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Postgrad Med J: first published as 10.1136/pgmj.55.647.625 on 1 September 1979. Downloaded from Postgraduate Medical Journal (September 1979) 55, 625-628

Recognition and chemotherapy of oculomycosis BARRIE R. JONES* YVONNE M. CLAYTONt F.R.C.P., F.R.C.S., F.R.A.C.S. B.Sc., Ph.D. ERASMUS 0. OJI* B.Sc., D.O., F.R.C.S. British Postgraduate Medical Federation, University of London, t Institute of Dermatology, St John's Hospitalfor Diseases of the Skin, London

Summary Introduction Oculomycosis may be divided into the orbital infec- Oculomycosis is of 2 main types: of the tions of phycomycosis of Aspergillus and other species orbit and mycosis of the globe, the latter being the and the of the globe. The latter comprise more common. Orbital mycosis arises by Protected by copyright. endogenous, post-surgical or traumatic intra-ocular from the paranasal sinuses, from trauma or from infections and direct infections of the cornea: these endogenous metastasis. The commonest types of are the commonest form of oculomycosis. They are phycomycoses affecting the orbit are infection by not easy to differentiate from other, more common Absidia spp., Mucor spp., or Rhizopus spp. in persons causes of septic infection of the eye. The early debilitated by severe diabetes, malignancy or toxic recognition of fungal infections of the eye thus rests therapy. Aspergillus spp. and a wide variety of other on maintaining an efficient service for all septic fungi can also invade the orbit. infections of the eye. The globe may be involved in metastatic fungal albicans and other dimorphic fungal endophthalmitis by Candida albicans, Cryptococcus infections are best treated with combined neoformans, Coccidioides immitis, or possibly Histo- with either polyenes such as and nata- plasma capsulatum and also by Aspergillus spp. or mycin or combined with such as clotrim- other opportunists in immunosuppressed patients. or . But outside the areas where the systemic mycoses Aspergillus spp. account for about 50%/ ofthe cases are likely to be encountered the commonest fungal of filamentous fungal infection of the cornea but more infections of the eye are corneal infections and post- http://pmj.bmj.com/ than 100 species of varying pathogenicity and drug surgical or post-traumatic fungal endophthalmitis. sensitivity have been implicated. , clotrim- There are large regional differences in prevalence but azole or miconazole combined with thiabendazole are Candida spp. accounts for about 50/o ofthe recorded recommended for Aspergillus spp. Econazole, thia- cases. Of the filamentous organisms, Aspergillus spp. bendazole or miconazole combined with flucytosine for account for about half, and a bewildering variety of Cladosporium sp. For and other over 100 organisms accounts for the remaining cases econazole is the best but some isolates are Richards and species drug (Jones, Morgan, 1969). Fusarium, on September 26, 2021 by guest. sensitive to thiabendazole or other imidazoles. especially F. solani is increasingly recognized in this Alternatively, filamentous fungal infections may be group (Jones et al., 1969; Jones, Sexton and Rebell, treated with which has a broad spectrum of 1969; Jones, 1975). activity; but does not penetrate well and, like other Keratomycosis presents as suppurative, usually polyenes, should not be combined with ulcerative infection of the cornea, and may range chemotherapy because of antagonistic drug in virulence from the leisurely chromoblastomycoses, interaction. through intermediate organisms like Aspergillus or Overall, econazole emerges as the most widely Cladosporium to the most rapidly destructive F. acting drug; but successful results are dependent on rather with intensive and complex investigation pro- *Correspondence: Professor Barrie R. Jones, Institute of tracted care that can best be provided in a few centres Ophthalmology, Moorfields Eye Hospital, CityRoad, London of referral. ECI 2PD. 0032-5473/79/0900-0625$02.00 ©( 1979 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.55.647.625 on 1 September 1979. Downloaded from 626 B. R. Jones, Y. M. Clayton and E. O. Oji solani (Jones, 1975). Certain typical features may be Acanthamoeba plates at 25°C (Culbertson, 1961; present and suggest the diagnosis of keratomycosis, Culbertson, Ensminger and Overton, 1965). such as a dry, raised ulcer with crenate, spiculate or Unless the stained smears give clear proof of pseudo-hyphate border, or satellite lesions, recurrent fungal infection, and bacteria are not seen, each case hypopyon, posterior chamber endophthalmitis with of suppurative corneal infection should be treated, in progressive shallowing of the anterior chamber, or the first instance, on the assumption of being involvement of the vitreous and failure to respond to bacterial (Jones and Clayton, 1978). antibacterial treatment. The occasional unequivocal If the smears show both yeast forms and fila- recognition of actual fungal hyphae in the cornea ments, there is a dimorphic in the lesion, can establish a firm diagnosis but this is unusual with a very high probability of its being Candida, (Jones, 1975). especially C. albicans. This demands intensive 15- However, all these typical signs may be absent, min to 30-min treatment with 1'5% flucytosine leaving fungal infection unrecognized amonst other drops, so long as the cornea is ulcerated, combined suppurative infections of the eye. The early and rapid recognition of fungal infection of the cornea there- Flucytosine fore rests on establishing and maintaining an efficient IUU,AA - ·(N=13) ....___ Miconazole emergency service for the immediate investigation ._ 4~ (N)N-13 and optimal management of all suppurative infec- - Amphotericino.. / (N= 16) tions of the globe, be they due to bacterial, fungal, 80 acanthamoebic or viral infection (Jones and Clayton, / ._ 1978). As with other infections, early recognition is the greatest contribution to effective chemotherapy. .... _ The recognition of a 'suppurative infection of the ,- bV eye', characterized by intense polymorphonuclear cn Protected by copyright. thus E infiltration, demands immediate and vigorous C collection of specimens to detect organisms of each O 40 _ type in the lesions and to culture them for identifica- tion and sensitivity tests. It is important to take scrapings from the whole of the ulcer base and from the whole length and depth of the ulcer edge. Such 20 _ corneas are often anaesthetic and if so should be scraped without using topical anaesthetics. Intra- I ocular fluids may be collected by anterior chamber i I i i i i i tap, or by vitrectomy-aspiration. Smears are stained 0 3 5 7 9 with Giemsa and Gram stains: cultures are set up on Antifungal minimal inhibitory concentration (mg/litre' blood and in at for agar thioglycollate 37°C bacteria FIG. 1. Cumulative percentage sensitivity distribution and on Sabouraud's agar and in brain-heart infusion curves, for various antifungal drugs, for all ocular at 25°C for fungi, as well as on Culbertson's isolates of Candida albicans and other yeasts. http://pmj.bmj.com/

