Clinical Microbiology Reviews, October 2003, p. 730-797, Vol. 16, No. 4
0893-8512/03/$08.00+0 DOI: 10.1128/CMR.16.4.730-797.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.
Current Perspectives on Ophthalmic Mycoses
Philip A. Thomas*Department of Ocular Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, Tiruchirapalli 620001, India
SUMMARY INTRODUCTION ETIOLOGICAL AGENTS AND LABORATORY DIAGNOSIS OF OPHTHALMIC MYCOSES Etiological Agents Hyaline filamentous fungi. Dematiaceous (phaeoid) fungi. Yeasts and zygomycetous fungi. Thermally dimorphic fungi. Organisms of uncertain taxonomic classification. Laboratory Diagnosis Direct microscopic detection of fungi in ocular samples. Culture. Sensitivity testing of fungi isolated from ophthalmic lesions. PCR. PATHOGENESIS Putative Agent Factors in the Pathogenesis of Mycotic Keratitis Invasiveness. Toxigenicity. Putative Host Factors in the Pathogenesis of Mycotic Keratitis ANTIFUNGAL AGENTS USED TO TREAT OPHTHALMIC MYCOSES General Considerations Polyenes Natamycin. Amphotericin B. Azoles Miconazole. Ketoconazole. Itraconazole. Fluconazole. Miscellaneous Compounds Polyhexamethylene biguanide. Chlorhexidine. Silver sulfadiazine. CLINICAL FEATURES, PREDISPOSING FACTORS, AND MANAGEMENT OF SPECIFIC OPHTHALMIC MYCOSES Fungal Infections of the Orbit Acute rhinocerebral (rhino-orbito-cerebral) zygomycosis. (i) Surgical debridement and restoration of sinus drainage. (ii) Intravenous amphotericin B. (iii) Other therapeutic options. Chronic rhinocerebral zygomycosis. Treatment of fulminant infections caused by non-Mucorales fungi. Orbital aspergillosis. Mycotic Infections of the Eyelids Mycotic Dacryocanaliculitis Mycotic Dacryocystitis Mycotic Dacryoadenitis Mycotic Conjunctivitis Conjunctival rhinosporidiosis. Mycotic Keratitis (Keratomycosis) Risk factors. Fungi causing mycotic keratitis. Diagnosis. (i) History and clinical features. (ii) Noninvasive techniques. (iii) Microbiological investigations. Management. (i) Specific antifungal therapy. (ii) Measures to suppress corneal damage due to microbe- or host tissue-derived factors. (iii) Therapeutic surgery. Mycotic Scleritis Intraocular Mycoses (Excluding Endophthalmitis) FUNGAL OCULAR INFECTIONS AFTER OPHTHALMIC SURGICAL PROCEDURES OPHTHALMIC MYCOSES ASSOCIATED WITH AIDS OPHTHALMIC MYCOSES ASSOCIATED WITH OCULAR BIOMATERIALS FUTURE RESEARCH IN OPHTHALMIC MYCOSES Diagnostic Methods New Antifungal Compounds Pathogenesis of Ophthalmic Mycoses ACKNOWLEDGMENTS REFERENCES
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Fungi may infect the cornea, orbit and other ocular structures. Species of Fusarium, Aspergillus, Candida, dematiaceous fungi, and Scedosporium predominate. Diagnosis is aided by recognition of typical clinical features and by direct microscopic detection of fungi in scrapes, biopsy specimens, and other samples. Culture confirms the diagnosis. Histopathological, immunohistochemical, or DNA-based tests may also be needed. Pathogenesis involves agent (invasiveness, toxigenicity) and host factors. Specific antifungal therapy is instituted as soon as the diagnosis is made. Amphotericin B by various routes is the mainstay of treatment for life-threatening and severe ophthalmic mycoses. Topical natamycin is usually the first choice for filamentous fungal keratitis, and topical amphotericin B is the first choice for yeast keratitis. Increasingly, the triazoles itraconazole and fluconazole are being evaluated as therapeutic options in ophthalmic mycoses. Medical therapy alone does not usually suffice for invasive fungal orbital infections, scleritis, and keratitis due to Fusarium spp., Lasiodiplodia theobromae, and Pythium insidiosum. Surgical debridement is essential in orbital infections, while various surgical procedures may be required for other infections not responding to medical therapy. Corticosteroids are contraindicated in most ophthalmic mycoses; therefore, other methods are being sought to control inflammatory tissue damage. Fungal infections following ophthalmic surgical procedures, in patients with AIDS, and due to use of various ocular biomaterials are unique subsets of ophthalmic mycoses. Future research needs to focus on the development of rapid, species-specific diagnostic aids, broad-spectrum fungicidal compounds that are active by various routes, and therapeutic modalities which curtail the harmful effects of fungus- and host tissue-derived factors.
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Ocular fungal infections, or ophthalmic mycoses, are being increasingly recognized as an important cause of morbidity and blindness; certain types of ophthalmic mycoses may even be life-threatening (213, 435). Keratitis (corneal infection) is the most frequent presentation (363), but the orbit, lids, lacrimal apparatus, conjunctiva, sclera, and intraocular structures may also be involved (Fig. 1). A comprehensive review of fungal diseases of the eye, in particular endogenous and exogenous fungal endophthalmitis, has recently been published (194). In the present article, emphasis is placed on mycotic keratitis and mycoses of the orbit and adjacent external ocular tissues; intraocular mycoses (excluding endophthalmitis) are briefly mentioned. Emphasis has been placed on literature published within the last 12 years, but prior noteworthy reviews and case reports are included.
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FIG. 1. Schematic
representation of a cross-section of the human eyeball, depicting its
parts.
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A third problem is in assessing the accuracy of the genus or species identification of a fungal strain isolated in culture. For example, a fungal strain isolated from a patient with keratitis was initially identified as Arthrobotrys oligospora but later reidentified as Cephaliophora irregularis (128); C. irregularis was subsequently isolated from another patient with keratitis as well (235). Similarly, a filamentous fungus isolated from an intraocular lesion arising out of a retained contact lens was identified as Scedosporium prolificans (19); it now appears that this identification may have been erroneous (J. Guarro and J. Gené, Letter, J. Clin Microbiol. 40:3544, 2002).
To overcome these limitations, reports of single cases or small numbers of patients were considered acceptable for this review if they satisfied criteria similar to those described earlier (237): when an adequate clinical history was presented that suggested a mycotic infection; when the fungus was seen in the clinical specimens; and when the morphology of the fungus in the clinical specimens was consistent with the reported etiologic agent. Papers describing a series of patients with keratitis (120, 334) or other ophthalmic infection (313), many of which were based on retrospective analysis of patient records, were assessed differently since such publications rarely provided detailed descriptions of the fungi isolated from individual patients or of the appearance of the fungi in the specimens or tissues. The observations made in these papers were considered valid if definite criteria had been used to assess the significance of the fungi isolated; for example, the presence of clinical features suggesting a fungal infection, growth of the same fungus from repeated samples, growth of the same fungus on two or more solid media, or confluent growth at the site of inoculation in one solid medium with direct microscopic demonstration of fungal hyphae or yeast cells in the sample (85, 120, 208, 216, 364, 377).
A recent review of fungal infections of the eye (194) listed exceptions to the rule requiring isolation of the fungus from ocular tissue. The exceptions listed included entities such as endogenous endophthalmitis, in which fungi known to cause this disease had been isolated from blood culture and the clinical presentation was compatible with vascular dissemination of the fungus; histoplasmosis and coccidioidomycosis, which are commonly associated with characteristic chorioretinal lesions and in which isolation of the fungus from another anatomical site or measurement of titers of antibody to the fungus is usually deemed sufficient evidence to establish one of these fungi as the cause of the eye disease; and ophthalmic infections due to Cryptococcus neoformans, which usually occur in conjunction with meningoencephalitis and in which isolation of cryptococci from blood and/or cerebrospinal fluid is usually sufficient to explain the associated eye findings. Most of these exceptions pertain to reports of intraocular mycoses, whereas the present review highlights external ophthalmic infections.
In this review, fungal genera and species are cited as they have been reported in the literature. Unfortunately, in the majority of published reports, the strains have not been deposited in recognized culture collections to permit others to confirm the validity of the identifications; moreover, there is a need to apply modern molecular biological and other methods to the process of identification of fungi in the future (129; J. Guarro and J. Gené, Letter, J. Clin. Microbiol. 40: 3544, 2002). Hence, at present, only an uncritical compilation of the fungal genera and species as reported is possible.
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Fungi are opportunistic in the eye, since they rarely infect healthy, intact ocular tissues. Even the trivial trauma of a dust particle falling on the cornea may disrupt the integrity of the corneal epithelium, predisposing to mycotic keratitis. In a compromised or immunosuppressed individual, serious sight-threatening and life-threatening infections such as rhinoorbitocerebral zygomycosis may supervene (435).
An overwhelming number of fungal genera and species have been implicated as causes of ophthalmic mycoses, and this number is steadily increasing. Species and genera of fungi implicated as genuine ophthalmic pathogens in the past 5 years include Chrysosporium parvum (415), Metarhizium anisopliae var. anisopliae (76), Phaeoisaria clematidis (131), and Sarcopodium oculorum (132). In this review, no attempt has been made to list every single fungal genus or species implicated in ophthalmic infection, given the limitations listed above. Instead, the salient features of the most important genera and species are highlighted, since it appears that only a relatively small number are repeatedly isolated in ophthalmic mycoses or have been isolated from more than one ocular site (Tables 1 to 5). For purposes of simplicity, the fungal genera and species have been grouped as hyaline filamentous fungi (Table 1), dematiaceous fungi (Table 2), yeasts and zygomycetes (Table 3), thermally dimorphic fungi (Table 4), and organisms of uncertain classification, namely, Pythium insidiosum, Rhinosporidium seeberi, and Pneumocystis carinii (Table 5). In Tables 1 to 5, brief descriptions and line drawings are included to highlight the salient microscopic morphological features of some ocular fungal pathogens which may be unfamiliar to most clinical microbiologists; more intricate details are provided in other papers and specialist mycology texts (50, 237, 238, 325, 329, 373).
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TABLE 1. Hyaline
filamentous fungi implicated in ophthalmic infections
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TABLE 5. Ophthalmic
lesions due to Pythium insidiosum, Rhinosporidium seeberi, and
Pneumocystis carinii
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TABLE 2. Dematiaceous
fungi frequently implicated in ophthalmic infections
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TABLE 3. Yeasts
and zygomycetes implicated in ophthalmic infections
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TABLE 4. Thermally
dimorphic fungi implicated in ophthalmic infections
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Aspergillus spp. abound in the environment worldwide, thriving on a variety of substrates such as corn, decaying vegetation, and soil. These fungi are also common contaminants in hospital air (367) and have been implicated in a recent outbreak of endophthalmitis following cataract surgery that was traced to ongoing hospital construction (375); they are also implicated in other types of ophthalmic mycoses.
Scedosporium apiospermum (teleomorph Pseudallescheria boydii) (Fig. 2) has been isolated from soil, sewage, and polluted water and from the manure of farm animals (373). It has been reported to cause severe ocular infection following trauma by plant material, contact with polluted water, and immunosuppression (211, 325, 379, 430). The fungus Scedosporium prolificans, which was first described as a human pathogen in 1984, has been reported as a cause of sclerokeratitis (202, 370).
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FIG. 2. Hyaline
filamentous fungi S. apiospermum, Paecilomyces, and
Acremonium.
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Species of Acremonium (Fig. 2) are widespread, occurring in soil, decaying plant material, and the air (129). Several cases of keratitis (93, 237, 315, 317) and occasional cases of endophthalmitis (93) due to Acremonium spp. have been reported in the literature.
Dematiaceous (phaeoid) fungi. The primary factor unifying the dematiaceous fungi (Table 2; Fig. 3) is the dark pigmentation of their hyphae (238). At least 20 species of fungi belonging to 11 different genera have been implicated as causes of keratitis (the most frequently reported ones are listed in Table 2). Dematiaceous fungi have been reported to be the third most frequent cause of mycotic keratitis (behind Aspergillus and Fusarium) (111, 120, 208, 288, 364, 383) and may also cause infections of the orbit (164, 167, 233 W. J. Chang, C. L. Shields, J. A. Shields, P. V. De Potter, R. Schiffman, R. C. Eagle, Jr., and L. B. Nelson, Letter, Arch. Ophthalmol. 114: 767-768, 1996) or intraocular infections (182). These fungi exhibit a brown-to-olive-to-black color in the cell walls of their vegetative cells, conidia or both, colonies thus appear olive to black.
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FIG. 3. Dematiaceous
fungi Bipolaris, Curvularia, Exophiala,
Exserohilum, Lecytophora, Phialophora, and
L.
theobromae.
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FIG. 4. A
5-day growth of L. theobromae on Sabouraud glucose-neopeptone
agar, Emmons' modification. Growth has reached the edge of the
petri dish (90 mm in diameter), indicating rapid growth. The colony is
floccose and grey to brown-black. Macroscopic fruiting bodies
(pycnidia) have not yet
appeared.
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Ocular infections by the zygomycetes (Table 3; Fig. 5) include rhino-orbitocerebral zygomycosis (435) and keratitis (231). Although Rhizopus spp., especially Rhizopus arrhizus, are most frequently involved, other genera of the order Mucorales may also cause ocular disease (87, 323, 435). The detection of fungi belonging to the Mucorales by direct microscopy in clinical material or tissue sections (Table 3) is more significant than their isolation in culture (323, 324).
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FIG. 5. Zygomycetes
Rhizopus, Mucor, R. pusillus, A.
corymbifera, A. elegans, and S.
vasiformis.
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FIG. 6. Thermally
dimorphic fungi P. brasiliensis, C. immitis, B.
dermatitidis, and S.
schenckii.
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Blastomyces dermatitidis (Fig. 6), which has been isolated from moist soil with high organic content, is known to cause pulmonary, cutaneous, osteoarticular, and genitourinary disease (373). Ocular infections include eyelid lesions (26, 355; G. C. Barr and J. W. Gamel, Letter, Arch. Ophthalmol. 104:96-97, 1986), orbital disease (215, 409), keratitis (332), and endophthalmitis (215, 338).
Histoplasmosis is classically caused by Histoplasma capsulatum var. capsulatum, while a variant form, known as African histoplasmosis or large-celled histoplasmosis, is caused by H. capsulatum var. duboisii. The disease is most prevalent in the central region of North America, in Central and South America, in the tropics, and in certain river valleys in temperate regions (373). H. capsulatum var. capsulatum has been implicated in the "presumed ocular histoplasmosis syndrome" and in several other ophthalmic infections, mostly of intraocular structures (118, 180, 224, 303, 424); H. capsulatum var. duboisii has been reported to cause orbital disease (5).
Sporothrix schenckii (Fig. 6), which has been isolated from soil and decaying plant material worldwide, generally causes nodular lesions in the cutaneous and subcutaneous tissues, which ultimately suppurate, ulcerate, and drain. This fungus has been reported to cause lesions of the orbit (369), sclera (I. Brunette and R. D. Stulting, Letter, Am. J. Ophthalmol 114:370-371, 1992), and intraocular structures (205).
Organisms of uncertain taxonomic classification. Pythium insidiosum (Table 5), a cosmopolitan fungus-like aquatic organism, is found predominantly in swampy environments, where water lilies, various vegetables, and especially certain grasses support the asexual phase of its life cycle; motile zoospores, which appear to be chemotactically attracted to plant leaves or human and horse hairs, are the likely infective particles (244). This organism, originally considered to be an oomycete in the kingdom Fungi and later a member of the kingdom Protoctista (244, 373), is now placed in the kingdom Stramenopila, containing organisms that are related to algae (373). P. insidiosum has been implicated in diseases of plants and animals (horses, cattle, dogs, cats, or fish), particularly in tropical and subtropical parts of the world (22, 155, 260, 381). In Thailand, this organism causes subcutaneous lesions and chronic inflammation and occlusion of blood vessels (especially of the lower extremities) in thalassemic and nonthalassemic patients (381). Keratitis due to P. insidiosum has been noted in tropical (22, 155, 244, 411) and temperate (260) regions. Two particularly aggressive cases of orbital cellulitis with deep facial tissue involvement have occurred in the United States (244).
Rhinosporidium seeberi (Table 5; Fig. 7) an endosporulating microorganism which causesrhinosporidiosis, has traditionally been considered a fungus but is now of uncertain taxonomic classification (295). Lesions of rhinosporidiosis manifest as polypoid or papillomatous, very friable, proliferative outgrowths principally in the nasal cavity; ocular lesions may account for 13% of all lesions, with the ratio of nasal to ocular lesions being 1.4:1 (284).
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FIG. 7. Photomicrograph
showing presence of sporangia (cysts) of R. seeberi in stroma
of the lacrimal sac. The cysts are of all sizes, with a sharply
defined, chitinous-appearing wall. The largest sporangium reveals
maturing spores (endospores). The smaller cysts represent
"trophic" stages of the organism. Hematoxylin-eosin
stain; magnification,
x400.
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Laboratory investigation of a suspected ophthalmic mycosis begins with the collection of an appropriate specimen (Table 6); these samples are subjected to direct microscopic examination (Table 7), culture, histologic testing, or other investigations.
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TABLE 6. Specimens
used for diagnosis of ocular fungal
infectiona
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TABLE 7. Important
direct microscopic techniques in ophthalmic mycoses
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FIG. 8. A
24-h growth of F. solani on Sabouraud glucose-neopeptone agar,
Emmons' modification, that had been inoculated with corneal
scrapes. Note that growth has occurred on the "C"
streaks, representing the sites of inoculation. Only growth on C
streaks is considered
significant.
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The ability to detect and differentiate gram-positive and gram-negative bacteria within 3 min in an ocular sample is the most important function of the Gram stain (329) (Table 7); an additional advantage is that fungi (Fig. 9), filamentous bacteria, and cysts of the protozoon Acanthamoeba can also be detected (314, 329). Identification of the fungal genus by direct examination is generally not possible (175, 271). Direct microscopy of corneal scrapes stained by a fluorescent Gram stain technique permitted a rapid presumptive diagnosis of mycotic keratitis in five patients (335); culture confirmed the diagnosis in all five (three infections were due to F. solani, and one each was due to A. flavus and C. albicans). This stain also detected fungi in the vitreous biopsy specimen of one patient with culture-proven endophthalmitis due to A. flavus (335). Advantages of this fluorescence technique over the conventional method need to be assessed by experiments with samples from more patients.
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FIG. 9. Photomicrograph
showing branching, septate fungal hyphae in corneal scrapes. The cell
walls and cross-walls are unstained, but the protoplasm has taken up
the stain, permitting easy visualization of the fungus. Gram stain;
magnification,
x400.
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Lactophenol cotton blue is a mounting medium commonly used in microbiology laboratories for preparing mounts of fungal cultures. This mounting medium has been recommended for the preparation of clinical samples, including corneal scrapes and aqueous and vitreous aspirates, for direct microscopic examination (24). Although lactophenol cotton blue mounts of ocular samples can be stored for long periods, they must be sealed properly to prevent dehydration.
The Gomori methenamine silver (GMS) and the periodic acid-Schiff (PAS) stains are special stains for detection of fungi in tissue. A modified GMS staining technique has been used for this purpose in corneal scrapes (216), in paraffin-embedded tissue sections (406), and in other ocular samples (Table 7). The entire procedure comprises nine steps and takes about 1 h. This stain can also detect filamentous bacteria such as Nocardia and cysts of Acanthamoeba (175). Although widely available, the PAS technique has been infrequently used as a stain for smears from ophthalmic specimens; the reason for this is not known. PAS stains fungal elements well, and hyphae and yeast cells can be readily distinguished; fungal structures were detected in 91% of the PAS-stained sections of corneal buttons which were positive by culture (431).
In recent years, nonspecific fluorochromatic stains have become popular for the detection of fungi in ocular samples. Calcofluor white appears to be the most widely used of these stains (56, 120, 351, 372) since it can detect fungi in 50% of smears previously considered negative by Gram and Giemsa staining methods (372). Calcofluor white is more sensitive than KOH wet mounts in detecting the common ocular fungi F. solani, A. fumigatus, and C. albicans in corneal scrapes (55, 120, 351). A fluorescence microscope fitted with appropriate filters is needed to view mounts of ocular samples that have been stained with calcofluor white. Blankophor and Uvitex 2B, while similar to calcofluor white in many respects, have certain other advantages for detecting fungi in specimens (337, 414) but have apparently not been used widely for the diagnosis of ophthalmic mycoses; the reasons for this are not known.
Several recent studies of small numbers of patients (126, 179) have confirmed that the acridine orange stain is useful to detect fungal hyphae in corneal scrapes. However, the sensitivity of this method in diagnosing culture-proven mycotic keratitis and its specificity when used for patients with ulcerative keratitis need to be assessed in a large series of patients. A fluorescence microscope fitted with appropriate filters is needed for this technique.
Lectins are ubiquitous proteins, which are particularly common in plant seeds that bind specifically to carbohydrates. Fluorescein-conjugated concanavalin A was found to provide consistently bright staining of the fungal structures in corneal scrapes from 18 patients with culture-proven mycotic keratitis (330) and was thought to be a promising first-line fluorochromatic stain to visualize fungi in ocular samples. Again, this technique does not appear to be used as widely as calcofluor white, perhaps because of the cost involved in preparing the necessary reagents.
Garcia et al. (110) have recently described a peroxidase-labeled wheat germ agglutinin staining technique for diagnosis of experimental mycotic keratitis due to C. albicans, A. fumigatus, and F. solani. In addition to excellent sensitivities and specificities for detecting these infections, there was a high degree of test-retest and inter-rater concordance between two independent observers for all three fungi tested. This technique needs to be assessed in the clinical setting, since the use of the peroxidase label for the lectins would eliminate the need for expensive fluorescence microscopes fitted with appropriate filters. One potential disadvantage of this technique is that tissue sections of corneal biopsy material are required, whereas ophthalmologists and patients would probably feel more comfortable if corneal scrapes could be used as the samples.
