles to fungal components, and increased efficiency of removal of the azole within fungal cells. Although resistance to amphotericin-B has been reported, it continues to be the most important treatment for life-threatening conditions and more severe ophthalmic infections.

Conclusions

Fungi are ubiquitous organisms that can be found in association with healthy eyes. The incidence of actual fungal eye infection, however, is relatively low compared with that attributable to viruses and bacteria. Nevertheless, fungal infection of the eye is increasing, most notably by the species of Fusarium, Aspergillus, Candida, and dematiaceous fungi. At present, there are a limited number of compounds available to control ocular mycoses. Natamycin is often first choice for filamentous fungal keratitis and topical amphotericin-B for Candida keratitis. Continued monitoring of the behaviour of ocular fungi will be essential in future, together with the development of new anti-fungal agents.

Module questions Course code: C-18803 O/D

PLEASE NOTE There is only one correct answer. All CET is now FREE. Enter online. Please complete online by midnight on June 1, 2012--You will be unable to submit exams after this date. Answers to the module will be published on www.optometry.co.uk/cet/exam-archive. CET points for these exams will be uploaded to Vantage on June 11, 2012. Find out when CET points will be uploaded to Vantage at www.optometry.co.uk/cet/vantage-dates

1. The yeast Candida is a cause of which major ocular infection?

a) Conjunctivitis

b) Endogenous uveitis

c) Retinitis

d) Optic neuritis

2. Trauma to the cornea may be followed by infection caused by:

a) Aspergillus

b) Candida

c) Fusarium

d) Cryptococcus

3. In the normal ocular flora of healthy individuals:

a) Fungi are a normal constituent in most cases

b) Most species of fungi in the conjunctiva are pathogenic

c) Species of Penicillium are the most common fungi to be isolated

d) Yeasts may be the most common in less developed countries

4. The most important fungi to affect the eyelids is:

a) Microsporum

b) Candida

c) Cryptococcus

d) Aspergillus

5. Regarding keratomycosis:

a) Surgery is indicated in all cases

b) The least common cause is Aspergillus fumigatus

c) Surgical trauma is a possible risk factor

d) It does not respond well to treatment by azoles

6. Considering fungal infections of the orbit:

a) They are a very common cause of orbital infections

b) Most fungal invaders are opportunistic saprophytes

c) They do not occur in immuno-supressed patients

d) They are normally asymptomatic

References

See www.optometry.co.uk/ clinical. Click on the article title and then on 'references' to download.

Dr Richard A Armstrong, BSc, DPhil Maryam Mousavi, RO (Canada)

The surface of the eye is rich in nutrients and supports a variety of microorganisms, including bacteria and fungi. (1-4) Fungi are a diverse group of organisms, ranging from microscopic unicellular entities to large multicellular forms.5 Although not as common as bacteria or viruses as a cause of eye infection, a large number of fungal species have been associated with the eye.6 Several species are known to cause eye infections (ocular mycoses), which may even be life-threatening. (6,7) This article discusses the most common ocular mycoses, the importance of fungal contamination of materials in contact with the eye, and the methods of treatment.

About the authors

Richard Armstrong was educated at King's College London and St Catherine's College, Oxford. He has been a lecturer in botany, microbiology, ecology, neuroscience, and optometry during his 36 years at Aston University. His research interests include the neuropathology of neurodegenerative diseases, with special reference to vision and the visual system. He also has a particular interest in the application of statistical methods in research. Maryam Mousavi is a third year undergraduate on the optometry programme at Aston University. Previously she was a registered been a lecturer in botany, microbiology, ecology, neuroscience, and optometry during his 36 years at Aston University. His research interests include the neuropathology of neurodegenerative diseases, with special reference to vision and the visual system. He also has a particular interest in the application of statistical methods in research. Maryam Mousavi is a third year undergraduate on the optometry programme at Aston University. Previously she was a registered optician working in Vancouver, Canada. She conducts charity work supporting eye hospitals in less developed countries. Through this she has developed a particular interest in fungal infections of the eye as they are a growing problem in less developed countries.
Table 1

Major eye infections caused by fungi

Region of the eye          Fungal infections

Lids, Lacrimal apparatus   Ringworm associated with
                           Microsporum and Trichophyton.
                           Eyelid lesions may be caused
                           by Cryptococcus, Candida, and
                           Sporotrichum Inflammation of
                           lacrimal gland by Aspergillus,
                           Leptothrix, Sporotrichum, and
                           Rhinospiridium

Conjunctiva                Conjunctivitis caused by
                           Leptothrix, Sporotrichum,
                           Candida, Trichophyton,
                           Aspergillis Ulcerating nodules
                           by Rhinosporidium

Cornea                     Keratomycosis caused by
                           Aspergillus and Fusarium,
                           Alternaria, Cephalosporium
                           (Acremonium), Dematiaceous
                           fungi and Pythium insidiosum

Sclera                     Cryptococcus, Metarrhyium
                           anispliae

Uvea                       Uveitis caused by Aspergillus
                           and Candida, and Coccidiodes.
                           Rare cases caused by
                           Paecilomyces sp. and
                           Cephalosporium

Vitreous                   Abscess caused by Aspergillus,
                           Cephalosporium, Fusarium and
                           Candida

Retina                     Candida retinitis in immuno-
                           compromised patients Local
                           lesions caused by Cryptococcus

Optic disc, optic nerve    Papillitis and optic neuritis
                           caused by Phycomycetes and
                           Cryptococcus

Orbit                      Invasive aspergillosis in HIV
                           infection, mucormycosis,
                           Pythium insidiosum

Table 2

Treatment of ocular mycoses (IVA = intravenous administration)

Agent            Effective against       Administration

Amphotericin-B   Candida                 Topical, IVA
Natamycin        Broad spectrum          Topical
Thiabendazole    Candida                 Topical, oral
Clotrimazole     Candida                 Topical
Miconazole       Broad spectrum          Topical, IVA but not in UK
Ketoconazole     Broad spectrum          Topical, oral
Econazole        Filamentous fungi       Topical
Fluconazole      Candida                 Topical, IVA
Posaconazole     Broad spectrum          Oral
Itraconazole     Aspergillus keratitis   Oral

Agent            Side effects

Amphotericin-B   Impaired renal
Natamycin        IVA toxic
Thiabendazole    None reported
Clotrimazole     None reported
Miconazole       Eye irritant
Ketoconazole     Eye irritant
Econazole        Eye irritant
Fluconazole      None reported
Posaconazole     None reported
Itraconazole     Gastro-intestinal problems
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Title Annotation:CET: CONTINUING EDUCATION & TRAINING: PEER REVIEWED
Author:Armstrong, Richard A.; Mousavi, Maryam
Publication:Optometry Today
Geographic Code:4EUUK
Date:May 4, 2012
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