When fungi such as Candida or Aspergillus are stained with eosin, they fluoresce under UV illumination; this facilitates their detection. Mucin and vegetable fibers do not interfere with this fluorescence (314). Fluorescence microscopy of a tissue section stained with hematoxylin-eosin revealed the presence of yeast cells of B. dermatitidis in periocular cutaneous lesions that had initially been misdiagnosed as squamous cell carcinoma (229).
Because of their size, polysaccharide content, and morphologic diversity, most mycotic agents can be satisfactorily stained and studied in tissue sections by light microscopy. Sections stained with hematoxylin-eosin have many advantages (Table 7), but species of Fusarium or Candida may not be stained at all. Similarly, fungal structures can be easily detected in sections of corneal tissue stained with the GMS or PAS stains (406), but little else can be visualized. Hence, a replicate tissue section stained with hematoxylin-eosin should always be examined before special stains for fungi are used; alternatively, a section stained with GMS can be counterstained with hematoxylin-eosin for simultaneous demonstration of a mycotic agent and the evoked tissue response (57).
Direct immunofluorescence of fungi in formalin-fixed, paraffin-embedded ocular tissue sections has been used to confirm presumptive histologic diagnoses of ocular infection due to B. dermatitidis, H. capsulatum var. capsulatum, S. schenckii, P. insidiosum, and a zygomycete (98, 224, 244, 283, 409). Other dimorphic fungi and hyaline filamentous fungi can also be detected by this technique (57). Factors that have possibly prevented the routine use of immunofluorescence for diagnosis of ophthalmic mycoses include the need for a fluorescence microscope fitted with appropriate filters, antibodies of good quality, and the standardization of reagents and procedures. This technique is especially helpful when atypical forms of an agent are encountered or when infectious elements are sparse. Moreover, for retrospective studies, tissue sections previously stained by the hematoxylin-eosin, Giemsa, and modified Gram procedures can be decolorized in acid-alcohol and then restained with the specific reagents used for immunofluorescence; however, this is not possible with sections previously stained with GMS or PAS (57).
Culture. Even with the advent of many new techniques, culture remains the cornerstone of the diagnosis of most ophthalmic mycoses, except for rhinosporidiosis (since Rhinosporidium seeberi cannot be cultivated) and perhaps rhino-orbito-cerebral zygomycosis, where direct microscopic examination of necrotic material or biopsy samples yields more reliable results (324). Commonly used culture media include Sabouraud glucose neopeptone agar (Emmons' modification, neutral pH) incubated at 25°C, blood agar (preferably sheep blood agar) incubated at 25 and37°C, brain heart infusion broth incubated at 25°C, and thioglycolate broth incubated at 25 to 30°C (271). These media were found to be sufficient to permit the isolation of different types of ocular fungi (216, 334). Using these different media, growth of fungi was identified within 2 days in 54%, within 3 days in 83%, and within 1 week in 97% of patients with mycotic keratitis; a positive initial culture was observed in 90% of scrapings (334).
Other media that have been found useful for primary isolation of ocular fungi include chocolate agar (334), cystine tryptone agar (384) and rose bengal agar (P. A. Thomas, unpublished observations). Since many of these media also support bacterial growth, antibacterial antibiotics, such as chloramphenicol (40 µg/ml) or a penicillin-streptomycin combination, are usually incorporated to suppress bacterial growth and permit the isolation of fungi alone. However, cycloheximide must never be used in culture media meant for the isolation of ocular fungi, since most of the fungi implicated in ocular infections are suppressed by this chemical (271). Wherever possible, it is best to use more than one medium, preferably a combination of appropriate solid and liquid media, and to incubate these at 37°C and at 25 to 30°C for the optimal recovery of ocular fungi; the use of liquid-shake cultures may facilitate the recovery of ocular fungi (398). However, some workers feel that since liquid cultures are prone to contamination by environmental fungi, they should not be used in the microbiological workup of patients with mycotic keratitis, to avoid erroneous results (364, 398). Uninoculated culture media should be incubated for a long period to ensure the sterility of the media used; frequent sterility checks are needed.
Sensitivity testing of fungi isolated from ophthalmic lesions. The clinical relevance of antifungal susceptibility testing is thought to lie in guiding the clinician in the selection of an appropriate antifungal compound. Such tests have been reported to help in the selection of the appropriate antifungal in different ophthalmic mycoses (161, 173, 233, 234). Unfortunately, many of these reports have not provided details of the test procedures used, the criteria by which MICs were deemed significant, details of the severity of the clinical lesions, or the criteria used for authentic diagnosis of mycotic infection. The use of reproducible tests conforming to rigorous standards, such as the approved document (M27A) of the National Committee for Clinical Laboratory Standards (NCCLS) for sensitivity testing of yeasts (261), and a standard method for susceptibility testing of filamentous fungi, especially Aspergillus spp., may clarify in the future whether antifungal susceptibility testing is at all useful in guiding the therapy of ophthalmic mycoses. Interestingly, when the in vitro antifungal susceptibilities of nine isolates of filamentous fungi were determined by the NCCLS method in 11 different laboratories and compared to antifungal treatment outcomes in animal infection models, only a limited association between MIC and treatment outcome was seen, due to drawbacks in the models used (278). Curvularia senegalensis was isolated from a patient with mycotic keratitis, and the MIC of itraconazole for this isolate was found (by a broth microdilution method performed as described by NCCLS guidelines for filamentous fungi) to be 0.25 µg/ml; however, the patient did not respond to antifungal therapy with natamycin or itraconazole (130). Above all, the relationship between in vitro susceptibility data and clinical response to topical antifungal medication needs to be clarified; hitherto, no studies have been performed in this important area.
PCR. Since the revolutionary molecular biology technique of PCR involves enzymatic amplification of even minute quantities of a specific sequence of DNA (Table 8), it is of great benefit in rapidly detecting the presence of organisms which are difficult to culture. Ocular samples which can be submitted for PCR include intraocular fluid (aqueous or vitreous), tears, any fresh ocular tissue, formalin-fixed or paraffin-embedded tissue, and even stained or unstained cytology slides or tissue sections from which DNA can be extracted. Minute samples (1 to 10 µl) of aqueous, vitreous, or tear fluids generally suffice (311). Table 8 summarizes the salient observations of studies employing PCR in the diagnosis of ophthalmic mycoses. The results of all these studies suggest that PCR is more sensitive than culture as a diagnostic aid in ophthalmic mycoses. However, concern persists regarding the specificity of this technique and the problems that may arise from the production of false-positive results. In most of these studies, insufficient detail has been provided to permit an independent assessment of the adequacy of the techniques used for culture. In the diagnosis of ophthalmic mycoses, PCR would probably be most valuable in providing a positive result in a shorter period than that required for culture (91, 92) and in identification of a fungal isolate which does not sporulate (22). Although PCR is more advantageous than the estimation of antibodies in serum or ocular fluids because of its extreme sensitivity and specificity, it cannot be used (unlike serological tests, for which serial antibody titers can be studied) to monitor the patient's response to treatment. PCR does not distinguish viable from nonviable organisms; it may therefore be difficult to assess the relevance of a positive PCR result in a healing corneal ulcer, where culture is negative (7), or in locations such as the conjunctival sac, where fungi may be found as transient commensals (112). A few culture media will suffice to detect and grow the common ocular pathogens, but PCR must be multiplexed for each microorganism that is suspected; the use of panfungal primers may alleviate this problem. Finally, PCR can detect only fungi for which the DNA sequence is known and primers are available; it also does not provide details of cellular morphology or localization (311).
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TABLE 8. Use
of PCR for diagnosis of ophthalmic mycosesa
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Ocular fungal infections probably occur due to an interaction between various agent (fungus), host (tissue and immunological mechanisms), and other factors. Since such factors have been fairly extensively studied in mycotic keratitis, they are reviewed here. The virulence factors of A. fumigatus (207) and zygomycetes (323) in human disease have been extensively described elsewhere.
The ideal test to identify a virulence factor is to compare the infectivity of the fungus in the absence and the presence of the factor, by using naturally occurring mutants or those obtained by UV or chemical means; however, such methods may result in the mutant strains being deficient in more than just one factor (207). Molecular biological techniques can overcome such problems by detecting the gene encoding for the presumed virulence factor being studied; such techniques have not been applied to a great extent to study fungal pathogens in the setting of ocular disease. Therefore, the putative virulence mechanisms reviewed here require confirmation in the future.
The key agent factors thought to be involved in pathogenesis of mycotic infections include adherence, invasiveness, morphogenesis, and toxigenicity (Table 9). There is a paucity of data relating to the role of fungal adhesins in pathogenesis of mycotic keratitis.
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TABLE 9. Putative
agent factors contributing to pathogenesis of mycotic keratitis
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Morphogenesis and phenotypic switching permit fungi to adapt to live in different microenvironments and to survive in the infected host (341). The presence of "intrahyphal hyphae" or "hypha-in-hypha," and thickened fungal cell walls (Table 9) may reflect such morphogenesis occurring in fungi invading corneal tissue; these morphological alterations may constitute a barrier against antifungal drugs or host defenses (392, 393) or may be a virulence factor for fungi in corneas where the defense mechanisms have been compromised by the application of corticosteroids (190). Rigorous experimental and other studies are required to elucidate these aspects. Interestingly, in the study referred to earlier (406), there was no mention of the occurrence of such morphological changes in the fungi seen in corneal tissue.
Toxigenicity. Fusarium spp. are known to cause myelosuppression through toxin production (263), but little is known about whether Fusarium toxins such as nivalenol, T-2 toxin, deoxynivalenol, diacetoxyscirpenol and fusaric acid contribute to the pathogenesis of mycotic keratitis (Table 9). The results of two studies (316, 383) suggest that these factors do not make any such contribution, but further investigation is required.
Some other studies have examined the possible role of fungal proteinases in the pathogenesis of mycotic keratitis (Table 9). Clearly, isolates of F. solani and A. flavus from patients with keratitis possess the ability to secrete proteinases (71, 119, 438). What is not clear, however, is whether these fungi actually secrete these proteinases when infecting corneal tissue and whether such proteinases appreciably influence the outcome of such infections. A recent study attempted to correlate the presence of fungal proteinases in vitro and in an experimental animal system (119). When corneal isolates of A. flavus and F. solani were grown in vitro, the fungal cultures were found to contain predominantly serine proteinase activity, and, to a lesser extent, metalloproteinase activity. However, homogenates of rabbit corneas that had been infected with the same strains of A. flavus and F. solani exhibited metalloproteinase activity alone, and no serine proteinase activity; this suggests that although the fungal strains could secrete proteinases in vitro, they did not do so while infecting corneal tissue. None of the available evidence conclusively establishes or refutes the contribution of fungal proteinases to the pathogenesis of mycotic keratitis. This requires the demonstration of fungal toxins and enzymes in situ in fungus-infected tissues (320) in humans. Similarly, the disease produced in experimental animals by fungal strains secreting a particular proteinase or toxin should be more severe than that produced by a mutant not secreting these products. With the rapid strides made in molecular biological techniques, it should be possible, in the coming years, to investigate these aspects.
Defects in local ocular defense mechanisms, such as epithelial or stromal ulceration due to antecedent herpes simplex keratitis or contact lens-associated corneal abrasions (334, 377, 423), as well as lid notches, lagophthalmos (seen frequently in patients with leprosy), impaired tear secretion, defective secretion of immunoglobulin A in tears, and defective positioning of the lids and mechanisms of lid closure (174, 271) are risk factors for mycotic keratitis, especially that caused by yeasts and less virulent filamentous fungi. Systemic diseases, such as diabetes mellitus, and conditions of general immunosuppression may also be contributory factors. Spontaneous fungal corneal ulceration has been reported in a patient with AIDS (291).
A transient commensal fungal flora is present in a variable percentage of healthy eyes (363). Fungal conidia from the environment which colonize the conjunctival sac as innocuous commensals possibly turn pathogenic after ocular trauma or corticosteroid use, after which they invade corneal tissue through minute breaks in the corneal epithelium (268). This hypothesis needs to be tested in a suitable experimental model.
In some cases of mycotic keratitis which are responding well to antifungal therapy, a sudden deterioration accompanied by renewed tissue destruction (in the absence of a demonstrable microbial cause) has been noted; this phenomenon is thought to occur because dying fungal hyphae may elicit a type of hypersensitivity reaction (100). This hypothesis also needs testing in a suitable experimental model; if substantiated, it may result in modifications to conventional therapeutic protocols for mycotic keratitis.
Polymorphonuclear leukocytes are known to be pivotal in preventing fungal infections since they phagocytize and subsequently destroy fungal structures by oxygen-dependent mechanisms; the presence of disease or the use of corticosteroids, tetracycline, doxycycline, or certain other drugs may interfere with these mechanisms and hence lower the host resistance to fungal infection (366). Polymorphonuclear leukocytes, other acute inflammatory cells, the corneal epithelium, and keratocytes appear to also play a key role in sterile corneal ulceration (184); however, their role in stromal matrix degradation is not clear. When amidated glucose oxidase was inoculated into rabbit corneas, an initial corneal opacification and a later corneal melting were observed; the initial lesions were thought to arise due to the effects of hydroxyl radicals derived from hydrogen peroxide-generated glucose oxidase, with the later lesions occurring after the release of collagenases and lysosomal hydrolases from invading phagocytic cells (53). In another study, the basal proteolytic activity (65 kDa) detected in uninfected rabbit corneas was shown to reside in matrix metalloproteinase 2 (MMP-2) (119). When rabbit corneas were experimentally infected with A. flavus or F. solani, additional proteolytic activity (92 and 200 kDa) was detected, with the 92-kDa activity being identified as MMP-9. The expression of 92- and 200-kDa gelatinases correlated positively with the number of polymorphonuclear leukocytes in infected corneas. These authors contended that activated corneal cells or inflammatory cells (polymorphonuclear leukocytes) were responsible for the increased proteolytic activities seen in fungus-infected corneas.
Lesions simulating keratitis were produced in rabbit eyes by applying lipid mediators, such as prostaglandins, leukotriene, and platelet-activating factor (395). The urokinase-plasminogen activator system plays an important role in the regulation of collagen synthesis, secretion, and activation during wound remodeling and stromal ulceration (30). MMP-2 and MMP-9, derived from corneal stromal keratocytes, have also been shown to contribute to the degradation of corneal stroma and epithelial basement membrane, respectively (94). It is not known to what extent these various factors contribute to the progression of stromal ulceration in a case of mycotic keratitis, but they certainly need to be considered when dealing with a patient whose keratitis is refractory to antifungal therapy alone.
There is compelling experimental (276) and clinical (366, 394, 428) evidence to suggest that the administration of corticosteroids may predispose humans to mycotic keratitis. This may occur because corticosteroids suppress ocular immune mechanisms by inhibiting chemotaxis and ingestion by phagocytes, by blocking degranulation, and by reducing the production of phagocytes (366). They may also cause changes in the infecting fungal strain itself, the reasons for which are not clear (394).
Traditional eye remedies are routinely used for the "therapy" of eye ailments in many agricultural communities in the developing world. In India, traditional remedies described include extracts of green leaves, the juice of the banyan tree, coconut and castor oil, goat and human breast milk, and chicken blood (120, 388). Fungi contaminating such concoctions could conceivably be carried into the deeper corneal layers when applied to a traumatized cornea. The use of certain oils may be associated with excessive corneal irritation, thus predisposing to mycotic keratitis. Experimental studies may help to clarify the validity of such hypotheses.
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In treating ophthalmic mycoses, the ultimate aim is to preserve vision, and this depends on rapid diagnosis and efficient administration of appropriate antifungal therapy (227). There are three main chemical groups of drugs with antifungal activity for use in therapy of ophthalmic mycoses, namely, the polyenes, azoles (imidazoles and triazoles), and flucytosine (5-fluorocytosine). The clinical use of additional classes of antifungals, such as the allylamines and candins, is not widespread. In this section, the salient characteristics of antifungal agents currently used for therapy of ophthalmic mycoses are highlighted (Table 10); the efficacies of these antifungals in specific ophthalmic mycoses are discussed later (see "Clinical features, predisposing factors, and management of specific ophthalmic mycoses"). Antifungals such as clotrimazole, econazole, flucytosine, and nystatin were widely used in the 1970s and early 1980s for treatment of ophthalmic mycoses. Unfortunately, the data pertaining to these drugs were derived from case reports or uncontrolled studies. Moreover, these drugs have generally poor pharmacokinetics or poor therapeutic profiles in the eye or are obsolete. Hence, they are not included in this review. While the reported in vitro spectrum of antifungal activity is mentioned in certain instances, it should not be taken to imply that there is necessarily a correlation between in vitro antifungal susceptibility data and efficacy in the clinical setting of ophthalmic mycoses.
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TABLE 10. Antifungal
drugs currently used to treat ophthalmic mycoses
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The clinical efficacy of an antifungal agent in an ophthalmic mycosis depends to a great extent on the concentration achieved in the target ocular tissue. This, in turn, depends on a number of factors including the molecular mass and concentration of the drug and the route by which it has been administered, the duration of contact with the target ocular tissue, and the ability of the compound to penetrate the eye (28, 227). Compounds with a molecular mass exceeding 500 Da, such as amphotericin B (924.10 Da), natamycin (665.75 Da), or ketoconazole (531.44 Da) barely penetrate an intact corneal epithelium because the force of friction increasingly reduces diffusion (227). Solubility in lipid-rich tissue is another determinant of diffusion. The ocular penetration of molecules with intermediate molecular masses, such as miconazole (416.12 Da) or fluconazole (306.30 Da) is probably determined by both factors. Lipophilic compounds, such as itraconazole, easily cross the lipid-rich epithelial and endothelial cell membranes and the blood-aqueous barrier; hydrophilic compounds more easily cross the corneal stroma; and biphasic compounds (which possess both lipid and water solubility) penetrate all corneal layers (107). The exact relevance of these considerations in the use of topical antifungals for therapy of mycotic keratitis, where the integrity of the corneal epithelium and superficial stroma is usually breached by the disease process itself, needs to be addressed.
The concentration of the drug applied to the eye may be increased by the preparation of fortified eye drops (107), but this is not generally done for antifungals. Frequent topical application of drops is a useful means of achieving therapeutic levels in the eye, but this is laborious and may cause irritation. Ointments and subconjunctival injections may prolong the contact time between the antifungal and the corneal and conjunctival tissue. Only amphotericin B and miconazole are available as ophthalmic ointments. Subconjunctival injections can be painful for the patient and inconvenient for the physician (107) and can cause damage to the ocular tissue at the site of injection (236).
Collagen shields, iontophoresis, and pumps have all been used in an attempt to enhance drug delivery to the eye. The use of iontophoresis and pumps has not gained acceptance, and these techniques should now probably be considered obsolete. However, the collagen shield, which is shaped like a contact lens and is packaged in a dehydrated form and rehydrated before use, has been used to promote corneal epithelial healing and deliver drugs. The source of the collagen may be porcine sclera or bovine corium (107). The collagen shield has been found useful to deliver drugs to the eye since therapeutic levels of medication are delivered reliably with a minimum number of applications. Drug delivery depends on absorption and subsequent release of the medication by the shield. When a solution containing a water-soluble drug is used for rehydration, the drug becomes trapped in the interstices of the collagen matrix; the drug is released as the shield dissolves (107). Shields soaked in water-soluble drugs have been found to produce corneal and aqueous levels comparable to those obtained with frequent topical therapy. The prolonged exposure time of medication to the cornea provided by a presoaked shield may produce higher levels in tissue than a single drop that is rapidly carried away by the tears (107). Currently, the only antifungal to be used in collagen shields is amphotericin B (267, 299, 347). Clearly, the potential of this technique for delivery of antifungals to the eye should be explored further.
Polyenes continue to be an important component of the ocular antifungal armamentarium. These bond directly to ergosterol, a sterol unique to fungal cytoplasmic membranes; the integrity of these membranes is disrupted, resulting in leakage of essential intracellular constituents (267). The extent of damage to fungal membranes is dose related; however, it is not possible to increase the drug dosage beyond a certain concentration, since the cytoplasmic membrane of human cells may then be affected (toxicity of polyenes). Natamycin (pimaricin) and amphotericin B are the polyenes in current use for treatment of ophthalmic mycoses.
Natamycin. Natamycin was the first antifungal specifically developed for topical ophthalmic use (Table 10) and is currently the only topical ophthalmic antifungal compound approved by the Food and Drug Administration of the United States (267). It is reported to have a broad spectrum of activity against various fungi, including species of Fusarium, Aspergillus, Acremonium, Penicillium, Lasiodiplodia, and Candida (236, 267, 271), but the validity of the methods used to derive these data, as well as the relevance of these data to the clinical use of natamycin, which is given only topically, is a contentious issue.
Natamycin is poorly soluble in water. It is stable in a 5% suspension and, in this form, adheres well to the cornea for clinically useful periods (236). The 5% topical ophthalmic suspension, although viscous, is well tolerated and causes no pain or secondary corneal damage (236). Punctate keratitis is sometimes encountered (170). It was initially thought that natamycin penetrated the cornea and conjunctiva poorly after topical application, that effective drug levels were not achieved in either the cornea or aqueous, and that it was therefore useful only in the treatment of superficial mycotic keratitis (236). However, radiolabeling studies suggest that it actually penetrates the cornea well after topical application (274). Thirteen topical applications every 5 min resulted in a drug concentration of approximately 2.5 mg/g cornea in rabbit corneas debrided of epithelium; levels peaked at approximately 10 min after administration. Far lower levels (7.0 µg/g) were attained in corneas where the epithelium was left intact (274). It is unclear whether these levels are actually achieved during therapy of clinical mycotic keratitis.
Natamycin is the drug of choice for therapy of mycotic keratitis in many countries (235, 288, 328, 334), particularly for keratitis due to filamentous fungi. It has also been used in association with other treatment modalities for therapy of mycotic scleritis (370), conjunctivitis, and endophthalmitis (267); controlled clinical trials are needed to confirm the efficacy of natamycin for these indications.
Amphotericin B. Amphotericin B (Table 10) is variably fungistatic and occasionally fungicidal, depending on the concentration achieved in serum (187) and the susceptibility of the pathogens; maximum activity is seen at a pH range from 6.0 to 7.5. Amphotericin B has been administered by the intravenous, topical, intravitreal, and intracameral routes for therapy of ophthalmic mycoses (236, 267).
For intravenous infusion of amphotericin B, a solution of 0.1 mg/ml in a 5% solution of dextrose is used (saline cannot be used since the drug may precipitate out). Unused solutions should be discarded after 24 h. Amphotericin B is both heat labile and light sensitive; hence, the dry powder should be refrigerated and protected from light (236). The recommended dosage is usually 1 mg/kg of body weight/day; smaller doses may be relatively ineffective (236). However, since tolerance to amphotericin B varies greatly among patients, the dosage must be individually adjusted; the safest approach is to initially give low test doses and to gradually increase the dose (236). Treatment needs to be given only once daily, or on alternate days once clinical improvement is noted; alternate-day therapy is advised for at least 2 months for many infections, with administration of a total dose of at least 3.0 g of amphotericin B (236). Renal toxicity is estimated to occur in almost 80% of patients receiving intravenous amphotericin B (187); this should be zealously guarded against by frequent monitoring of the blood urea nitrogen and other tests of kidney function. Headaches, chills, fever, and anorexia are common with systemic use; other adverse side- effects include moderate anaemia, nausea, vomiting, gastrointestinal cramps and diarrhea, and local thrombophlebitis at the infusion site (236). In view of these toxic effects, treatment should be reserved for patients in whom a diagnosis of mycotic infection is reasonably well substantiated; patients receiving systemic amphotericin B for ophthalmic reasons should be comanaged with an internist, who will monitor the patient for toxicity (236).
Intravenous amphotericin B continues to be the treatment of choice for invasive fungal infections of the orbit (164, 213, 323, 349); it has also been used in the treatment of endophthalmitis due to dimorphic fungi (205, 215, 224, 253, 338, 357) and lesions of the eyelids, conjunctiva, and cornea caused by P. brasiliensis (353). The efficacy of intravenous amphotericin B in endophthalmitis due to dimorphic fungi is difficult to evaluate since, in many of the reports cited, posttreatment cultures were negative but the affected eyeball had to be enucleated due to other complications.
Lipid formulations of amphotericin B have been evaluated because of the renal and systemic toxicity of conventional amphotericin B, especially when high doses are required, as in the treatment of zygomycosis (416). These formulations include amphotericin B-lipid complex, which consists of amphotericin B complexed with two phospholipids, dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol (340, 368); and amphotericin B colloidal dispersion, which combines cholesteryl sulfate and amphotericin B in a 1:1 molar ratio, forming a novel lipid delivery system in a disk-like array (diameters range from 120 to 140 nm), which is dispensed in a lyophilized form (257). Local nebulized amphotericin B (308) is reported to be a useful adjunct to conventional therapy in rhinocerebral zygomycosis. However, controlled trials are needed to assess the efficacy of these lipid formulations of amphotericin B and of conventional amphotericin B administered by these different routes in the therapy of ophthalmic mycoses.
For topical administration, a solution (0.15 to 0.3%) may be freshly prepared with sterile water (amphotericin B precipitates in saline); the preparation must be refrigerated in a dark bottle to reduce the speed of disintegration (236). Drops may be instilled every 30 to 60 min. The corneal penetration of amphotericin B is reduced in the presence of an intact corneal epithelium (273, 274). One persistent concern in the topical application of amphotericin B is the problem of possible corneal toxicity (102). Fortunately, the 0.15% solution of amphotericin B in sterile water used in clinical practice appears to be well tolerated (377, 429). Topical application of 0.5% ointment may cause some conjunctival irritation (236), although a 2% ointment was reported to be well tolerated in therapy of mycotic keratitis (148). Subconjunctival injection has been reported to lead to severe toxic effects and is no longer recommended. Amphotericin B in solution or as an ointment has been used topically to treat conjunctivitis, scleritis, and keratitis (31, 148, 334, 377, 429); it is the treatment of choice for keratitis due to Candida spp. (see below).
Delivery of amphotericin B by a collagen shield may improve compliance and ensures a more constant rate of drug delivery in mycotic keratitis (236). In one study, collagen shields soaked in amphotericin B were found to achieve corneal amphotericin B levels comparable to those achieved by hourly topical administration of drops (347). In another study, collagen shields presoaked with 0.5% amphotericin B and applied for 1 h/day were found to be as effective as topical applications of 0.15% amphotericin B every hour for 8 h/day in reducing fungal colony counts in experimental C. albicans keratitis (299). Peak levels with collagen shield delivery were found to occur at 1 h and then to fall to achieve a steady state between 3 to 6 h; however, even at 6 h, corneal amphotericin B levels obtained with the collagen shield were still within the therapeutic range (347). These observations require validation in controlled clinical studies. The use of collagen shields may make it difficult for the clinician to perform frequent clinical examination of the affected eye; improper use may also lead to increased toxicity (347).
Intravitreal injections of amphotericin B (in amounts of 1 to 5 µg) have been recommended for the treatment of mycotic endophthalmitis. This mode of administration can be highly destructive, leading to retinal necrosis and detachment, if the injection is not made slowly exactly in the center of the vitreous, as far as possible from the retina (236). Intracameral administration (7.5 to 10 µg in 0.1 ml) has been used to treat intraocular mycoses, including endophthalmitis (348) and three patients with keratitis and hypopyon due to A. flavus (183), with minimal toxicity being reported. Again, the efficacy of these modes of administration is difficult to evaluate in the absence of evidence from controlled clinical trials.
Azoles bind to a cytochrome P-450 fungal enzyme involved in the 14
demethylation of either lanosterol or 25-methylenedihydrolanosterol,
resulting in a decrease in ergosterol synthesis and an accumulation of
14--methylated sterols; this leads to increased
permeability of the fungal cell membrane, alteration of membrane
enzymes, inhibition of growth, and ultimate death of the fungal cell.
All azoles, except fluconazole, appear to decrease the function of
immune system cells, especially lymphocytes; this may lessen the degree
of tissue damage occurring with the inflammatory reaction but also
affects the efficacy of the azoles in vivo
(432). Since azoles,
with the exception of fluconazole, achieve only limited concentrations
in the eye, they are to be considered as fungistatic when used in
ocular fungal infections
(170). Miconazole. Miconazole (Table 10) is available as a solution for intravenous administration in some countries; it can be used for topical administration as a 1% (10-mg/ml) solution (101) or for subconjunctival administration (5 to 10 mg) (96). Topical administration of 1% miconazole nitrate was not found to retard the closure of 8.5-mm corneal epithelial defects in a rabbit model (102). In the clinical setting, topical miconazole therapy is sometimes associated with reversible superficial punctate keratitis (101).
In an experimental rabbit model, aqueous levels of 8 µg/ml were noted 1 h after intravenous administration of miconazole (30 mg/kg), levels of 10 µg/ml were noted after subconjunctival injection (10 mg), and levels of 4.5 µg/ml were noted after topical administration (1% solution) every 15 min for eight doses to corneas with the epithelium debrided (103). Corneal miconazole levels were not attained by intravenous injection, but following subconjunctival injection, levels of 35 µg/g were noted in corneas where the epithelium had been debrided; after topical administration of miconazole, concentrations of 10 µg/g (in undebrided corneas) and 93 µg/g (in debrided corneas) were achieved (103). These results suggested that miconazole administered topically and, to a lesser extent, subconjunctivally was a potentially effective means of treating mycotic keratitis.
In the 1980s, miconazole was reported to be useful for therapy of mycotic keratitis in two series of patients. In the first series (101), topical and subconjunctival miconazole therapy resulted in resolution of all lesions in seven patients with mycotic keratitis (four cases due to C. albicans, two due to A. fumigatus, and one due to A. flavus); four of these patients had had deep lesions (endothelial plaque in three and descemetocele in one). In the other series (96), miconazole (applied by the topical and subconjunctival routes) was used with ketoconazole (administered orally) to treat 20 patients with mycotic keratitis (eight cases due to Fusarium spp., and four each due to Curvularia spp. and Candida spp.); this regimen resulted in healing in 13 patients. However, the severity of the keratitis in the patients was not clearly defined in the second series. Topical miconazole administration has been reported to be useful in therapy of superficial keratitis due to S. apiospermum (P. boydii) (77, 336). Intravenous administration of miconazole (600 to 3,600 mg/day) was reported to result in successful outcomes in patients with S. apiospermum orbital infection (16, 264), as well as in a few patients with mycotic keratitis (161, 173; Y. Ishibashi and Y. Matsumoto, Letter, Am. J. Ophthalmol. 97:646-647, 1984). It is difficult to derive conclusions based on the small number of patients evaluated; moreover, the intravenous use of miconazole is known to be associated with significant toxic reactions.
Ketoconazole.
Ketoconazole (Table
10), the first successful
orally absorbable broad-spectrum antifungal azole, is currently
available as an oral preparation (200 mg) worldwide. Formulations for
topical or subconjunctival administration are not available, which is
unfortunate since experimental studies suggest that concentrations as
high as 1,391.5 ± 130.0 µg/g can be achieved,
particularly after topical administration and to a lesser extent after
subconjunctival injection, if the corneal epithelium has been debrided
(145). Topical
application is not associated with significant corneal toxicity
(102). Another
experimental study suggested that a single intravitreal dose of
ketoconazole (
540 µg) in dimethyl sulfoxide could be
safely used for fungal endophthalmitis
(436), although this
finding has not been verified in patients. Since the absorption of
ketoconazole is heavily dependent on the gastric pH, cimetidine or
other antacids that inhibit gastric secretion or alter the pH should
not be given concurrently with ketconazole (Table
10). Oral administration
of ketoconazole may lead to various reversible side effects (Table
10). Ketoconazole-induced
papilledema was reported in a patient who received 800 mg/day of
ketoconazole over a 4-month period
(282).
Ishibashi (157) reported that oral ketoconazole therapy (300 mg/day) was effective in two patients with mycotic keratitis, one case due to F. solani (therapy for 3 weeks), and the other due to an unidentified fungus (therapy for 8 weeks). The use of oral ketoconazole in therapy of keratitis due to Fusarium spp., Aspergillus spp., and Curvularia spp. and in therapy of mycotic blepharitis and other ophthalmic mycoses is discussed below. In addition, long-term oral ketoconazole therapy has been credited with improvement in a woman suffering from the keratitis-ichthyosis-deafness syndrome (141) and, in association with cyclosporin, has been shown to be effective in controlling and preventing reactivation of endogenous uveitis as well as in treating chronic uveitis affecting the posterior pole of the eye (312).
Itraconazole. The synthetic dioxolane triazole itraconazole is well absorbed after oral administration (Table 10). It is larger than fluconazole, very hydrophobic, and more than 90% bound to protein in serum (342). It is highly concentrated in lipid-rich tissue and poorly soluble in aqueous solution but well absorbed orally, especially when given with a meal or formulated in polyethylene glycol (401). Itraconazole is generally well tolerated after oral administration; the most common complaint is gastrointestinal upset (310, 390). Less frequently observed side effects include hypertriglyceridemia, hypokalemia, edema, decreased libido, and gynecomastia (267).
The major drawback of using itraconazole by the oral route for therapy of ocular fungal infections is its poor penetration into the cornea, aqueous humor, and vitreous compared to that of fluconazole and ketoconazole. This was the case in a rabbit model of Candida endophthalmitis, even when itraconazole was given at a dose of 80 mg/kg orally (342). However, when treatment was started 24 h postinoculation, itraconazole was at least as effective as fluconazole or ketoconazole (342). Itraconazole was found to be effective in experimental keratitis due to Aspergillus spp. (402). In a recent study, prophylactic administration of an itraconazole oral solution, at a dose of 2.5 mg/kg body weight twice daily, was found to significantly reduce superficial fungal infections in patients with hematological malignancies and neutropenia (139). The ocular pharmacokinetics of this itraconazole oral solution need to be defined.
Attempts have been made to administer itraconazole topically to the eye. In one study, topical 1% itraconazole cream was found to be effective only in nonsevere mycotic keratitis (310). In another study, a 1% suspension of itraconazole, prepared in a commercial isotonic eye drop formulation containing methylcellulose, borax, boric acid, sodium chloride, and potassium chloride, was found to be well tolerated when used for therapy of mycotic keratitis; however, it was also not very effective in treating severe mycotic keratitis, perhaps due to insufficient corneal penetration (385). The vehicle used to prepare the solution or suspension of itraconazole or ketoconazole may influence corneal penetration. Bioassay of rabbit corneas which received topical applications of itraconazole in different vehicles (balanced salt solution, polyvinyl alcohol, boric acid, or olive oil) demonstrated approximate itraconazole concentrations of 200 to 250 µg/g of tissue (136). In an experimental animal model, itraconazole (2.5 mg/ml) that had been administered subconjunctivally was found to persist for at least 24 h in normal and debrided corneas, in contrast to amphotericin B, miconazole, fluconazole, and ketoconazole, which did not persist beyond 4 to 8 h (193). However, intravitreal injection of itraconazole appears to cause focal areas of retinal necrosis when doses exceeding 10 µg are used (344). There are no reports of itraconazole being administered subconjunctivally or intravitreally in a clinical setting.
Fluconazole. The synthetic bistriazole antifungal compound fluconazole exhibits outstanding physical and pharmacokinetic properties (Table 10). Orally administered fluconazole was found to readily penetrate all ocular tissues and fluids of Dutch-belted rabbits; there was no difference between phakic and aphakic eyes (272). After a single oral dose of 20 mg/kg, the levels achieved were 13.3 ± 1.4 µg/g (cornea), 7.4 ± 0.3 mg/liter (aqueous), 9.8 ± 0.9 mg/liter (vitreous), and 5.2 ± 0.4 µg/g (choroid and retina); the concentrations in the cornea correlated highly with those in serum. A steady accumulation in both normal corneas and those infected with C. albicans was noted when fluconazole was given in a twice-daily divided dose; the presence of inflammation induced by fungal infection did not influence corneal uptake (272).
Since fluconazole is a stable, water-soluble, bis-triazole antifungal with low molecular weight, high bioavailability, and low toxicity, it is potentially useful as a topical ocular agent. The penetration of 0.2% fluconazole into corneas (with or without epithelial debridement) and the aqueous humors of New Zealand White rabbits was assayed by gas-liquid chromatography (434). Peak levels of 8.2 ± 1.2 µg/g (debrided corneas) and 1.6 ± 0.6 µg/g (nondebrided corneas) in corneas were noted after 5 min, and levels of 9.4 ± 2.3 and 1.6 ± 0.6 µg/ml, respectively, in aqueous humor were noted after 15 min; the half-life of fluconazole in debrided eyes was 15 min, and that in nondebrided eyes was 30 min. A loading dose of a 20-µl drop per min for 5 min resulted in levels of 59.9 ± 11.3 µg/g in debrided corneas and 32.4 ± 1.9 µg/ml in the corresponding aqueous; this loading dose, followed by 1 drop (20 µl) every 1 or 6 h, resulted in lower levels (434). This confirms that relatively high drug concentrations are achieved in the cornea after topical application of a loading dose of fluconazole, especially if the epithelium has been debrided.
Intravenous administration of fluconazole (5 or 25 mg/kg) in albino rats resulted in aqueous, vitreous, and serum drug levels (1 h after administration) of 2.87, 1.72, and 4.6 µg/ml (5 mg/kg) and 14.9, 7.05, and 20.6 µg/ml (25 mg/kg), respectively; the intraocular penetration was moderately enhanced by vitrectomy (250). In addition, in vitro electroretinograms remained unchanged after perfusion with fluconazole (20 µg/ml) while the in vivo electroretinogram and visual evoked potentials were unchanged after daily fluconazole (25 mg/kg) for 8 days, suggesting a good safety profile. Following intravenous inoculation of 20 mg of fluconazole per kg as a single dose or 20 mg/kg every 12 h for four doses in nonpigmented rabbits, fluconazole concentrations in the aqueous, vitreous, cerebrospinal fluid, and serum were determined by a microbiological assay; the penetration of fluconazole into all the anatomical compartments was found to be >70% of that in serum (246). Since the cerebrospinal fluid and ocular pharmacokinetic parameters closely resemble each other, either could be used as a surrogate for the other (246).
A biodegradable polymeric scleral implant containing fluconazole was reported to be a promising intravitreal drug delivery system to treat fungal endophthalmitis (249). Scleral implants loaded with 10, 20, and 30% doses gradually released fluconazole over 4 weeks in vitro, while those with 50% doses released most of the drug in 1 week; implants with 30% fluconazole that were studied in pigmented rabbits resulted in vitreous concentrations of fluconazole (sustained for 3 weeks) sufficient to inhibit C. albicans. In another study (345), intravitreal injection of up to 100 µg of fluconazole per 0.1 ml of vitreous did not produce biomicroscopic, ophthalmoscopic, electroretinographic, or light microscopic evidence of intraocular toxicity, even 8 days after inoculation.
Oral fluconazole therapy has been used with success in treating one patient with mycotic keratitis (380), one with multifocal choroiditis due to coccidioidomycosis (72), one with chorioretinitis and iridocyclitis complicating disseminated coccidioidomycosis (222), and four with endogenous Candida endophthalmitis (222). Oral fluconazole therapy for 8 weeks also resulted in a remarkable improvement in retinitis following disseminated cryptococcosis in a renal allograft recipient (2). These promising results require confirmation in a larger number of patients and in controlled clinical trials.
Polyhexamethylene biguanide. Polyhexamethylene biguanide (PHMB) is a general environmental biocide that is believed to act on the cytoplasmic membrane of microorganisms, causing leakage of cellular components and inhibition of the respiratory enzymes that are necessary for survival; this molecule exhibits good in vitro activity against bacteria, fungi, and Acanthamoeba (95). It has been used as a swimming pool disinfectant, sanitizer, and preservative in topical ophthalmic preparations. Since PHMB is water soluble, a 0.02% solution can be prepared by dilution of the 20% concentrate with sterile distilled water. PHMB has been used for the treatment of Acanthamoeba keratitis at concentrations of 0.02 to 0.053% without causing adverse effects (84). PHMB at 0.02% was found to be effective in significantly reducing fungal growth in a New Zealand white rabbit model of F. solani keratitis; no growth was obtained in 58% of PHMB-treated eyes and in only 17% of placebo-treated eyes (95). These preliminary results need to be corroborated in other experimental studies using other fungal species that cause mycotic keratitis and in controlled clinical trials.
Chlorhexidine. The cationic antiseptic bis-biguanide chlorhexidine (PHMB is a polyhexamethylene biguanide) inhibits microbial function by affecting the functioning of the cell membrane, therein leading to a leak of cell electrolytes. The bactericidal and amoebicidal effects of chlorhexidine gluconate are well known (348). Attempts have been made to evaluate the efficacy of chlorhexidine in the treatment of mycotic keratitis. In a study conducted in Bangladesh (319), 0.2% chlorhexidine gluconate was compared with 2.5% natamycin therapy in the treatment of 71 patients with suspected mycotic keratitis (2.5% natamycin was used since this formulation was commercially available in Bangladesh); 22 patients had keratitis due to Aspergillus spp., and another 22 had keratitis due to Fusarium spp. None of the severe ulcers was fully healed at 21 days, but three of those treated with chlorhexidine eventually healed in times up to 60 days. Of the nonsevere ulcers, 66.7 and 36% were healed at 21 days by treatment with chlorhexidine and natamycin, respectively (319). When 5% natamycin was used instead of the 2.5% preparation, better results were obtained. The results obtained in this study are misleading, since the 2.5% natamycin formulation used apparently delivered subtherapeutic concentrations of natamycin to infected corneas, resulting in less than optimal outcomes. It might be erroneously infered from this study that natamycin per se is less effective than chlorhexidine against Aspergillus species and other filamentous fungi, whereas in fact an effective formulation of natamycin was not used. Moreover, before performing this study, the pharmacokinetics and antifungal activity of this 2.5% natamycin formulation should have been compared to that of the 5% natamycin formulation that is used worldwide. Recent attempts to use chlorhexidine in the treatment of mycotic keratitis in two locations in Africa have not had encouraging results (171).
Silver sulfadiazine. Silver sulfadiazine derives synergistic benefits from sulfonamides and heavy metals; it functions as an organic base-heavy metal release system. Silver is liberated and binds to microbial DNA, preventing unzipping of the helix and thereby inhibiting the replication of microorganisms without interfering with epithelial cell regeneration (251). The efficacy of a 1% silver sulfadiazine ointment was compared with that of 1% miconazole in therapy of clinical mycotic keratitis in a prospective, controlled, randomized, double-blind clinical study (251). Overall, a higher success rate was achieved with silver sulfadiazine (80%) than with miconazole (55%), although the response of Aspergillus keratitis was comparable in the two groups. Miconazole was totally ineffective in patients with Fusarium keratitis; however, all four patients who received silver sulfadiazine as primary therapy, as well as three other patients who had not responded to initial miconazole therapy and who subsequently received silver sulfadiazine, responded to treatment. The absence of significant ocular or systemic adverse effects, coupled with the efficacy of the compounds, led these workers to suggest that silver sulfadiazine was a safe and effective broad-spectrum antifungal agent for use in mycotic keratitis (251). Unfortunately, details of the severity of the keratitis in the patients who responded to silver sulfadiazine, and in those who did not respond to miconazole were not clearly provided in this paper. Also, since the publication of this report in 1988, there has been no confirmation by others of the results obtained. This compound was not found effective in therapy of culture-proven mycotic keratitis in one study in southern India (Thomas, unpublished).
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Fungal infections of the orbit rarely occur spontaneously. Fungi may gain access to the orbital space by direct extension from adjacent tissues (sinuses, teeth, lacrimal sac, lids), by traumatic implantation of foreign bodies contaminated with fungi, or by hematogenous seeding from a distant focus. Spread of infection from the sinuses to the orbit is thought to occur in 67 to 85% of orbital infections (15, 290) due to the proximity of the sinuses to the orbit (194). Thus, virulent fungal pathogens causing sinusitis can devastate orbital structures by contiguous spread (233). The variable presentations of orbital fungal infections parallel the presentations of paranasal sinus mycoses (192, 233), the salient features of which are listed in Table 11. Just as differences between these types of paranasal sinus mycoses are not always clear, due to closely associated patterns of clinical behavior and pathological reactions (78, 176, 213), differences between presentations of orbital fungal infections, especially the chronic varieties, may not always be distinct.
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TABLE 11. Clinical
presentations of fungal sinusitis with orbital involvement
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The Mucorales are generally considered to be opportunistic pathogens. Neutrophil dysfunction induced by diabetic ketoacidosis underlies most cases of human zygomycosis (323); juvenile diabetics are not spared (1). Neutropenia induced by bone marrow suppression during chemotherapy or immunosuppression induced following transplantation is also thought to be an important risk factor; however, zygomycosis was observed in only 13 (0.9%) of 1,500 consecutive patients who underwent bone marrow transplantation (256). Thus, zygomycosis may occur in both neutropenic and nonneutropenic patients. The use of corticosteroids may be another risk factor, acting by suppressing the normal inflammatory cell response and by inducing a diabetic state.
Patients undergoing hemodialysis and receiving deferoxamine/desferrioxamine for iron or aluminium overload are thought to be at special risk (35, 323). A review of case records of 25 patients who developed zygomycosis while taking deferoxamine for iron overload (74) revealed 7 patients with rhinocerebral zygomycosis Four received no treatment and died, one died in spite of surgery, and one died in spite of surgery and amphotericin B therapy; only one survived after treatment with surgery and amphotericin B. This association between deferoxamine therapy and the occurrence of zygomycosis was confirmed in an alloxan-induced diabetic, immunocompromised murine model of zygomycosis; deferoxamine iron chelation caused rhinocerebral zygomycosis in animals that were challenged intraethmoidally with Rhizopus spores (15). This is thought to occur because feroxamine, which is the iron chelate form of deferoxamine, provides the iron that is an essential growth factor for fungi of the order Mucorales (152).
Other putative risk factors for rhinocerebral zygomycosis include protein-calorie malnutrition and iron overload (with or without the concomitant use of deferoxamine in patients undergoing hemodialysis), intravenous drug abuse, leukemia, aplastic anemia, myelodysplastic syndrome, burns, and treatment with the immunosuppressive medications necessary to maintain liver and other solid organ transplants (74, 265, 308, 323). When disease occurs in nonimmunocompromised individuals, which is rare, there is usually some associated antibiotic use or a breakdown in the mucocutaneous barrier (32, 292, 340); such patients may fare better than immunocompromised patients.
In recent years, the thermophilic fungus A. elegans has emerged as a cause of rhinocerebral zygomycosis (43, 87, 306) in patients without well-recognized immunologic or metabolic abnormalities following traumatic inoculation and/or soil contamination. Such cases have occurred in countries with warm climates (43, 87, 306), which again differs from the pattern of the disease observed with the more "traditional" genera.
Fever, nasal ulceration or actual necrosis, periorbital or facial edema, decreased vision, ophthalmoplegia, sinusitis, and headache have been reported as the most frequently observed clinical features of rhinocerebral zygomycosis and occur in 25 to 44% of patients; facial pain, decreased mental status, leukocytosis, nasal discharge, nasal stuffiness, corneal anesthesia, orbital cellulitis, and proptosis are less frequent manifestations (435). In contrast, another set of investigators (265) opined that a susceptible patient classically presents with unilateral severe headache and facial pain, nasal stuffiness with granular or purulent discharge, facial or eyelid edema, fever, and leukocytosis.
Orbital findings occur due to ischemic necrosis of the intraorbital contents and cranial nerves, while bony involvement is uncommon because of the angioinvasive nature of the fungus. In addition to the usual manifestations listed above, rhino-orbito-cerebral zygomycosis sometimes manifests as a painless orbital apex syndrome without any sign of orbital cellulitis or acute systemic disease (23), which may have a good outcome with medical therapy; orbital infarction syndrome (38); bilateral cavernous sinus thrombosis (13); isolated pontine infarction (49); palatal ulcer (292, 403); sudden blindness (209); fever with right-sided hemiparesis, and dysarthria (1); and numbness and loss of sensation over the temporal region, with loss of vision and proptosis on one side of the face (21). Other conditions which can mimic these manifestations include sinusitis, viral infections, diabetic ketoacidosis, cavernous sinus thrombosis, bacterial orbital cellulitis, fulminant orbital aspergillosis, and pseudallescheriosis. Early visual loss and retinal artery occlusion would favor a diagnosis of rhinocerebral zygomycosis over bacterial cavernous sinus thrombosis, in which blindness occurs much later (87). When the fungus infecting the orbital cavity actually invades the eyeball, the prognosis is particularly poor (359).
Magnetic resonance imaging (MRI) and computerised tomography (CT) can help to establish an anatomical, if not pathological, diagnosis in suspected rhinocerebral fungal infections (213, 252, 302). Findings of diagnostic significance (in descending order of occurrence) include soft tissue opacification of sinuses with hyperdense material, nodular mucosal thickening, and an absence of fluid levels in different sinuses. Sinus contents have a variety of MR signal characteristic, including T2 hyperintensity or marked hypointensity on all sequences. There is often soft tissue infiltration of the deep face and obliteration of the normal fat planes. Typically, proptosis occurs because of enhancing soft tissue masses crowding the orbital apex and the cavernous sinuses; thickening and lateral displacement of the medial rectus muscle are characteristic features indicating orbital invasion from disease in the adjacent ethmoid sinuses. These techniques may have certain limitations in establishing the diagnosis of both cerebral zygomycosis and cavernous sinus thrombosis, which can be overcome by performing sequential CT and MRI studies on a patient suspected to have rhino-orbito-cerebral zygomycosis (252, 323). Whether any specific radiological findings exist for rhinocerebral zygomycosis is a contentious point, although CT nonenhancement of the superior ophthalmic artery and vein, which is related to vasculitis and thrombosis, may represent one such specific sign (109). A combination of MRI and pathology helped to document the perineural spread of rhinocerebral zygomycosis, following the trigeminal nerve to the pons (241). While CT and MRI scans aid in making the diagnosis and in defining the extent of bone and soft tissue destruction, they are more useful in planning surgical intervention (324). MRI scans may be preferred for diabetic patients, for whom CT contrast agents may be contraindicated (324).
A prompt and accurate diagnosis of rhinocerebral zygomycosis necessitates a high level of clinical suspicion, as well as good coordination between the clinical and laboratory staff. Specimens that should be collected to establish a microbiological diagnosis of rhinocerebral zygomycosis have been outlined in Table 6. Swabs are not satisfactory. Instead, abscesses should be aspirated, and lesions on the mucous membranes should be irrigated or scraped; multiple biopsy specimens should be taken (324). Zygomycetes may be found not in the center of the necrotic tissue but, rather, at the edge of or proximal to it (324). Once collected, samples should be transported immediately to the laboratory due to the fragility of zygomycetes, which do not survive more than a few hours at refrigerator temperature; if overnight storage is required, it is recommended that samples be kept in Stuart's transport medium and left at room temperature. Tissue samples should be minced and not ground in order to avoid the destruction of any viable fungal elements that are present.
The microscopic demonstration of zygomycetes in KOH mounts or stained smears of clinical material taken from necrotic lesions (Tables 3 and 7) is more significant than their isolation in culture (323, 324). Although invasion of intact tissue by nonseptate hyphae is good evidence of a zygomycetous infection, failure to observe such elements does not exclude the diagnosis. In tissue stained with hematoxylin-eosin (Table 7), abundant large, irregularly branching hyphal elements can be seen. If cultures are deemed necessary for accurate identification of the fungus involved, nasal, palatal, and sputum cultures can be done, although these are seldom helpful. However, isolation of Mucorales from sputum, material aspirated from sinuses, or bronchial washings taken from diabetic or immunocompromised patients should not be ignored (324). Although zygomycetes are not especially fastidious, they frequently do not growth out in cultures of necrotic tissue, although direct microscopy is positive; therefore, culture media should be inoculated with as much material as possible. Sabouraud glucose neopeptone agar (with an antibacterial such as chloramphenicol or polymyxin B, but no cycloheximide) is adequate (324). Growth is usually rapid (2 to 5 days) and fills the petri dish or tube.
An enzyme-linked immunosorbent assay was used to demonstrate antibodies to S. vasiformis in the serum of a patient with rhinocerebral zygomycosis due to this fungus in whom conventional methods helped to establish the diagnosis (181). Although demonstration of antibodies to Mucorales by this assay may be a rapid yet specific technique for identification of the etiological agent in rhinocerebral zygomycosis, this method does not seem to have attained widespread use, perhaps due to the inherent limitations of applying a serological technique to the diagnosis of so rapidly fulminant an infection as rhinocerebral zygomycosis.
General principles in the treatment of acute invasive rhinocerebral zygomycosis and other acute invasive orbital mycoses include (i) control of diabetic ketoacidosis or other systemic underlying diseases, along with elimination of predisposing factors; (ii) surgical debridement and restoration of sinus drainage; and (iii) intravenous amphotericin B. Table 12 summarizes the salient features of recent series of patients treated on the basis of these principles.
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TABLE 12. Management
of invasive mycoses with orbital involvementa
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(i) Surgical debridement and restoration of sinus drainage. Surgical debridement of all necrotic tissue is crucial and often quite mutilating; it usually requires multiple operations. Wide local excision and debridement of all involved and devitalized oral, nasal, sinus, and orbital tissue is required, while establishing adequate sinus and orbital drainage. Wherever possible, all necrotic tissue should be removed until normal bleeding is encountered, since infected tissue typically bleeds little due to the vaso-occlusion caused by the Mucorales; however, this may not be possible in the setting of extensive infections which can extend to the dura or beyond (435). Serial radiological imaging identifies the extent of disease and the response to treatment. A frozen-section-guided surgical debridement technique for biopsy-proven rhinocerebral zygomycosis has recently been described (206) (Table 13), although it may not be possible to use this technique when there are extensive lesions extending to the dura. Reoperation to debride areas of progressive disease should be planned if the morbidity of the often mutilating surgery does not outweigh its potential benefits (35). The importance of prompt and extensive surgical debridement in the management of rhinocerebral zygomycosis cannot be overstated. A review of evaluable patients with this condition reported in the literature between 1970 and 1994 (435) revealed that 81% of patients survived when the interval between onset of symptoms and surgery was 1 to 6 days, compared to 52% when the interval was 7 to 12 days and 42% when the interval was 13 to 30 days. Interestingly, the percentage of diabetic patients who survived was higher than that of nondiabetics in each group.
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TABLE 13. Alternative
therapeutic regimens reported for mycoses of the orbita
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Traditionally, an external or transantral approach has been the classic method to perform surgical debridement. Recently, endoscopic sinus surgery has been tried on several occasions to reach the goal of radical resection, with survival of 89% of the patients (168). It has been suggested that when endoscopic sinus surgery is used to treat rhinocerebral zygomycosis, alone or in combination with the traditional surgical procedures, there is lower morbidity and greater accuracy during surgery. However, this needs to be confirmed in studies of a larger number of patients.
(ii) Intravenous amphotericin B. Although treatment modalities have not undergone clinical trials, the combination of aggressive surgical debridement and intravenous amphotericin B therapy is still considered appropriate for treatment of rhinocerebral zygomycosis (Table 12). Intravenous amphotericin B treatment should be rapidly instituted in order to be effective; when this is done within 1 to 6 days of onset of symptoms, 76% of patients have been reported to survive, compared to 36% when the interval is 7 to 30 days (435). In spite of the emergence of new antifungals in therapy of invasive fungal disease (Tables 10 and 13), amphotericin B is still regarded as the antifungal of choice for treating rhinocerebral zygomycosis (Table 12).
In an attempt to improve the outcome of rhinocerebral zygomycosis, efforts have been made to deliver amphotericin B directly to the infected tissue. When daily irrigation and packing of the involved orbit and sinuses with amphotericin B (1 mg/ml) were incorporated into the standard therapeutic regimen for rhinocerebral zygomycosis, excellent results were obtained in a small series of patients (195); the focal nature of the lesions may have contributed to the success of this treatment modality. Rhinocerebral zygomycosis in a juvenile diabetic was successfully treated by using intravenous, intracavitary/interstitial, and cerebrospinal fluid (intraventricular) amphotericin B (1). Local irrigation via a percutaneous catheter, in addition to intravenous amphotericin B, has also been tried, with a fair degree of success (265).
Several novel formulations of amphotericin B, including amphotericin B colloidal dispersion, liposomomal amphotericin B, and amphotericin B-lipid complex, have recently been developed (187, 416). These formulations have been used in small numbers of patients with rhinocerebral zygomycosis (257, 308, 340, 368), with favorable outcomes being reported (Table 13). These preliminary results require corroboration in controlled clinical trials on larger numbers of patients.
(iii) Other therapeutic options. Other therapeutic options for treating rhinocerebral zygomycosis include the use of itraconazole (292), fluconazole (339), and granulocyte colony-stimulating factor (339) (Table 13). The results of these studies require careful interpretation since either long-term follow-up details were not provided (292) or the lesions described seemed to have been focal and to have occurred in relatively young patients (339).
Experimental studies have demonstrated that 100% hyperbaric oxygen, at 1 to 3 atms, exerts a fungistatic effect (90). Hyperbaric oxygen may also decrease tissue hypoxia, enhance oxygen-dependent cidal mechanisms, and decrease tissue acidosis. Treatments have consisted of exposure to 100% oxygen at 2 to 2.5 atm for 90 to 120 min every 12 to 24 h (90, 109). Adverse effects of hyperbaric oxygen therapy include decompression sickness and aeroembolism; there is also the ever-present fire hazard and the expensive and cumbersome equipment (233). The exact role of this therapeutic modality in the therapy of rhinocerebral zygomycosis is uncertain. A review of the literature indicated that 22% of patients with bilateral rhinocerebral zygomycosis who received standard therapy survived while 83% of patients who received standard therapy plus adjunctive hyperbaric oxygen survived; it was therefore suggested that hyperbaric oxygen should be considered part of the initial therapy for rhinocerebral zygomycosis, and should be continued until evidence of disease regression is observed (435). Others, however, do not think that there is sufficient evidence to support the view that the use of adjunctive hyperbaric oxygen therapy has changed the prognosis of this infection (35).
Over the past 20 years, the prognosis for patients with rhinocerebral zygomycosis has improved. Factors contributing to a lower survival rate appear to include delayed diagnosis and treatment, hemiparesis or hemiplegia, bilateral sinus involvement, leukemia, renal disease, and treatment with deferoxamine (435). The presence of facial necrosis (435), intraocular invasion by the fungus (359), and cerebral lesions (15) also appear to carry a poor prognosis. The mortality of rhinocerebral zygomycosis caused specifically by A. elegans is currently unknown because of the rarity of diagnosed cases, but it would seem to fall at the more favorable end of the spectrum (87).
Chronic rhinocerebral zygomycosis. Chronic rhinocerebral zygomycosis is indolent and slowly progressive, often evolving over weeks to months. A review of the case records of 18 patients with this presentation revealed that the median time from onset of symptoms to diagnosis was 7 months; the most common presenting features were ophthalmologic, including ptosis, proptosis, visual loss, and ophthalmoplegia; this seemed to occur in those with diabetes and ketoacidosis; and the overall survival rate for the chronic disease was 83%, even though the incidence of internal carotid artery and cavernous sinus thrombosis was higher than in patients with the acute disease (138). Chronic rhinocerebral zygomycosis is clinically distinct from chronic infection due to the Entomophthorales (principally due to Conidiobolus coronatus and Basidiobolus ranarum). In chronic rhinocerebral zygomycosis, ophthalmologic features predominate (sinusitis predominates for C. coronatus, and subcutaneous mycosis predominates for B. ranarum), angioinvasion is an important feature (most Entomophthorales infections are localized, with no angioinvasion), and surgical resection of necrotic tissue is an important component of disease management (surgical resection may actually hasten the spread of infection due to B. ranarum, while the surgical approach is not always optimal in infection due to C. coronatus) (138, 323, 324).
Treatment of fulminant infections caused by non-Mucorales fungi. Treatment would probably be along the lines of the treatment outlined above; however, antifungals other than amphotericin B may play a role in such infections. A devastating bilateral optic neuropathy due to Bipolaris hawaiiensis (repeatedly culture positive) did not respond to 3,700 mg of amphotericin B but ultimately responded to oral itraconazole therapy (233); it is possible that the initial amphotericin B therapy may have reduced the fungal load sufficiently to permit itraconazole to exert a therapeutic effect. A child with acute orbital infection and brain abscess due to S. apiospermum (P. boydii), who did not respond to initial intravenous amphotericin B therapy, ultimately responded to intravenous miconazole and multiple surgical debridements, although it was not clear whether the surgery or the miconazole was more important (16). Surgical debridement of the orbit and a 6-week course of intravenous miconazole led to a reduction of S. apiospermum orbital infection in another patient as well (264). However, firm conclusions cannot be derived based on the results of these few individual case reports.
Orbital aspergillosis. Aspergillus species have been implicated in a wide variety of primary ocular orbital conditions, characterized by rapid, uncontrollable progression and sometimes death (201, 374). Some presentations of orbital aspergillosis, such as optic nerve involvement, may lead to use of systemic corticosteroids, which delays the diagnosis and may potentiate the infectious process (213). Levin et al. (213) described four patients who represented the spectrum of orbital aspergillosis, namely, infection of an exenteration socket, a complex dacryocystitis, a nerve tumor, and postoperative periorbital swelling; they cautioned that in neutropenic or otherwise immunocompromised patients, a high index of suspicion should be maintained to forestall the emergence of fulminant aspergillosis.
The key presenting complaints of sino-orbital aspergillosis appear to be abrupt onset of proptosis, ophthalmoplegia, and blepharoptosis with precipitous visual loss; debilitating periorbital pain or headache, without inflammatory signs, may also be noted (213). Predisposing factors include alcoholism, high-dose corticosteroid therapy, and insulin-dependent diabetes mellitus (367). Invasive Aspergillus rhinosinusitis occurring as a potentially lethal complication of chemotherapy-induced neutropenia in patients with acute leukemia has also been described (376); the majority of cases are due to A. flavus. Such patients may develop symptoms of orbital or cavernous sinus disease.
Aspiration cytology and immunohistochemistry have been described for diagnosis of orbital aspergilloma (367).
In a recent study, it was observed that even with limited surgical debridement and local and systemic amphotericin B in patients with sino-orbital fungal infections, all patients retained their preoperative visual acuities and only one patient underwent an orbital exenteration for progressive orbital fungal infection (349). Thus, conservative orbital debridement with local amphotericin B irrigation may be an effective adjunct in the control of sino-orbital infections, especially in patients with reversible immunosuppression and good preoperative visual activities. Massry et al. (234) reported successful resolution of sino-orbital aspergillosis following initiation of itraconazole treatment, without recurrence at 10 months follow-up, in an immunocompetent patient; notably, traditional therapeutic modalities (surgical debridement and amphotericin B therapy) had not resulted in resolution. Oral itraconazole could be considered as a treatment option in orbital aspergillosis occurring in immunocompetent patients who have recurrent or recalcitrant disease or in those who cannot tolerate amphotericin B (234), but this requires confirmation in studies of a larger number of patients.
Although infections of the eyelids are caused almost exclusively by bacteria (particularly Staphylococcus), fungi may also cause superficial or deep eyelid lesions (Table 14).
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TABLE 14. Mycotic
blepharitis (mycoses of the eyelids), dacryocystitis and conjunctivitis
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An eyelid lesion due to Candida spp. usually suggests spread from a focus, with the use of broad-spectrum antibacterials or immunosuppressive agents predisposing to the infection (14). Ulceration begins at the base of an eyelash; small granulomas are present at its edge, and vesicles and pustules may be present. In a study of 407 patients with chronic severe ulcerative blepharitis, 47 (12%) had positive cultures for Candida spp.; most of these patients also had atopic dermatitis (154).
Lesions caused by the dermatophytes begin as erythematous scaly papules that slowly enlarge; healing occurs simultaneously in the central, paler area. Induration of the lid margin and fracture of the cilia may occur (424). A kerion celsi reaction in the eyebrow due to Trichophyton rubrum has recently been described (149).
Although the lid is generally considered to be the most common ocular tissue affected by B. dermatitidis infection (338, 355; Barr and Gamel, letter), Bartley (26) reported that only 1 of 79 patients with systemic blastomycosis seen by him had such lesions. The lesions may arise due to contiguous spread from facial lesions or due to hematogenous dissemination from a pulmonary lesion. Small abscesses may be visible around the eyelashes; these later form granulomatous ulcers with thick crusts and an underlying purplish discoloration of the skin. Healing of the lesions may lead to severe cicatrization and ectropion (14, 355). The evolution of eyelid lesions due to the dimorphic fungi C. immitis and S. schenckii is similar to that seen in B. dermatitidis infections (14).
Eyelid lesions, alone or in association with corneal and conjunctival lesions, occur in more than 50% of reported cases of ocular paracoccidioidomycosis (46, 353). Males, particularly those older than 30 years who are engaged in agriculture and come from an area of endemic infection seem to be at greatest risk (353). The palpebral lesion starts as a papule, usually close to the lid border, and grows and ulcerates in the center. The base of the ulceration reveals fine hemorrhagic, punctate, elevated, thickened, and hardened borders. The lesions evolve toward palpebral coloboma, with loss of the eyelashes. Ocular lesions due to P. brasiliensis need to be differentiated, particularly in the initial stages, from hordeolum, bacterial blepharitis, trachoma, leishmaniasis, sporotrichosis, lupus erythematosus, tuberculosis, and secondary syphilis.
Malassezia furfur (formerly Pityrosporum orbiculare and Pityrosporum ovale) is a cause of pityriasis versicolor, a chronic mild skin infection sometimes found around the eyebrows and eyelids, and may be associated with seborrheic blepharitis (20, 373). Lid scrapes from 40 symptomatic patients with seborrheic or mixed seborrheic and staphylococcal blepharitis were subjected to direct microscopy and culture; yeast and hyphal forms suggestive of Malassezia spp. were detected in scrapes from 39 of the 40 patients; fungi were isolated from the scrapes from about half the patients (262).
The hyphae or yeast cells of fungi causing eyelid lesions can be easily demonstrated by examination of a 10% KOH wet preparation or a Gram-stained smear of lid scrapes.
Many therapeutic regimens for mycoses of the eyelids have been recommended (14, 28), but the basis for these suggestions is not clear. Table 14 lists some of the therapies and outcomes described in recent reports of various eyelid mycoses, which are briefly summarised below. Eyelid lesions due to rhinosporidiosis require excision (226).
A double-blind, placebo-controlled clinical trial of topical 2% ketoconazole cream with lid hygiene was conducted to treat seborrheic and mixed seborrheic and staphylococcal blepharitis (262). Although ketoconazole was no better than placebo at improving the symptoms of blepharitis, more ketoconazole-treated patients had normal, or markedly improved, lids after treatment than did the placebo group (262). Two doses of ketoconazole (100 mg per day) with topical miconazole ointment for 6 weeks has been recommended for treatment of mycotic blepharitis due to Candida spp. (154).
Preseptal cellulitis due to Trichophyton spp. was recently described in a 10-year-old boy (405). The cellulitis did not respond to antibacterials, prompting microbiological studies. Trichophyton spp. were recovered from two skin scrapings taken on two separate occasions. The lesions rapidly resolved after administration of oral itraconazole at 100 mg daily for 6 weeks but recurred 15 weeks after therapy was stopped. Therapy was restarted, the lesions were completely resolved, and there was no further recurrence. In another study, lesions of the eyebrow (kerion celsi) due to T. rubrum were found to disappear almost entirely after 3 weeks of oral itraconazole therapy (149).
Verrucous lesions of the eyelid due to B. dermatitidis were reported to resolve after treatment with a combination of antifungals (potassium iodide and intravenous amphotericin B) and surgery (Barr and Gamel, letter). Six patients with papular lesions of the eyelids due to P. brasiliensis (some patients also had conjunctival, corneal, and anterior uveal lesions) were treated with intravenous amphotericin B (one patient also received oral ketoconazole); all five patients for whom outcome data were evaluable responded to medical therapy alone (no surgery was required). Lesions of the eyelid were recently described in one patient who had disseminated cryptococcosis (66); the infection was controlled (with occasional recurrences) by a combination of surgical excision and intravenous amphotericin B and fluconazole.
Gram-positive filamentous bacteria are frequent causes of dacryocanaliculitis (28). Fungi such as Alternaria spp., A. fumigatus and other Aspergillus spp., Candida spp., dermatophytes, Fusarium spp., Penicillium spp., Scopulariopsis spp., and Sporothrix schenckii have been reported as causes of canaliculitis (28, 213), although the significance of some of these isolates is doubtful since they do not appear to satisfy the criteria described previously (237). Most of the clinical features described and the surgical procedures recommended are for dacryocanaliculitis in general and are not necessarily specific for mycotic infection.
Usually, only one canaliculus on one side is affected; there is no good evidence that the inferior canaliculus is affected more frequently than the superior (28). Persistent unilateral epiphora (watering) with an itching sensation is the frequent presentation, and there may be unilateral mucopurulent conjunctivitis. Clinical features include a red, swollen eyelid in the area of the affected canaliculus, a unilateral conjunctivitis (conjunctival follicles may be present), reddening and swelling of the canaliculus itself (the opening is dilated and the edges are elevated and inflamed), and a mucopurulent discharge; white, yellow, or brown concretions (dacryoliths) may be visible in the lacrimal punctum or may be extruded after applying pressure to the canaliculus (28, 404). The remainder of the lacrimal passage is patent, and there is no preauricular lymphadenopathy.
Local environmental factors in the canaliculus, such as stasis arising out of congenital diverticula, may promote the growth of anaerobic bacteria and hence lead to local infections; however, most cases do not have an identifiable predisposing factor (28). Accumulated bacterial growth, cellular debris, and products of inflammation cause a progressive expansion and ectasia of the canalicular lumen, producing the characteristic fusiform swelling noted externally. Mixed aerobic and anaerobic bacterial infections may also be present. Rubbery concretions occur in the presence of infections due to species of Candida, whereas brown or black debris may be seen in infections due to A. niger (28).
Pavilack and Frueh (294) emphasized the importance of thorough curettage as the most effective treatment for chronic canaliculitis. Although their recommendations were not based on the study of specific actinomycotic or fungal causes of canaliculitis, the same principles can be applied for therapy of mycoses of the canaliculi. In essence, the punctum is dilated after topical and local anesthesia and a small curette is introduced. If there is extensive ectasia and retention of concretions in diverticuli, a canaliculotomy may be necessary (28). Following curettage (294), the canaliculus is thoroughly irrigated to remove any remaining fragments, to identify unrecognized pockets of retained debris, and to ensure the patency of the distal drainage system.
Mycotic dacryocanaliculitis is reported to respond satisfactorily to topical administration of 5% natamycin or to topical application and local syringing of the canaliculi and sac with amphotericin B (1.5 to 8 mg/ml) or nystatin (25,000 to 100,000 units/ml) solutions (28, 424); however, again, the basis of these recommendations is not clear. If medical management fails, surgery (canaliculotomy) is performed. All the material removed is used to prepare smears and to inoculate various culture media; the canaliculus is then syringed with the medications. Silicone intubation may be required for reconstruction of the canaliculus (28).
In a study of 40 patients with canaliculitis (404), only 10% were cured by medical treatment alone, while 40% showed a recurrence; 80% of individuals who underwent canaliculotomy in addition to receiving medical therapy were cured. Epiphora was a side effect of the surgery in a few patients. These results suggest that surgical treatment of canaliculitis in combination with medical therapy yields better results than those obtained by medical therapy only.
Dacryocystitis refers to an infection of the lacrimal sac (41). This is the most common infection of the entire lacrimal apparatus and generally arises due to the stasis resulting from obstruction of the nasolacrimal duct. There are several possible causes of this obstruction (28). Infection may be acute or chronic; fungi usually do not cause acute dacryocystitis. Chronic dacryocystitis is usually due to a single site of partial or complete obstruction within the lacrimal sac or within the nasolacrimal duct. With partial or complete obstruction of the nasolacrimal duct, a laminated concretion (dacryolith) may develop in the lacrimal sac and is often associated with bacterial and fungal infections.
Bacteria are the etiological agents in 95% of patients with acquired dacryocystitis, with aerobic and facultative anerobic bacteria predominating; fungi were found to account for only 5% of infections in two studies (41, 177). However, fungi may account for almost 14% of cases of congenital dacryocystitis (114).
Although several fungi have been implicated as causes of dacryocystitis, including Acremonium spp., Aspergillus spp., Candida spp., Paecilomyces spp., R. seeberi, dermatophytes, and S. schenckii (114, 177, 213, 226, 304, 424), the significance of some of these isolates is doubtful, on the basis of the criteria described previously (237). Infections due to S. schenckii and Acremonium spp. are reported to generally manifest as chronic suppurative dacryocystitis; there may be preauricular and submaxillary lymphadenitis, and an abscess may develop which ruptures outside, resulting in an indolent ulcer (28). Aspergillus spp., Candida spp., Paecilomyces spp., R. seeberi, and dermatophytes may cause chronic granulomatous dacryocystitis (178, 199, 200, 213, 226, 304).
Kristinsson and Sigurdsson (200) described a patient in whom A. fumigatus caused plugging of the lacrimal sac, leading to epiphora, extreme tenderness of the sac, and discharge from the lacrimal punctum. Two patients with dacryocystitis due to C. albicans have also been described (304).
A microbiological evaluation of congenital dacryocystitis in 86 eyes of 66 patients was undertaken (114). Fungi (principally Aspergillus spp. and C. albicans) were isolated from 32 eyes of 26 patients, but these results must be viewed with caution since there was no mention of direct microscoopy findings, and four isolates of Rhizopus spp. were reported. In another study, 65 eyes of 65 patients with chronic dacryocystitis were subjected to microbiological investigations (177); fungi (principally A. flavus) were recovered from 6 eyes. This report also made no mention of direct microscopy observations, although the fungi isolated appear to have been significant since they were recovered from material taken from the interior of the lacrimal sacs incised at surgery.
Krishnan et al. (199) described the occurrence of a diverticulum of the lacrimal sac in association with rhinosporidiosis, while Kalavathy et al. (178) recently described rhinosporidiosis of the lacrimal sac in two patients; the etiology of the lesions was confirmed by histopathological examination of the excised lacrimal sacs.
While epiphora is frequently the only clinical finding in patients with chronic dacryocystitis, there may also be lid edema, conjunctival injection, and swelling in the medial canthus; pressure over the area usually results in a purulent discharge through the lower punctum (177). In rhinosporidiosis of the lacrimal sac, blood-stained epiphora is a frequent complaint, due to the extreme fragility of the lesion (178).
Table 14 lists some of the therapies and outcomes described in recent reports of mycotic dacryocystitis, which are briefly summarized below.
Mycotic dacryocystitis is managed by dacryocystectomy (for rhinosporidiosis), where the lacrimal sac is removed in toto, or dacryocystorhinostomy, where the patency of the nasolacrimal duct is restored. Dacryoliths, if present, are surgically removed, and dacryocystorhinostomy is then performed. Dacryocystitis following plugging of the lacrimal sac by A. fumigatus was reported to have been relieved after the plug was removed by opening the lacrimal sac; dacryocystorhinostomy did not have to be performed, and the patient was symptom free 1 year after the procedure (200). Dacryocystitis due to C. albicans resolved with surgery alone in one patient and with surgery and topical miconazole and natamycin therapy in another (304). Some patients with congenital dacryocystitis were reported to respond satisfactorily to topical antifungals, probing, and syringing (114), although complete details of the therapy were not provided in the report. Chronic mycotic dacryocystitis in six patients was found to resolve completely following dacryocystectomy (177). Recently, endoscopic and laser technologies for minimally invasive transnasal dacryocystorhinostomy have been introduced. Postoperative infection following surgery on the lacrimal sac could probably be reduced by intraoperative or postoperative antifungal therapy.
Acute fungal infections of the lacrimal gland are rare. Zygomycetes are reported to be capable of causing acute necrotizing dacryoadenitis following contiguous spread from a rhinoorbital lesion, while chronic granulomatous dacryoadenitis can be caused by certain filamentous fungi (28, 424). Treatment is by systemic antifungal agents.
Fungal infection in patients with acute conjunctivitis appears to be uncommon. In a microbiological study of 102 patients with clinically diagnosed acute conjunctivitis, fungi were isolated from only 14 samples (36); no mention was made about the results of direct microscopic observations or about the criteria used to define significant growth in culture (Table 14).
Although the clinical manifestations of mycotic conjunctivitis are described as being dependent on the fungi involved (28, 424), the basis for these observations is unclear. Infections due to Candida spp. present as purulent, acute or subacute superficial epithelial lesions; Malassezia spp. may cause a catarrhal conjunctivitis. The dimorphic fungi B. dermatitidis, C. immitis and P. brasiliensis have been reported to cause conjunctival lesions (225, 353, 355). Although conjunctival lesions in patients with blastomycosis may occur due to contiguous spread from eyelid lesions, they may also occur as separate entities (355). Severe, necrotizing granulomatous conjunctivitis due to C. immitis has been described in a patient who had received treatment with corticosteroids by various routes (225).
Treatment of mycotic conjunctivitis can be difficult. Topical antifungal therapy may suffice for superficial conjunctivitis, while deeper lesions may require systemic antifungal therapy. Necrotizing granulomatous conjunctivitis due to C. immitis required aggressive debridement of the affected area and months of topical amphotericin B and oral fluconazole therapy (225).
Conjunctival rhinosporidiosis. Rhinosporidioisis appears to be endemic in the Indian subcontinent (54, 199, 258, 352), but significant numbers of cases have also been reported from Malawi and Kenya (295), northern Serbia (413), Zaire (397), Kuwait (371), and the United States of America (108, 169, 321). The prevalence of this condition in a south Indian village was reported to be 470 per 100,000 population (61). Children and young adults (up to 30 years of age) living in rural areas, who work in rice fields or bathe in stagnant water, appear to be the most severely affected (61, 258, 284, 295, 352, 413). Most studies have reported a male preponderance, but one study reported a female preponderance (61), while yet another study did not report a predominance of either sex (258). The mode of transmission is not definitely known but is thought to involve frequent exposure to contaminated water (258); this hypothesis is strengthened by a paper describing an unusual outbreak of rhinosporidiosis in the Balkans, where most patients reported having bathed in the same accumulation of stagnant water (the Silver Lake) just prior to the onset of symptoms (413). The causative organism possibly spends some or all of its life cycle in water; the organism may also be airborne (226). Conjunctival rhinosporidiosis may follow accidental injury to the eye by possible contaminated soil dust (169).
Most reported ocular lesions due to rhinosporidiosis have occurred in hot, dry climatic regions, with the occasional case being reported from temperate zones (321). Nasal lesions are thought to predominate in areas of endemic infection, while ocular lesions reportedly predominate during an epidemic (413). Ocular lesions are supposedly more frequent in Sri Lanka than in India, especially in Sinhalese women (226); however, no explanation has been given for this observation. Ocular rhinosporidiosis most frequently involves the palpebral conjunctiva; conjunctival growths are pink or red, granular, or lobulated (occasionally flattened); they may be sessile or stalked and are attached to the upper or lower fornix or tarsal conjunctiva (108, 295, 321, 352, 397). Conjunctival rhinosporidiosis with associated scleral melting and staphyloma formation, a rare occurrence, has recently been found in three Indian patients (54); the lesions presented as grey-white spherules without polyps. Other sites of ocular rhinosporidiosis are the lacrimal sac (178, 199, 352), lid margins, canaliculus, and sclera (226). Most infections of the eye are unilateral, and a solitary lesion develops. These lesions usually cause no discomfort to the patient; however, there may be increased lacrimation, discharge, tenderness of the lids, and photophobia.
A clinical diagnosis of rhinosporidiosis is suggested by the presence of lesions in other parts of the body, the extreme friability of the lesion, and the presence of small, white dot-like structures against a red background, i.e., the sporangia embedded in the vascular tissue bed (Fig. 10). However, other causes of a focal lesion on the conjunctiva, eyelid, or sclera, such as a cystic inclusion or adenoma of the various glandular structures, pterygium, pedunculated granuloma due to retained foreign body, or end-stage chalazion need to be excluded.
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FIG. 10. Surgical
removal of a lacrimal sac infected with Rhinosporidium
seeberi. Small, spherical structures (arrows) are seen on the
surface of the sac; these represent the sporangia
(cysts).
|
Two distinct phases of the tissue life cycle, namely, trophic and endosporulating, have been discerned by light and electron microscopic studies on conjunctival rhinosporidiosis (343). Electron microscopic studies suggested that the formation of the wall is a continuous morphological and biochemical spectrum throughout the cytological maturation of the organism (371). A different pattern of wall formation was observed in the conjunctiva of a patient who had concurrent rhinosporidiosis and papillomavirus infection; this modification was possibly a protective mechanism by R. seeberi against the virus (371). An additional feature noted in this patient was the absence of the marked inflammatory reaction that characterizes the histological picture of rhinosporidiosis.
No drug treatment has proven effective for ocular rhinosporidiosis. This condition is treated by surgical excision of the lesions.
Mycotic keratitis presents as a suppurative, usually ulcerative, corneal infection. This entity may account for more than 50% of all cases of culture-proven microbial keratitis and of ophthalmic mycoses (137), especially in tropical and subtropical areas.
The fungi most frequently implicated appear to vary depending on the geographical location and the period for which the infection is observed. In the first half of a 9-year study of microbial keratitis in south Florida, nine strains of C. albicans were isolated, but only one strain was isolated in the second half of the study (216). Although F. solani has been reported as the most common cause of mycotic keratitis in many parts of the world (137, 334, 364, 429), species of Aspergillus have predominated in some authentic, carefully documented recent studies from the Indian subcontinent (85, 398) and other countries (186). C. albicans was reported to be the most common cause (377, 394), or one of the most common causes (334, 398), of mycotic keratitis in the United States and Nepal, but it has been infrequently reported in several other major studies (Table 15).
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TABLE 15. Major
studies of mycotic keratitisa
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Risk factors. Most of the studies done exclusively on mycotic keratitis (120, 288, 334, 431) have listed trauma as being the most common risk factor (occurring in 44 to 55% of patients); less frequently reported risk factors include prolonged use of topical corticosteroids or antibacterials, systemic diseases such as diabetes mellitus, preexisting ocular diseases, and contact lens wear. In all these studies, filamentous fungi, mainly Fusarium spp. or Aspergillus spp., were the most frequent isolates. Similarly, in a review of 32 patients with keratitis due to Curvularia spp. (418), trauma and prior use of corticosteroids were the most frequent risk factors (Table 15). In contrast, in a study in Philadelphia (377), the three most common risk factors were found to be chronic ocular surface disease, contact lens wear, and use of topical corticosteroids; interestingly, C. albicans was the most common isolate in this study (46%). Only two studies (85, 429) have sought to compare the most frequent risk factors in mycotic and bacterial keratitis (Table 15). In one of these studies (in Bangladesh), antecedent ocular trauma was reported by 35% of patients with mycotic keratitis and 52% of patients with bacterial keratitis; dacryocystitis was noted in 12% of those with bacterial keratitis and 4% of those with mycotic keratitis (85). Data derived from the other study, a retrospective case-control study in Singapore (429), suggested that mycotic keratitis (principally due to Fusarium spp. and Aspergillus spp.) was more likely to be related to mechanical ocular trauma and bacterial keratitis (principally due to Pseudomonas aeruginosa) was more likely to be related to contact lens wear and preexisting ocular diseases. Preexisting inflammatory ocular diseases were less frequently seen in mycotic keratitis than in bacterial keratitis, but systemic immunosuppressive conditions appeared to be of equal significance in both mycotic and bacterial keratitis. Interestingly, antecedent topical corticosteroid therapy, which is frequently perceived to be a specific risk factor for mycotic keratitis, did not appear to predispose more frequently to mycotic keratitis (25%) than to bacterial keratitis (38%) in this study (429).
One study attempted to compare the risk factors for keratitis due to filamentous fungi and that due to yeasts and yeast-like fungi (334). Ocular trauma appeared to predispose most frequently to infections due to Fusarium spp. (70%), Curvularia spp. (11%), and Aspergillus spp. (5%). Similarly, diabetes mellitus may have been a specific risk factor for keratitis due to Fusarium spp. (67% of diabetic patients had such infections) and to Candida spp. (13%). In patients who had used prolonged topical medications, Candida spp. (44%) and Fusarium spp. (38%) were the most frequent isolates. In patients who used topical corticosteroids, Candida spp., Aspergillus spp., Acremonium spp., and Curvularia spp. were the most frequent isolates (22% each) (334). Although these data are interesting, a case-control study is needed to compare the relative contribution of different risk factors to determining whether a patient develops keratitis due to filamentous fungi or to yeast or yeast-like fungi.
Fungi causing mycotic keratitis. Filamentous fungi are the principal causes of mycotic keratitis in most parts of the world; in 12 of the 14 studies listed in Table 15, either Fusarium spp. or Aspergillus spp. were the most common isolates. Dematiaceous fungi, such as Curvularia spp. and Bipolaris spp., are the third most important cause of keratitis in a number of studies (111, 120, 208, 364), while the coelomycete L. theobromae has been reported to cause keratitis in India (111, 383, 389, 392) and the southern United States (216, 334).
Filamentous fungal keratitis appears to occur most commonly in healthy young men engaged in agricultural work or outdoor occupations (120, 334); mycotic keratitis has been reported to occur in onion harvesters in Taiwan (219). Trauma was the most common risk factor reported in all the studies listed in Table 15 in which filamentous fungi were the principal isolates. Various traumatizing agents have been reported, including vegetable matter, mud or dust particles, paddy grain, the swish of a cow's tail, tree branches, and metallic foreign bodies (120, 334). There have been reports of mycotic keratitis associated with the use of nylon-line lawn trimmers in the United States; the fungi implicated have included Curvularia spp. and F. oxysporum (65, 334). Preexisting allergic conjunctivitis (400) or vernal keratoconjunctivitis (134) may also predispose to the occurrence of filamentous fungal keratitis.
Environmental and corneal isolates of various species of Fusarium and Aspergillus have been found to be virtually indistinguishable in certain growth characteristics (71, 383). Seasonal variations have been observed in the incidence of mycotic keratitis and in the predominant genera of fungi isolated from such cases; such variations have been linked to environmental factors, such as humidity, rainfall, and wind, and also to the harvest (133, 216, 334, 383). The fungi most frequently present in the environment are also frequently found as transient commensals in the conjunctival sac in a variable percentage of healthy eyes (363); these fungi are thought to become virulent for the cornea under certain circumstances, such as following trauma or administration of corticosteroids (17, 424). However, this mechanism of infecting the cornea may be less important than the direct implantation of environmental fungi in the cornea by trauma.
Keratitis due to yeasts and yeast-like fungi is most frequently caused by C. albicans (100, 174, 216, 377). Since C. albicans is a ubiquitous commensal of mucous membranes in humans, with no geographic dominance, keratitis due to this organism tends to occur more frequently in areas where traumatic keratitis is uncommon but where other predisposing factors are important (174, 394). C. albicans was reported to be the most common fungal species isolated from patients with culture-proven mycotic keratitis in Philadelphia (377), but species of Candida accounted for only 12.5% of isolates from patients with culture-proven mycotic keratitis in Miami (334). C. albicans and related fungi have been infrequent isolates in most recent studies performed in tropical countries (85, 117, 120, 137, 208, 364), possibly due to the predominance of livelihoods, such as agriculture, which carry a higher risk for the occurrence of trauma-related keratitis caused by filamentous fungi than for keratitis due to C. albicans. Keratitis due to yeast-like and related fungi usually develops in eyes with preexisting epithelial or stromal ulceration due, for example, to previous herpes simplex keratitis or contact lens-induced corneal abrasions (100). This type of keratitis can also occur in the presence of systemic disorders or preexisting ocular abnormalities
Diagnosis. A rapid and accurate diagnosis of mycotic keratitis improves the chances of a complete recovery, especially in the tropics, where patients may delay presenting to an ophthalmologist. A systematic approach, comprising a detailed elicitation of the clinical history, a meticulous examination with the slit-lamp or the confocal microscope, and appropriate microbiological investigations, should be adopted.
(i) History and clinical features. Details elicited in the clinical history should include possible risk factors (trauma or use of contact lenses); prior therapy with antibacterials, corticosteroids, or other compounds; and preexisting ocular disease (allergic conjunctivitis or lagophthalmos). The clinician should then look for ocular or systemic defects that may have predisposed the patient to the keratitis, since these require correction. Symptoms are usually as in any other type of keratitis but, perhaps, are more prolonged in duration (5 to 10 days).
Filamentous fungal keratitis may involve any area of the cornea (100). The clinical features usually noted are the firm (sometimes dry) elevated necrotic slough (Fig. 11), "hyphate" lines extending beyond the ulcer edge into the normal cornea, multifocal granular (or feathery) gray-white "satellite" stromal infiltrates, "immune ring," minimal cellular infiltration in the adjacent stroma, and mild iritis (100, 174). An endothelial plaque and hypopyon generally do not occur within the first week, but the presence of an hypopyon in an indolent ulcer may suggest a fungal etiology. An elevated firm slough and hyphate margins are found in more than 50% of culture-proven cases (388). The most common manifestations of culture-proven mycotic keratitis were reported to be (in descending order of occurrence) a gray or dirty-white surface, anterior-chamber cellular reaction, irregular feathery margins, elevated borders, dry rough texture, satellite lesions, Descemet's folds, hypopyon, ring infiltrate, endothelial plaque, and keratitic precipitates (334). However, a comparison of the most frequently occurring manifestations of bacterial and mycotic keratitis is needed.
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FIG. 11. Clinical
keratitis due to Fusarium solani. The necrotic slough is
elevated above the surface of the cornea. Hyphate lines are seen
extending into the surrounding
cornea.
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FIG. 12. Clinical
keratitis due to a Curvularia species. The necrotic slough
exhibits a brownish pigmentation. Such pigmentation may be seen in
corneal lesions due to dematiaceous filamentous fungi and should not be
mistaken for an incarcerated
iris.
|
Keratitis due to a zygomycete such as Rhizopus sp. (334) or A. corymbifera (231) occurs very rarely; when it does occur, it is very fulminant and unresponsive to medical therapy. The progression of lesions was so rapid in one patient with keratitis due to A. corymbifera that penetrating keratoplasty was required within 9 days of the initial presentation; antecedent ocular trauma was the sole risk factor for the keratitis in this patient (231). Rodrigues and Laibson (332) described two patients with apparently primary exogenous keratitis due to B. dermatitidis.
(ii) Noninvasive techniques. Confocal microscopy is an imaging technique that allows optical sectioning of almost any material, with increased axial and lateral spatial resolution and better image contrast, which may be useful for the identification of corneal pathogens in the early stages of infection. In clinical keratitis due to Aspergillus spp., fungal hyphae were imaged as high-contrast filaments, 60 to 400 µm long, and 6 µm wide (426). In one patient with keratitis due to F. solani (97), in vivo scanning slit confocal microscopy helped in first establishing the diagnosis, then demonstrating nonresponsiveness to medical therapy by showing an increased load of fungal filaments, and finally confirming that the entire fungal load was eradicated following penetrating keratoplasty, aiding the decision to administer corticosteroids and to quickly discontinue antifungals. Subsequently, there have been reports of the use of this technique, in conjunction with culture, in establishing a diagnosis of mycotic keratitis (408, 431). Thus, confocal microscopy is a potentially useful, noninvasive technique to determine the presence of fungal hyphae in vivo within the human cornea. Limitations in the use of this technique for routine diagnosis relate to instrument configuration, movement of either the tissue or the microscope, difficulty in reproducibly returning to the area of interest for serial examination, lack of a distinctive morphology of some pathogens, and limited resolution of the microscope.
(iii) Microbiological investigations. Although there is some controversy regarding the need to perform microbiological investigations on all patients presenting with suspected microbial keratitis, it appears that such investigations are essential in the diagnosis of suspected mycotic keratitis (242). The specimens to be collected from a patient with suspected mycotic keratitis have been briefly described in Table 6. Prior to performing a corneal scraping, specimens for lid and conjunctival cultures are usually taken to ensure that the organisms isolated on the corneal media have not come from the transient commensal fungal flora of the conjunctival sac.
(a) Samples. Corneal scrapings are obtained by using an instrument (platinum spatula, Beaver blade, Bard Parker knife no. 15, or blunt cataract knife) to debride material from the base and edges of the ulcerated part of the cornea (3); this should be done several times to obtain as much material as possible. The blade or spatula may be reused if a sterile medium has been streaked but must be changed (the spatula can be flamed) if the instrument has made contact with an unsterile slide (3). Cotton swabs do not seem to be a useful means of debriding the necrotic corneal slough. However, if calcium alginate swabs, premoistened with tryptone soy broth, are used for the debridement, recovery of fungi in culture may be facilitated (163).
Corneal scrapings do not yield positive results in a small percentage of patients. In this case, corneal biopsy may aid the diagnosis since a larger amount of tissue can be obtained from a greater depth of the cornea (158, 196, 210). A corneal biopsy can be performed by using a corneal trephine which defines the precise diameter and depth (0.2 to 0.3 mm) of corneal tissue that is to be removed (196, 210). A second method involves the free dissection of the corneal lamellae by a sharp surgical knife; corneal perforation needs to be carefully guarded against in this procedure. Another method involves removal of the epithelium and necrotic debris overlying the suppurated area and then incising the corneal stroma with a Bard-Parker no. 15 blade and corneal forceps to about one-half the corneal thickness (160).
Several experimental (160) and clinical (42, 158, 196, 334) studies have highlighted the potential value of corneal biopsy samples in diagnosis of mycotic keratitis when the conventional corneal scrapes do not yield positive results. The biopsies may be relatively superficial (the procedure of keratectomy) or deep (42), and the tissue obtained may be stained with ink-KOH (158, 160) or lactophenol cotton blue (196). However, some workers (210) have reported inferior results in samples from patients with clinically evident infectious ulcerative keratitis.
(b) Direct microscopic examination. Direct microscopic examination of corneal scrapes or corneal biopsy samples permits a rapid presumptive diagnosis of mycotic keratitis to be established. Examination of a wet preparation (using KOH, ink-KOH, or lactophenol cotton blue), a smear stained by the Gram or Giemsa method, and a smear stained with special fungal stains (GMS silver, PAS, or calcofluor white) may yield valuable results. The corneal material should be spread out as thinly as possible on the microscope slides to facilitate easy visualization of the fungal structures (Fig. 9). The advantages and disadvantages of different staining techniques have already been described (Table 7). In major studies of mycotic keratitis (Table 15), the sensitivities of different staining techniques for culture-proven mycotic keratitis were 72.2% (431) to 91% (120) for KOH, 31.6% (288) to 98% (85) for the Gram-stained smears, 27% (334) to 85% (120) for Giemsa-stained smears, 91.4% for calcofluor white (120), 91% for PAS (431), and 56% for GMS (398).
In other studies, direct microscopic examination of corneal scrapes stained with lactophenol cotton blue yielded positive results in 78% of culture-proven cases of mycotic keratitis (387); Acanthamoeba cysts can also be detected in corneal scrapes stained with lactophenol cotton blue (P. A. Thomas and T. Kuriakose, Letter, Arch. Ophthalmol. 108:168, 1990). Examination of corneal scrapings from clinically suspected cases of mycotic keratitis yielded positive results in 76% of acridine orange-stained smears and in 65% of KOH wet mounts (179). Thus, microscopic examination of corneal material is an important means of arriving at a rapid presumptive diagnosis of mycotic keratitis and correlates well with culture positivity.
Excellent results were reported when the nonspecific fluorescent stain calcofluor white was used to stain corneal scrapes or biopsy specimens prior to direct microscopic examination (120, 55, 351, 372). However, not all fungi are adequately stained (314). The use of blankophor or Uvitex 2B may yield better results (314). Fungal autofluorescence and fluorescein-conjugated lectins have yielded promising results in some studies (229, 330), but these techniques need to be applied on a larger scale before conclusions can be drawn.
It is generally reported that the identity of the infecting fungus cannot be deduced from the direct microscopic examination, particularly where the infecting fungi closely resemble each other morphologically, as in Fusarium, Paecilomyces, and Acremonium; however, Liu et al. (220) studied adventitious sporulation in tissue samples, including some from corneal ulcers and found that this might serve as an aid to identify the possible genus involved. This requires further study.
(c) Culture. Culture of corneal scrapes or biopsy specimens is essential to confirm a diagnosis of mycotic keratitis and to initiate appropriate antifungal therapy. Corneal material is inoculated on the surface of solid media by making rows of "C" streaks (two rows from each scraping); only growth on the C streaks (Fig. 8) is deemed significant (175). Liquid media are inoculated by twirling the tip of the spatula, loop, or swab in the broth several times.
The media commonly used for recovery of corneal fungi are as described above (see "Etiological agents and laboratory diagnosis of ophthalmic mycoses"). Blood agar plates should be incubated at 25 and 37°C, while Sabouraud glucose-neopeptone agar is kept at 25°C. Liquid media should be included; brain heart infusion broth is perhaps the best single medium to use, especially when corneal material is scanty. An incubation temperature of 30°C and the use of liquid-shake cultures may also aid the recovery of corneal fungi.
Fungal growth on the culture media (Fig. 4 and 8) usually occurs within 3 to 4 days (334), but culture media may need to be kept for up to 4 to 6 weeks. "Sham cultures" should also be maintained to ensure that there is no contamination from the environment or media during sample collection. The criteria used to consider a fungal strain isolated in culture as significant are described in the Introduction.
(d) Histopathology. Histopathological studies offer certain advantages over culture in the diagnosis of mycotic keratitis since contamination is avoided, tissue penetration can be gauged, and the outcome of surgical procedures can be anticipated (406). In some studies (160, 334), direct examination of corneal biopsy specimens or corneal buttons was found to yield positive results when cultures of the same samples were negative, both in experimental animals and in patients; however, other investigators (8) are of the opinion that microbiological evaluation of the corneal biopsy specimen is more sensitive than histopathological examination as a diagnostic aid in microbial keratitis. Material for histopathological testing is obtained as a corneal biopsy (8, 196, 210) or button following penetrating keratoplasty(334). Fungal structures in corneal tissue can be stained by the PAS and GMS techniques, but fluorochromes such as calcofluor white and fluorescein-conjugated lectins can also be used (3, 57). The purulent inflammatory cellular reaction is usually less marked in fungal than in bacterial keratitis; filamentous fungi are usually found deep in, and arranged parallel to, the corneal stromal lamellae while being absent on the surface (Fig. 13). The inflammatory cells seen are usually lymphocytes and plasma cells, but polymorphonuclear leukocytes are also involved to various extents (3). There is coagulative necrosis of the stroma, resulting in stromal abscesses; "satellite" microabscesses may also be seen, with focal necrosis of the corneal stroma and clusters of acute inflammatory cells (3). At this stage, healing of the epithelium is seen with a coexisting active proliferation of the fungus in the deeper stroma; therefore, corneal scrapings may fail to demonstrate fungal structures. This may explain the superior results obtained by some workers when culturing corneal biopsy specimens compared to those obtained from culturing corneal scrapings (8, 42, 158, 196, 334). Invasion and penetration of an apparently intact Descement's membrane may occur rarely, perhaps when F. solani or Fusarium spp. are the infecting organisms (173, 204).
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FIG. 13. Photomicrograph
of a tissue section from a corneal button removed at the time of
keratoplasty. Fungal hyphae are seen below the epithelium (E), in the
superficial and middle layers of the corneal stroma. The hyphae are
oriented mostly in a direction parallel to that of the corneal collagen
bundles, although the hyphae in the superficial stroma are oriented
vertically (arrows). GMS stain; magnification,
x100.
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Management. Mycotic keratitis is managed by medical or surgical means. Medical therapy consists of nonspecific measures and the use of specific antifungal agents. Cycloplegics are used to relieve the iridocyclitis (anterior uveitis) that usually accompanies mycotic keratitis; broad-spectrum antibacterials may be needed to combat secondary bacterial infection (334, 429).
(i) Specific antifungal therapy. Various specific antifungals have been tried in the therapy of experimental and clinical mycotic keratitis (see "Antifungal agents used to treat ophthalmic mycoses" above). Treatment may be protracted, since the effective concentrations achieved by most antifungals in the cornea, with the possible exception of amphotericin B, only inhibit the growth of the fungus, and host defense mechanisms must eradicate the organism (267, 366).
The antifungal ultimately selected as primary therapy necessarily depends on its easy availability and on other criteria. If direct microscopic examination of corneal scrapes or corneal biopsy specimens yields unequivocal results that are consistent with the clinical picture, treatment may be initiated; otherwise, therapy may need to be withheld until culture reports become available. Topical natamycin (5%) or amphotericin B (0.15%) is usually selected as first-line therapy for superficial keratitis, whether or not septate hyphae or yeast cells have been seen by direct microscopy; if deep lesions are present, oral ketoconazole, oral itraconazole or oral fluconazole may be added to the therapeutic regimen (334, 377, 429). If hyphae have been seen by microscopy and a filamentous fungus is isolated in culture, natamycin appears to be the treatment of choice when available (334, 377); topical 0.15% amphotericin B (170, 429) is an alternative. If yeasts or pseudohyphae are seen by microscopy and species of Candida or Cryptococcus are isolated in culture, topical 0.15% amphotericin B appears to be the treatment of choice when available (334, 377), although natamycin (287, 334) and topical 1% miconazole (101, 287) have also been used as primary therapy. It is difficult to assess the validity of these choices of therapy in the absence of controlled clinical trials, especially since the number of patients dealt with is generally small. Moreover, satisfactory responses of filamentous fungal keratitis to, for example, natamycin or of yeast keratitis to, for example, topical 0.15% amphotericin B may appear so commonplace that clinicians do not deem it necessary to report their observations and will publish reports only when something out of the ordinary is encountered. Keeping these limitations in mind, an attempt has been made in this article to review the therapy of keratitis due to frequently encountered hyaline filamentous (Fusarium spp., Aspergillus spp., and S. apiospermum), dematiaceous (Curvularia spp.), and yeast (Candida spp.) fungal pathogens based on reports published in the literature.
(a) Therapy of keratitis due toFusarium spp. An analysis was made of 85 patients reported in the literature for whom details of outcome of therapy have been provided (Table 16). A total of 29 patients apparently had superficial keratitis; 22 (76%) of these responded to antifungals alone (topical amphotericin B alone or in combination with topical natamycin, oral and/or topical ketoconazole, and oral itraconazole). Seven patients with apparently superficial keratitis required surgery; interestingly, none of these had received natamycin at any time (Table 16). A total of 49 patients appeared to have keratitis with deep lesions; only 14 (29%) of these responded to antifungals alone. Overall, 6 of the 49 patients with apparently deep keratitis received topical natamycin at some time, and 4 of these responded to medical therapy alone; the other 43 patients did not receive natamycin at any time, and only 10 (23%) of these responded to medical therapy alone (Table 16). In seven patients with culture-proven keratitis due to Fusarium spp., the severity of the keratitis was not clearly described; three of the patients responded to antifungals alone. Thus, more than 70% of patients with superficial keratitis due to F. solani and other Fusarium spp. apparently respond to medical therapy alone; although several antifungals have been found effective, administration of natamycin may forestall surgical intervention. In striking contrast, almost 70% of patients with Fusarium keratitis with deep lesions do not respond to medical therapy alone, particularly if natamycin is not used, and some form of surgical intervention is necessary.
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TABLE 16. Treatment
of keratitis due to Fusarium spp.
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(b) Therapy of keratitis due toAspergillus spp. The data pertaining to the outcome of therapy have been analyzed for 61 patients (Table 17). A total of 17 patients had apparently superficial keratitis, of whom 15 (88%) responded to antifungals alone (oral itraconazole [6 patients], combined oral and topical ketoconazole [five patients], topical 2% ketoconazole [2 patients], and topical natamycin [2 patients]); the patients who responded to azole therapy had not received natamycin.
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TABLE 17. Treatment
of keratitis due to Aspergillus spp.
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In 15 patients, it was not clear whether deep lesions were present; 8 (53%) of these patients responded to medical therapy alone, including 2 of 3 patients who received natamycin. Of the 15 patients, 12 did not receive natamycin, and 7 (58%) of these ultimately required surgical intervention.
These data suggest that more than 80% of patients with superficial keratitis due to A. flavus, A. fumigatus, and other Aspergillus spp. respond to medical therapy with a variety of topical or systemic antifungals, with surgery not being required. However, in the presence of deep corneal lesions, almost 60% of patients do not respond to medical therapy alone, particularly if natamycin is not used, and surgery is required to control the infection.
(c) Therapy of keratitis due toCandida spp. Details of the response to therapy of Candida spp. have been analyzed for 38 patients (Table 18). Four patients appeared to have had superficial keratitis, which resolved after administration of topical amphotericin B alone (three patients) and combined topical amphotericin B and natamycin therapy (one patient). For an additional 12 patients, it was not clear whether deep lesions were present; the corneal lesions resolved in all 12, with 7 responding to topical amphotericin B alone, 4 responding to topical natamycin alone, and 1 (who had chronic granulomatous disease) apparently responding to the intravenous amphotericin B administered for coexisting systemic candidiasis. Keratitis with deep lesions appears to have been present in 22 patients, and the corneal lesions resolved in 18 (82%) by using medical therapy; 5 responded to topical amphotericin B alone, 7 responded to combined topical amphotericin B and systemic azoles, and 6 (who had not responded to natamycin or topical miconazole) responded to topical 2% fluconazole (the source of the drug was not mentioned in this study).
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TABLE 18. Treatment
of keratitis due to Candida spp.
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(d) Therapy of keratitis due to Curvularia spp. Data pertaining to 42 patients reported in the literature have been analyzed (Table 19). In 35 (83%) of the 42 individuals, the corneal lesions responded to antifungals alone; 19 patients responded to topical natamycin alone, another 8 responded to natamycin and other antifungals, 6 responded to oral ketoconazole, and 1 each responded to topical miconazole and topical amphotericin B. In an additional three patients, the keratitis resolved with keratectomy and antifungal therapy. Penetrating keratoplasty was required in four patients who did not respond to medical therapy alone. These data suggest that most patients with keratitis due to species of Curvularia can be treated by antifungals alone, particularly when natamycin is used. However, most of the papers analyzed did not provide details about the severity of the corneal lesions in the patients. This is an important aspect that needs to be studied. In one study of dematiaceous fungal keratitis (111), antifungal therapy alone (principally natamycin, alone or in combination with topical clotrimazole or topical miconazole) sufficed for resolution of lesions in 88% of patients with superficial lesions; however, only 46% of patients with deep keratitis responded to antifungal therapy alone (topical antifungals combined with oral ketoconazole), and surgery was required for the other patients (111) (Table 19).
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TABLE 19. Treatment
of keratitis due to Curvularia spp.
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(e) Therapy of keratitis due to S. apiospermum. The outcome of keratitis due to S. apiospermum is varied. A review of 13 cases reported up to 1979 revealed a generally poor outcome, with 6 of 13 patients eventually requiring enucleation or evisceration (437). Moreover, miconazole is thought to be an important drug in treatment of keratitis due to S. apiospermum in humans; a recent review of 15 patients with this condition (430) appears to endorse this view (only reports in which details of treatment regimen and visual outcome were provided were included in the review, and patients with initial scleral involvement were excluded). Four (67%) of six individuals who had received miconazole retained form vision (counting fingers or better), whereas three (33%) of nine persons who had not received miconazole retained form vision (430). However, it is difficult to draw conclusions based on the small number of patients studied; moreover, the severity of the keratitis at presentation could be an important determinant of outcome of medical therapy.
At least 14 patients with keratitis due to S. apiospermum have been reported in the literature since 1991 (Table 20). Medical therapy alone sufficed for resolution of lesions in 8 (57%) of these 14 patients (3 of the "responders" had keratitis with deep lesions); penetrating keratoplasty was needed in 3 patients (all of whom had deep keratitis), and evisceration or enucleation was needed for 3 patients (2 of whom had deep corneal lesions). Eight patients (five with deep keratitis and three with keratitis of undetermined severity) received natamycin at some time; the corneal lesions resolved with medical therapy alone in three of these, while penetrating keratoplasty was required in the eyes of three patients and enucleation had to be done for two patients. Six individuals (two with superficial keratitis, three with deep keratitis, and one with keratitis of unknown severity) received miconazole; the lesions of four of these patients resolved with medical therapy alone (two had superficial keratitis), while evisceration or enucleation was needed for two eyes (both with deep keratitis).
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TABLE 20. Treatment
of keratitis due to Scedosporium apiospermuma
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(f) Therapy of keratitis due to other fungi. A combination of topical antifungal therapy and keratoplasy appears to provide the most adequate treatment for keratitis due to Acremonium spp. (93). A prospective evaluation of the comparative safety and efficacy of topical natamycin and 0.2% fluconazole was made for eight patients with filamentous fungal keratitis, including five cases due to Acremonium spp. and two due to Curvularia spp. (315). Corneal lesions resolved in three of four patients receiving primary natamycin treatment for a mean duration of 20 days (the keratitis worsened in the fourth patient), whereas the lesions failed to resolve in all four patients who received topical fluconazole as the primary treatment (two subsequently responded to natamycin therapy). Although the identification of Acremonium spp. in some of these patients appears to have been erroneous, this study is important in providing evidence of the efficacy of topical natamycin and the relative inefficacy of topical fluconazole in therapy of keratitis due to filamentous fungi.
A recurring corneal infection due to Fonsecaea pedrosoi was treated by a large penetrating keratoplasty and removal of the involved part of the iris and the entire lens, followed by a 5-month course of oral itraconazole; this resulted in no recurrence of the infection (27). Oral fluconazole therapy, in association with topical natamycin and intracameral amphotericin B and various surgical measures, resulted in eradication of corneal infection due to Colletotrichum graminicola (326). A combination of ketoconazole and amphotericin B therapy and keratoplasty resulted in a favorable outcome of posttraumatic keratitis due to Scopulariopsis brevicaulis in one patient (307). A common problem reported by all those who have had to treat Pythium insidiosum keratitis is that it is not sensitive to any of the currently available antifungals; wide surgical excision including penetrating keratoplasty has been advised for such patients, with enucleation or evisceration being required in patients who fail to respond to these measures (22, 156, 381, 411).
(g) Other considerations. The collagen shield, which is shaped like a contact lens and is packaged in a dehydrated form and rehydrated before use, may protect the corneal epithelium from the action of the eyelids, and the collagen in the lens may promote healing; shields lasting up to 72 h may more conveniently protect the cornea than does repeated patching (107).
Triturated (crushed and suspended) ketoconazole has been recommended for the treatment of mycotic keratitis when commercial antifungal eye drops are not obtainable (136). Ketoconazole and itraconazole tablets were triturated to 20 mg/ml in polyvinyl alcohol, boric acid, olive oil, or balanced salt solution and applied topically to deepithelialized rabbit corneas (one drop/15 min for 2 h). The concentrations of ketoconazole in corneal tissue treated with the triturated drug in balanced salt solution, olive oil, polyvinyl alcohol, and boric acid were calculated to be 512, 773, 1,221, and 1,492 µg/g, respectively; the concentrations of itraconazole were about half those of ketoconazole (136). Therefore, since the vehicle used to triturate the antifungals may affect the tissue concentration, the development of effective vehicles may have an impact on the therapy of mycotic keratitis.
Mycotic keratitis usually responds slowly (over a period of weeks) to antifungal therapy. Clinical signs of improvement include diminution of pain, decrease in the size of the infiltrate, disappearance of satellite lesions, rounding out of the feathery margins of the ulcer, and appearance of hyperplastic masses or fibrous sheets in the region of healing fungal lesions (170, 173). Conjunctival chemosis and injection and punctate epithelial keratopathy may indicate toxicity of the antifungal agent being used. Although repeat scrapings taken during treatment may not yield growth in culture, this does not necessarily indicate that the fungus has been eradicated, since it may have become deep seated; therefore, therapy should be continued for at least 6 weeks (170).
There is a danger of antagonistic effects developing when certain antifungal agents are combined, for example, amphotericin B and miconazole (170). Therefore, methods to enhance the efficacy of existing antifungal agents require careful study.
(ii) Measures to suppress corneal damage due to microbe- or host tissue-derived factors. Corticosteroids are sometimes used in ocular infections in an attempt to reduce tissue damage wrought by the inflammatory reaction directed against an infecting microorganism. This approach seems to work well in disciform keratitis and central stromal keratitis due to herpes simplex virus (D. M. O'Day, Editorial Ophthalmology 98:845-846, 1991); corneal inflammation and ultimately scarring is reduced. This seems to have been the rationale, in a study in Miami, for the administration of topical corticosteroids to 19 of 125 patients after the diagnosis of mycotic keratitis had been made and after a period of antifungal therapy averaging 14 days (the average duration of corticosteroid therapy was 24 days); unfortunately, corneal lesions progressed in 2 patients in spite of the concurrent antifungal therapy (334). It is already well known that corticosteroid administration is frequently necessary to create experimental models of mycotic keratitis (158, 160, 276). Moreover, corticosteroids have been found to worsen the course of existing but unrecognized mycotic keratitis (366, 394). In one patient from whom a Fusarium sp. was ultimately isolated, the initial corticosteroid therapy appeared to contribute to a fulminant course (the eye was eventually enucleated), while in another patient from whom a Curvularia sp. was isolated, the infection progressed rapidly (a therapeutic penetrating keratoplasty had to be done) (366).
These data support the contention that corticosteroid use is definitely contraindicated when a fungal pathogen is present (366), perhaps even when specific antifungal therapy is given. Possible "inflammatory rebound," a potentially devastating complication that occurs when corticosteroid therapy is abruptly terminated, also needs to be guarded against, since this could be confused with a worsening of infection (O'Day, editorial).
In an animal model of C. albicans keratitis, ketorolac (a nonsteroidal anti-inflammatory compound) satisfactorily reduced the tissue necrosis occurring as a result of inflammatory mechanisms, without permitting progression of the infection (105). That paper reflected an important aspect of current research on corneal ulceration, i.e., the attempt to develop molecules other than corticosteroids which would inhibit the deleterious effects of inflammatory mechanisms in keratitis. Administration of a synthetic thiol peptide, which appeared to suppress corneal ulceration by inhibiting the action of corneal collagenase and by reducing infiltration by polymorphonuclear leukocytes (47), and application of inhibitors of oxidative metabolism, which reduced the release of free radicals (11), were found to exert beneficial effects on experimental keratitis caused by alkali burns. Symptoms of keratitis have been elicited in rabbit eyes by application of lipid mediators (395); antagonists of these mediators and inhibitors of lipid mediator synthesis may thus serve as alternatives to topical corticosteroid therapy. Platelet-activating factor was found to induce expression of MMP-1 and MMP-9 in the corneal epithelium, leading to corneal ulceration; it was suggested that specific antagonists of platelet-activating factor might deter corneal ulcer formation, thus facilitating corneal wound healing (378). Specific studies are necessary to determine whether such factors influence the progression or outcome of mycotic keratitis. Caution must be exercised in extrapolating the results obtained with sterile corneal ulceration to the different situation in infectious corneal ulcers, since the results obtained may vary dramatically (12).
(iii) Therapeutic surgery. Surgery may be necessary when mycotic keratitis responds poorly, or not at all, to medical therapy or when perforation or descemetocele formation is imminent. Every attempt should be made, however, to prolong medical therapy for as long as possible, since this will render the infecting fungus nonviable, thereby improving the outcome of surgery. In mycotic keratitis, surgery may aid medical management by increasing drug penetration, by bringing in blood vessels in the form of conjunctival flaps, by stabilizing the corneal epithelial surface, by removing infected corneal tissue (therein reducing or eliminating the microbial load), or by providing tectonic support to the globe when integrity is threatened, as in thinning or perforation of the cornea (3).
(a) Surgical management of small superficial corneal fungal infections. The methods advocated include debridement and pedicle (racquet) conjunctival flaps (for peripheral ulcers), in association with antifungal therapy; tissue adhesives and a bandage contact lens have also been advocated (10, 174, 334).
In mycotic keratitis, regular debridement of the base of the ulcer helps the elimination of fungi and necrotic material (3) and also facilitates the penetration of antifungal drugs into the corneal stroma (273). In a model of deep stromal C. albicans infection in rabbits, a significant reduction of the number of fungi occurred when daily debridement of the corneal epithelium and topical administration of amphotericin B or natamycin was performed; when the epithelium was left intact, this antifungal effect was much reduced. Debridement can be performed under topical anesthesia, with a Bard-Parker blade no. 15, ensuring that a margin of 1 to 2 mm is left at the limbus (3).
Superficial lamellar keratectomy helps to remove the thick mat of fungal filaments on the cornea and facilitates increased drug penetration in patients with dematiaceous fungal keratitis (111, 418).
It may be possible to ablate superficial stromal corneal infiltrates by using the excimer laser. The 193-nm excimer laser was used to ablate experimental keratitis due to Fusarium spp. (123). The infections were allowed to proceed for 24 and 72 h, and then ablation with the 193-nm excimer laser with 5.0-mm treatment zones was performed until all suppurative areas were treated; all cultures of excised corneas were negative in the 24-h group but positive in the 71-h group. Although excimer laser photoablation might be useful to eradicate early, localized microbial infections, it appears that advanced infections, with deep stromal involvement and suppuration, would not be eradicated by this technique. Moreover, caution is required when using the excimer laser for infectious keratitis (123).
Conjunctival flaps help in achieving a stable conjunctival surface in cases of persistent or recurrent epithelial defects and progressive ulceration (3, 10); such flaps are especially helpful in chronic peripheral disease, where the flap does not encroach onto the visual axis (300). Blood vessels present in the flap brought in to cover the ulcerated area help in healing of peripheral fungal corneal ulcers; a superficial lamellar keratectomy should first be done to remove the necrotic stroma, and then a thin conjunctival flap should be anchored over the ulcerated site (3, 10).
Recently, Kim et al. (189) reported that permanent or temporary amniotic membrane transplantation resulted in successful healing of the corneal surface in 21 eyes of 21 consecutive patients with microbial keratitis (including 2 with mycotic keratitis) who had already been treated with sufficient quantities of antimicrobial drugs to eradicate the infecting microorganisms; there was no recurrence of microbial infection in any patient. Prior to transplantation, the amniotic membrane was soaked in antimicrobials; after transplantation, follow-up times ranged from 4 to 28 months (mean, 18 months). Although amniotic membrane transplantation may be a potentially useful adjunctive surgical procedure for the management of microbial keratitis since it promotes wound healing and reduced inflammation, the extremely small number of patients with mycotic keratitis enrolled in this study does not allow firm conclusions to be drawn. This technique may not be successful in patients who have extensive corneal epithelial ulceration and stromal infiltration. Moreover, it is unclear whether the infecting fungus is eradicated in this procedure or whether foci of viable fungi continue to persist in the corneal tissue; these fungi may become reactivated under undefined circumstances to cause corneal damage.
Tissue adhesives (cyanoacrylate "glue") provide support to a thinned-out cornea and can seal a corneal perforation that is 2 mm or less in size (100). In addition, cyanoacrylate adhesive has been found to be bacteriostatic for gram-positive bacteria (3). Prior to application of the adhesive, necrotic stroma or epithelium and other debris must be removed from the base of the ulcer; a bandage contact lens is usually fitted after the application (3). The adhesive is left in place until it loosens spontaneously, the bed becomes vascularized, or keratoplasty is performed.
(b) Surgical management of keratitis with deep lesions. A Gunderson conjunctival flap has been advocated for deep keratitis; however, there are several limitations to this technique. The procedure is technically difficult to perform since the tissue bleeds profusely and the view of the ulcer is obscured, rendering follow-up examination difficult. Moreover, perforation of the flap and ulcer may occur, the infected material is not removed, and penetration of antifungals may be hindered (10). This procedure is now advocated only in desperate situations, where penetrating keratoplasty is not possible.
Full-thickness corneal grafting (penetrating keratoplasty) is indicated if there is impending perforation, if a perforation exceeding 2 mm has occurred, or if there is no response to medical therapy. The donor button is usually cut so as to be about 0.5 mm bigger than the recipient corneal bed. As far as possible, the lens should be left undisturbed to prevent spread of the infection to the posterior segment; however, where the lens is already exposed preoperatively due to a large perforation, lens extraction should be performed through the trephination wound (300, 384).
Due to the availability of specific antibacterial drugs, penetrating keratoplasty is rarely required for the treatment of active bacterial keratitis. However, it is required in 15 to 28% of patients with mycotic keratitis since medical treatment may be ineffective (111, 334). One study in Singapore indicated that fungal keratitis was associated with a five- to sixfold higher risk of subsequent perforation and need for penetrating keratoplasty than was bacterial keratitis (429). In Miami, penetrating keratoplasty was required in 22 (28%) of 79 patients with Fusarium keratitis, 4 (25%) of 16 patients with keratitis due to different Candida spp., 2 (18%) of 11 patients with Curvularia keratitis, 3 (60%) of 5 patients with Aspergillus keratitis, 2 (67%) of 3 patients with keratitis due to Acremonium spp., and 1 (50%) of 2 patients with keratitis due to Cylindrocarpon spp. (334). In Philadelphia, penetrating keratoplasty was performed for 2 of 11 patients with C. albicans keratitis, 2 of 6 patients with keratitis due to Fusarium spp., and the only patient who had Aspergillus keratitis (377). Other fungi that may cause a severe keratitis that does not respond to medical therapy and necessitates penetrating keratoplasty include L. theobromae (37, 389), P. insidiosum (155), and P. lilacinus (121, 197, 280).
When penetrating keratoplasty is performed for mycotic keratitis, the grafts may opacify in about 4.0 weeks, in contrast to grafts done for bacterial keratitis, where opacification may occur in about 12.9 weeks (70). Similarly, the reported success rate for grafts in mycotic keratitis (20 to 60%) appears to be much lower than the 70 to 75% success rate reported for bacterial keratitis (188, 289). In one study, 25% of grafts performed for mycotic keratitis showed reinfection (334). To decrease the incidence of recurrence, at least 0.5 mm of clear tissue all around the infected area should be excised. Postoperative antifungal therapy should be continued. When donor grafts 8 mm or less in diameter were used for penetrating keratoplasty in fungal corneal ulcers, the outcome was better than when larger grafts were used (188).
To prevent graft rejection in penetrating keratoplasty for mycotic keratitis, topical corticosteroids are given postoperatively, but these need to be used cautiously (366). Topical cyclosporin A has been suggested as an alternative to the use of topical corticosteroids (297). In a prospective, nonrandomized interventional case series, three patients with culture-proven mycotic keratitis who had undergone therapeutic keratoplasties were treated with topical 0.5% cyclosporin A as a primary or adjunctive therapy for prevention of allograft rejection (follow-up was performed for 15 to 42 months); two of the three patients maintained clear grafts, while the remaining patient developed an opacified graft secondary to preexisting ocular surface disease (297). These promising results require verification in studies with a larger number of patients and studies by other workers.
Although uncommon, mycotic lesions of the sclera are important. Scleritis arising due to spread of infection from keratitis due to A. corymbifera (231), Acremonium spp., and L. theobromae (37) has been reported. Similarly, scleritis due to Aspergillus spp. or S. schenckii has been reported to occur following ocular trauma (333; Brunette and Stulting, Letter). Endogenous infections have also been reported. A unique subset of microbial scleritis following ocular surgical procedures is being increasingly reported (see below).
One patient with S. prolificans corneoscleritis responded to intensive antifungal therapy and aggressive scleral debridement (202), whereas another patient responded poorly to medical therapy (topical natamycin and amphotericin B, oral itraconazole and ketoconazole) and eventually required enucleation (370). The outcome of scleritis due to S. apiospermum is also reported to be varied, with good results being obtained in some patients (254) and poor results being obtained in others (379). S. schenckii infection has been successfully treated with oral potassium iodide (50 mg/drop), 10 drops three times daily slowly increasing to 24 drops three times daily (Brunette and Stulting, Letter). Scleritis due to A. fumigatus following an injury to the eye by a tree branch worsened in spite of oral fluconazole and topical amphotericin B therapy; cryotherapy and duramater grafting were then performed, which appeared to control the infection (333). Oral itraconazole therapy resulted in resolution of inflammation in A. flavus scleritis; the patient's condition had worsened during therapy with oral ketoconazole and topical amphotericin B (51).
The uveal tract is the heavily pigmented, highly vascularized middle layer of the eye situated between the sclera externally and the retina internally. It is composed of three distinct regions, namely, the iris, the ciliary body, and the choroid. Infection of the anterior uveal tract is termed "iritis" when inflammation manifests chiefly anterior to the lens and "iridocyclitis" when inflammatory cells are seen in front of and behind the lens. Posterior uveitis and choroiditis are synonymous. The retina usually becomes involved secondary to lesions in the choroid, which manifests as chorioretinitis (424). Intraocular lesions may be caused by many different fungi but are caused chiefly by certain dimorphic fungi (B. dermatitidis, C. immitis, H. capsulatum var. capsulatum, and S. schenckii), yeasts (Candida spp. and Cryptococcus spp.), and P. carinii.
Latent disseminated blastomycosis with choroidal involvement was described in a 36-year-old man who developed blurred vision and a cough 5 months after traveling to an area where a large outbreak of acute blastomycosis had been reported (214); the patient had skin and pulmonary lesions, in addition to the choroidal lesions. Histopathology of the skin lesions confirmed the diagnosis of blastomycosis, and intravenous amphotericin B produced a rapid resolution of both his choroidal and pulmonary lesions (214). Safneck et al. (338) reported the occurrence of endophthalmitis due to B. dermatitidis. Their critical review of the world literature yielded nine cases of intraocular infection due to B. dermatitidis, of which six were verified by histological examination of the enucleated globe. In their case, and in the six cases reviewed, the organisms seen in infected tissue were in the highly characteristic yeast stage, which is found at temperatures of 37°C or greater. These workers contended that the microscopic appearance is sufficiently distinctive to permit presumptive identification without culture. However, culture should be done wherever possible. Pars plana vitrectomy and intravitreal amphotericin B may have a role to play, in addition to intravenous amphotericin B, in therapy of intraocular blastomycosis.
Intraocular coccidioidomycosis may occur in otherwise healthy individuals. Multiple, yellow-white, juxtapapillary chorioretinal lesions with pigmented borders are usually seen; retinal exudates or serous retinal detachment (331), unilateral granulomatous iridocyclitis with multiple iris nodules (72), or papilledema and multifocal choroiditis (72, 331) may also occur. In a report (72) on two patients with intraocular coccidioidomycosis in association with the disseminated form, the diagnosis was established by detection of C. immitis spherules in skin biopsy samples. However, the diagnosis of intraocular coccidioidomycosis is usually made if the suspicious chorioretinal lesions are present in association with anticoccidioidal antibodies in the serum and a positive coccidioidin skin test. Amphotericin B (local and systemic) and oral fluconazole have been used with success in treatment of C. immitis chorioretinitis (72); vitrectomy is necessary if these lesions are associated with endophthalmitis.
A. flavus retinitis was reported in two patients who had undergone bone marrow transplantation 120 days before; fungi were recovered in culture from the vitreous (69). The eyes responded poorly to antifungals. Another four patients developed endophthalmitis due to Candida spp. (69).
Intraocular cryptococcosis usually results from cryptococcal septicemia with severe meningeal infection (67); such sequelae may be seen in patients with AIDS (see "Ophthalmic mycoses associated with AIDS" below). However, isolated ocular cryptococcosis in an apparently immunocompetent individual has been reported (146). Hence, ocular cryptococcal infection must be suspected, even in the absence of predisposing factors or systemic findings. Cryptococcosis may produce visual loss by damaging multiple areas of the anterior visual pathway (67). The diagnosis of cryptococcal chorioretinitis is a presumptive one in a patient with characteristic fundus lesions, with or without vitritis, and documented cryptococcal meningitis or disseminated cryptococcosis. In one patient, transscleral needle biopsy of a subretinal mass was used to establish the diagnosis of subretinal cryptococcosis (146). A vitreous tap or biopsy may be done if vitritis is present. Cryptococcal chorioretinitis can be treated with intravenous amphotericin B (146) or oral fluconazole (2); vitrectomy may be needed if chorioretinitis progresses to endophthalmitis.
Patients with AIDS are at risk of developing pulmonary disease due to P. carinii; aerosolized pentamidine may be given as prophylaxis in such patients. However, patients receiving aerosolized pentamidine therapy are not protected against extrapulmonary disease. Dugel et al. (83) and Foster et al. (104) described the occurrence of choroidal lesions which appeared to be typical of P. carinii in two and three patients, respectively, who were receiving prophylactic aerosolized pentamidine therapy. The lesions resolved after administration of intravenous pentamidine therapy in four of the patients, while the lesions in the remaining patient resolved after administration of intravenous trimethoprim and sulfamethoxazole. None of these patients had clinical or laboratory evidence of P. carinii infection other than in the eye. The choroidal lesions of P. carinii manifest as yellow-white to orange spots without vitreous inflammation (255). Early ophthalmologic examination may detect these lesions before they are threatening to sight and allow systemic therapy to be instituted before widely disseminated infection due to P. carinii results in a fatal outcome.
Ocular involvement by species of Candida is a well-documented sequel to fungemia (81). Candida may spread hematogenously to the choroid and retina without extending into the vitreous to cause endophthalmitis. In a prospective multicenter study with observational design, 118 patients with candidemia were evaluated for the presence of intraocular candidiasis (81). None of the patients were shown to have endophthalmitis, and Candida chorioretinal lesions were observed in only 9% of the patients. Risk factors for Candida chorioretinitis included fungemia with C. albicans (in contrast to non-albicans species), multiple positive blood cultures, visual symptoms, and immunosuppression. It was suggested that when systemic antifungal agents are given early in the course of Candida fungemia, chorioretinal lesions do not progress to endophthalmitis. Choroidal neovascularization is a potential cause of late visual loss in patients who have had sepsis and endogenous chorioretinitis due to C. albicans (166); this complication may occur in spite of adequate antifungal therapy and apparently complete resolution of the chorioretinal lesions. Laser photocoagulation or surgical excision of the neovascular complex may be of benefit in selected cases.
The "presumed ocular histoplasmosis syndrome" is characterized by the presence of multifocal choroiditis scattered throughout the fundus, the peripapillary area, and sometimes the macular area; some lesions show healing with variable chorioretinal scarring (180). This syndrome is not associated with intraocular inflammation and is well tolerated by the eye, unless complications of subretinal neovascularization arise (118). H. capsulatum var. capsulatum has been isolated from the eyes of patients suffering from this syndrome, suggesting that this fungus is the etiologic agent (180). Thomas and Kaplan (382) treated two patients with presumed ocular histoplasmosis, subfoveal neovascular membranes, and progressive loss of visual acuity. Vitreoretinal surgical techniques were used to remove the subfoveal membranes, and good visual recovery was obtained. Therefore, vitreoretinal surgical techniques may be successful in mechanically removing subfoveal neovascular membranes with preservation of the overlying neurosensory retina, and hence preservation of central visual acuity, in the presumed ocular histoplasmosis syndrome.
Until 1990, 17 episodes of endophthalmitis due to S. schenckii had been reported (427). Since then, there have been additional reports of S. schenckii causing endophthalmitis (52, 427) and uveitis (410). Vieira-Dias et al. (410) reported the occurrence of concomitant ocular and cutaneous sporotrichosis, in which the fungus was isolated from skin lesions and the aqueous humor. Risk factors for endophthalmitis due to S. schenckii include AIDS (205) and trauma (427); however, this ocular infection may occur even in the absence trauma or systemic infection (52). Endophthalmitis due to S. schenckii usually presents initially as a granulomatous uveitis (52, 205) which may be treated with corticosteroids, leading to progression of the lesion. Improperly treated uveitic lesions may result in frank endophthalmitis (205) or scleral perforation (52). The only patient with successfully treated endophthalmitis due to S. schenkii responded to amphotericin B (topical and intravitreal) and vitrectomy (427); enucleation had to be peformed for all other patients with S. schenkii endophthalmitis reported in the literature.
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Certain surgical procedures are unique to ophthalmology. The most important ophthalmic surgical procedure is cataract extraction, and the most important fungal infection following cataract extraction is fungal endophthalmitis. Fungal endophthalmitis is beyond the scope of this review. Fungal infections such as keratitis and scleritis have been reported following corneal refractive surgical procedures (radial keratotomy, photorefractive keratectomy, laser-assisted in situ keratomileusis, keratoplasty [corneal transplantation], pterygium excision, and cataract extraction) (Table 21).
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TABLE 21. Ophthalmic
mycoses following ocular surgerya
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Laser-assisted in situ keratomileusis combines the precision of excimer laser photoablation with the advantages of an intrastromal procedure that maintains the integrity of Bowman's layer and the overlying corneal epithelium. Therefore, theoretically speaking, the risk of infectious keratitis after this procedure should be minimal. However, microbial contamination of the stromal bed may occur during surgery due to the proximity of the eyelids, eyelashes, conjunctiva, and microkeratome. The use of topical corticosteroids, unstable epithelium at the edge of the lamellar flap, reduced corneal sensitivity, and use of contact lenses all render these eyes more susceptible to infection. While risk of infection is high after photorefractive keratectomy because of the presence of a large epithelial defect, laser-assisted in situ keratomileusis can also be associated with severe, vision-threatening infectious keratitis.
Since the first reported case of mycotic keratitis following laser-assisted in situ keratomileusis in 2000 (317), there have been at least five other reports of this condition (Table 21). Six different species of fungi from five genera have been implicated. Only two of these patients responded to medical therapy alone; penetrating keratoplasty was ultimately required for the other four patients. Some workers (203, 327, 360, 361) feel that although mycotic keratitis following this surgical procedure is rare, it may pose an important therapeutic challenge due to poor intracorneal penetration of antifungals, especially through an intact epithelium. Sampling at the site of infection provides the best chance of obtaining a positive culture. A favorable outcome of such infections may be ensured by prompt and proper management, collection of corneal scrapings from underneath the flap, quick microbial identification, irrigation of the stromal bed with antimicrobials, and intensive treatment with specific antimicrobials.
Mycotic keratitis has also been reported to occur following lamellar (286) or penetrating (4, 29, 212, 419) keratoplasty, following keratoplasty dehiscence repair (191), and secondary to the endophthalmitis that occurred after phacoemulsification and intraocular lens implantation surgery (88, 417); all nine patients involved required surgery (therapeutic penetrating keratoplasty in seven, optical keratoplasty in one, and debridement in one) (Table 21). Four different yeast species (C. albicans, C. guilliermondii, C. parapsilosis, and Rhodotorula sp.) were isolated from the lesions of four patients, and four different species of filamentous fungi (Exophiala dermatitidis in two patients, and A. kiliense, Beauveria bassiana, and a presumed Fusarium sp. in one patient each) were isolated from the other patients.
Fungal scleritis has been reported to occur in at least 13 patients (Table 21) following various ophthalmic surgical procedures, including excision of pterygium (a fleshy conjunctival growth) without (379) or with beta irradiation (202, 230, 254,370) or cataract extraction (31, 51, 221), and after trabeculectomy (filtering surgery for glaucoma). For management of fungal scleritis, early debridement and culture, close microbiologic assistance, systemic antimicrobials for a prolonged period, and penetrating keratoplasty for perforation or incipient perforation are the measures that have been advocated (254). In the actual clinical setting, however, various modalities of antifungal therapy, as well as surgical debridement, were not found useful in 5 of 13 patients, with enucleation eventually having to be performed (Table 21). S. apiospermum was incriminated in two of the patients, S. prolificans was found in one, and Aspergillus sp. was found in one (230, 254, 370, 379); the identification of Rhizopus spp. in the remaining patient is contentious, since fungal hyphae were not visualized in the samples collected and since just one colony of a Rhizopus spp. was recovered in culture (221). Of the 13 patients, 8 required some form of surgical intervention, such as scleral debridement or resection or removal of plaque, to ensure resolution of the infection; the fungi involved were A. flavus and Aspergillus sp. in five patients, S. prolificans in two patients (one of the isolates had been described by the older name, Scedosporium inflatum), and S. apiospermum and Fusarium sp. (in one patient each) (31, 51, 202, 254). In view of the difficulty of managing mycotic scleritis following excision of pterygium, the following preventive measures have been advocated (254): limited use of low-dose radiotherapy after pterygium excision; adequate sterilization before covering of ulcer beds and calcific plaques at sites of radionecrosis; and careful removal of plaques, since ulcer beds and plaques might harbor infective agents.
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Infections by opportunistic microorganisms constitute an important ocular manifestation of AIDS, although ocular findings are infrequent in human immunodeficiency virus (HIV)-infected, asymptomatic individuals (162). Cytomegalovirus retinitis is reported to be the most common intraocular infection in AIDS patients (162, 348), while other opportunistic ocular infections are considerably less common (162, 348). Various types of ophthalmic mycoses, principally affecting the orbit and intraocular structures, have been reported to occur in association with AIDS (Table 22).
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TABLE 22. Ophthalmic
mycoses associated with AIDSa
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Opportunistic infections of the orbit from bacterial, fungal, and parasitic organisms are a serious complication of systemic HIV infection and are associated with high ocular morbidity and mortality. Orbital mycoses associated with AIDS (Table 22) have been reported in 15 patients since 1991 (Friedberg et al., letter; 143, 172, 201, 209, 245; S. P. Blatt, D. R. Lucey, D. DeHoff, and R. B. Zellmer, Letter, J. Infect. Dis. 164:215-216, 1991; A. T. Vitale, R. F. Spaide, F. A. Warren, H. F. Moussouris, and R. A. D'Amico, Letter, Am. J. Ophthalmol. 113:725-726, 1992). The outcome was generally poor in these patients (Table 22), with resolution or improvement of the orbital mycotic infection in just 6 of 15 patients. Surprisingly, there was resolution or improvement following debridement and intravenous amphotericin B therapy in two of the three patients with rhinoorbital zygomycosis, perhaps because these had relatively focal lesions (143; Blatt et al., letter). There was complete resolution of lesions in the one patient with P. carinii infection after treatment with trimethoprim and sulfamethoxazole (Friedberg et al., letter). Eleven patients had infections due to A. fumigatus, and 10 of these were treated with surgery and intravenous amphotericin B; the mycotic infection resolved and the patient survived in only 3 of these cases. Two of the three survivors underwent surgery and received amphotericin B (intravenous and local irrigation), while the third survivor was treated with debridement, amphotericin B lipid complex, liposomal amphotericin B, and orbital exenteration (172, 201; Vitale et al., letter); none of these three patients had intracranial disease, and all appeared to have relatively focal orbital lesions, which may explain the successful outcome. Overall, it appears that the outcome of orbital aspergillosis in patients with AIDS is poor.
There are many causes of optic neutritis in AIDS patients. There have been two reports of optic neuritis due to H. capsulatum var. capsulatum (357, 433); in one of these, the optic neuritis occurred in association with retinitis and uveitis (Table 22).
Although bacterial and fungal corneal infections appear to be infrequent in HIV-infected patients, they may be severe and associated with corneal perforation when they do occur. Known risk factors for ulcerative keratitis may be absent in HIV-infected patients (144). There have been reports of six patients with mycotic keratitis associated with AIDS (in one patient, the diagnosis of AIDS was made postmortem); C. albicans was the fungus implicated in all six patients (144, 291). The keratitis resolved in all six with topical 0.15% amphotericin B therapy.
Other mycotic infections of the anterior segment reported in AIDS include limbal nodules (and multifocal choroiditis) in one patient (259) and an iris inflammatory mass in another (60); a presumptive diagnosis of infection due to C. neformans var. neoformans was made in both patients by histopathological studies (Table 22).
Presumed mycoses of the posterior segment in patients with AIDS include multifocal choroiditis (choroidopathy) due to cryptococcosis, histoplasmosis, candidiasis, and P. carinii infection (162, 224, 255, 259, 350, 407), and retinitis (162, 357). Culture-proven endogenous endophthalmitis due to Bipolaris hawaiiensis, Fusarium sp., S. schenckii and H. capsulatum var. capsulatum has also been reported (115, 118, 205, 293); complete resolution of lesions was achieved by surgery and amphotericin B and fluconazole therapy only in the patient with B. hawaiiensis infection (Table 22). Although central nervous system infection with C. neoformans var. neoformans is common in patients with AIDS, actual invasion of the intraocular structures by this fungus appears to be uncommon. In one study of 80 HIV-seropositive patients with cryptococcal infections, ophthalmic manifestations included papilledema (32.5%), visual loss and abducens nerve palsy (9%) and optic atrophy (2.5%); interestingly, visual loss caused by optic nerve involvement was less frequent among the 62 patients who had received oral ketoconazole, itraconazole, or fluconazole only than among the 18 patients who had received amphotericin B alone or in combination with the azoles, and actual invasion of the intraocular structures was an uncommon complication (185).
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The topic of ophthalmic mycoses associated with ocular biomaterials has been extensively reviewed by Wilson (422). Microbial colonization of indwelling and implanted biomedical devices, such as shunts or catheters, can lead to serious, often lethal, infection. Polymers, silicones, and metals used to fabricate various devices may be implicated (422). The organisms responsible for such biomaterial-related infections are usually part of the resident microbial flora at a particular area of the body and hence pose a constant threat.
Several factors are though to contribute to the mechanisms of infection associated with biomedical devices (422). Intraoperative contamination during surgical implantation, or extraluminal migration of organisms, permits potential pathogens to transcend normal protective barriers. Production of mucoid substances by microorganisms facilitates the adhesion of colonizing microorganisms and also protects them from various host defense mechanisms. The presence of plasma proteins (especially fibronectin) on the surface of the biopolymer may promote attachment of staphylococci and Candida species to the surface.
Contact lens plastics and their storage cases and intraocular lens implants constitute the two most important categories of biomaterials used in ophthalmology. Infection associated with contaminated intraocular lenses results in endophthalmitis, which is beyond the scope of this review.
Contact lens wear is frequently implicated in the occurrence of bacterial (especially P. aeruginosa) keratitis, and Acanthamoeba keratitis, particularly in the United States (217, 218, 348). The likely route for the normal ocular microbiota colonizing contact lenses during wear is via the lid margins, whereas colonization by gram-negative bacteria, including potential agents of microbial keratitis, is likely to be from the domestic water supply (217, 421). Contact lens-associated mycotic keratitis may be comparatively uncommon because fungi isolated from the healthy outer eye only transiently colonize this area and are not normally resident in the outer eye (217, 363). When soft lenses are worn continuously, fungal conidia adhere to the lens surface and, under favorable conditions, germinate; fungal hyphae are able to enter the matrix of the soft lens, project through the posterior surface, and then penetrate the corneal epithelium, resulting in fungal infection (354). Filamentous fungi of the genera Acremonium, Aspergillus, Alternaria, Cladosporium, Curvularia, and Fusarium were found to penetrate the matrix of soft contact lenses both during normal usage and in laboratory studies. Growth of the fungal hyphae (which were coiled within the lens matrix) increased with increasing water content of the lens. Some species penetrated completely through the lens in 96 h (354). Disinfection of lenses after exposure to potentially high concentrations of these fungi in the environment is prudent (93).
Fungal infection was reported in 4 (4%) of 90 contact lens wearers and in 4 (27%) of 15 patients who wore therapeutic bandage contact lenses (420). If fungal conidia alight on the surface of a contact lens, they are normally removed by surface cleaning of the lens. If lenses are worn for an extended duration without proper cleaning, fungi may adhere and penetrate the contact lens (422). This explains why, when such infections have occurred, soft lenses for aphakia and therapeutic extended wear have been the most frequently implicated (140, 218, 365, 420, 423). Interestingly, soft lenses for cosmetic and aphakic extended wear are frequently associated with infections due to filamentous fungi whereas soft lenses for therapeutic use are frequently associated with yeasts and yeast-like fungus (420).
Rosa et al. (334) reported that 6 of their 125 patients with mycotic keratitis in south Florida wore extended-wear contact lenses; F. oxysporum was isolated from four patients, and C. albicans and Paecilomyces sp. were isolated from one patient each. In one patient who wore a bandage contact lens, keratitis due to C. parapsilosis developed. Liesegang and Forster (216) had earlier reported the occurrence of fungal keratitis in three patients who wore soft contact lenses; the fungi isolated were A. flavus and F. dimerum. Filamentous fungi (A. flavus, F. dimerum, and Fusarium sp.) had also been isolated from the corneal scrapes of several other patients in South Florida who had contact lens-associated fungal keratitis (9, 216).
Perry et al. (296) reported the occurrence of a conjunctival mass and keratoconjunctivitis in an immunocompetent patient; detailed examination revealed that at the posterior aspect of this mass, and covered by mucoid material, was a soft contact lens. Simple removal of the lens resulted in a resolution of all signs and symptoms; the contact lens grew Aspergillus fumigatus (296). Keratouveitis due to Scedosporium prolificans was recently reported in an elderly female patient; the keratouveitis was associated with the intraocular long-term retention of a contact lens (19). Although there is no doubt that a fungal pathogen was involved in this patient, the exact identity of the fungal isolate has recently been questioned (Guarro and Gené, letter).
A relationship has been demonstrated between the occurrence of contact lens-associated bacterial and Acanthamoeba keratitis and the presence of bacteria and Acanthamoeba in contact lens cases (240, 348). Whether such a relationship occurs in contact lens-associated fungal keratitis is unknown. However, Wilson et al. (425) demonstrated the adherence of C. albicans within a biofilm to polyethylene contact lens case plastic; this species was found to be more resistant to the action of contact lens disinfectants than bacteria were. A survey of contact lens cases from 101 asymptomatic daily-wear, cosmetic contact lens wearers in a domiciliary contact lens practice revealed contamination in 82 (81%) cases; 77% grew bacteria, 24% grew fungi, and 20% grew protozoa (125). These authors provided electron microscopic evidence of the polymicrobial nature of the biofilm found in many cases. Ritterband et al. (328) reported a unique case of keratitis due to C. laurentii and F. solani in a diabetic male patient who wore a gas-permeable contact lens; both fungi (and Staphylococcus aureus) were isolated from the patient's corneal button, infected toenails, and contact lens storage case, and enucleation eventually had to be done. C. parapsilosis keratitis, associated with contact lens wear, was reported in an elderly Israeli patient who developed stromal infiltration at the donor-recipient interface 2 years after penetrating keratoplasty, while wearing a "piggyback" type of contact lens; the infection resolved after treatment with amphotericin B and flucytosine (198).
Overnight
soaking of soft lenses in 3% hydrogen peroxide (longer than
4 h), with neutralization in the morning with thiosulfate
solution, catalase solution, or catalase tablets, is perhaps the safest
way to ensure killing of bacteria, Acanthamoeba, and fungi
(58,
422). However, Gray et
al. (125) reported that
81% of contact lens cases surveyed were contaminated with
microbes and that 75% of the subjects used hydrogen peroxide
disinfection for their contact lenses. All the contaminating
microorganisms were found to possess catalase (which breaks down
hydrogen peroxide to water and oxygen). Recommendations for contact
lens wearers to prevent microbial contamination of the lens and case
include regular scrubbing of the interior of contact lens cases to
disrupt biofilms, exposure of the contact lens case to very hot water
(
70°C), air drying of the contact lens case between
use, use of a two-step system for hydrogen peroxide disinfection, and
regular replacement of the contact lens case
(125,
348).
Punctal occluders or plugs are used to facilitate the management of dry-eye syndrome. Since these devices are left in situ for a long duration, nonspecific microbial attachment, surface colonization, and biofilm formation may occur (422). Fungi are rarely implicated. In one instance, in a patient with mycotic keratitis due to C. lunata, the same fungus was isolated from the plug on removal (422).
Several alloplastic biomaterials have been used for orbital floor repair (243) and to restore the anophthalmic socket (113). Oestreicher et al. (279) described a patient who developed an Aspergillus abscess within a hydroxyapatite orbital implant 58 months following uncomplicated implant surgery; the symptoms resolved following removal of the implant.
Patients with corneal or scleral defects have been treated with Gore-Tex grafting; although this material offers some advantages, there are disadvantages, such as poor epithelialization, poor adhesion between the graft and the surrounding tissue, and the possibility of infection. Huang et al. (153) reported the occurrence of fungal contamination in one such graft, which ultimately led to fungal endophthalmitis some months after graft removal and penetrating keratoplasty.
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Future research in ophthalmic mycoses needs to focus on improvement in diagnostic techniques, development of new antifungal compounds and a better understanding of the pathogenesis of the conditions.
A rapid and accurate identification of the fungal species causing an ocular infection will permit the immediate institution of specific antifungal therapy. The nonspecific fluorescent staining techniques (55), immunohistochemical methods (311), and DNA hybridization and DNA amplification techniques (165) are very promising methods, but they need to be simplified and standardized before they can be applied on a large scale. However, culture continues to provide many advantages. New culture media need to be developed.
Amphotericin B continues to be the mainstay of therapy of many, especially severe, ophthalmic mycoses, since fungicidal concentrations may be achieved in ocular tissues (267). Research needs to focus on methods to increase the concentrations of other available antifungals in ocular tissues following administration of therapeutic doses. A change in the vehicle used, or the method of application, may help to do this (136). However, to achieve improved outcomes of ocular infections due to Fusarium spp., various zygomycetes, and P. insidiosum, new compounds need to be developed. Many new azole antifungals and other compounds against Aspergillus spp. have been developed (267) but must still be evaluated for their efficacy in severe ophthalmic mycoses due to Aspergillus spp. O'Day et al. (277) recently described a model of experimental keratitis due to C. albicans, where a standardized inoculum of blastoconidia was placed on the corneal surface and covered with a contact lens. These workers found that invasive corneal disease was established by this surface inoculum and that administration of corticosteroid increased corneal penetration of hyphae. This model mimics human disease since the only fungi present are those actively growing within the cornea. Such a model may prove valuable in evaluation of antifungals in the future.
A better understanding of pathogenetic mechanisms in ophthalmic mycoses is required. In particular, the possible role of fungal extracellular proteinases (438) and fungal morphogenesis (392) in ophthalmic mycoses requires clarification. The role of nonspecific inflammatory mechanisms and specific immunological mechanisms in the pathogenesis of ophthalmic mycoses needs to be studied. A better understanding of these various pathogenetic mechanisms will permit the development of molecules and methods to neutralize these mechanisms and to augment antifungal therapy.
I am grateful to P. Geraldine, J. Kaliamurthy, C. M. Kalavathy, C. Madhavan, D. Arvind Prasanth, A. Geetha, and R. T. Rajagowthamee for their abundant help and to C. A. Nelson Jesudasan for permitting me to utilize the patient and laboratory records and other facilities available at the Institute of Ophthalmology, Joseph Eye Hospital, in the preparation of this review.
* Department of Ocular Microbiology, Institute of Ophthalmology, Joseph Eye Hospital, P.B. 138, Tiruchirapalli 620001, India. Phone: 91-431-2460622. Fax: 91-431-2415922. E-mail: philipthomas{at}satyam.net.in.
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