TABLE 1. In vitro susceptibility of ocular fungal isolates to antifungal drugs. Values - geometric mean inhibitory concentration mg/l Flucytosine Amphotericin B Natamycin Clotrimazole Miconazole Econazole Thiabendazole Candida albicans 0.75 1.1 6-7 2-7 3-1 8-8 (13/13) (16/16) (15/15) (16/16) (13/13) (12/13) on September 26, 2021 by guest. Aspergillusfumigatus 17-1 7-3 9-8 1.3 1.6 1.0 6-9 (11/20) (38/42) (38/42) (42/42) (38/38) (34/34) (7/7) Cladosporium herbarum 1.9 9.9 91 - 14 0-9 1-4 (6/8) (9/9) (9/9) (8/8) (7/7) (9/9) 50 (2/8) spp. - 11-6 20'0 3-8 1-9 1-1 2-2 (10/13) (7/13) (13/13) (13/13) (13/13) (2/2) Fusarium solani and other spp. - 39 5.2 10-7 10.0 3-9 5.0 (6/24) (24/24) (18/20) (16/17) (12/13) (10/15) Postgrad Med J: first published as 10.1136/pgmj.55.647.625 on 1 September 1979. Downloaded from Chemotherapy of oculomycosis 627 with 1Y/ clotrimazole in arachis oil or ointment, or rests on a series of anecdotal case reports (Jones, 1% miconazole in similar vehicles. Alternatively 1975); but placebo-controlled trials are not possible 0.6% ointment may have a place; nata- in this disease, and the clinical course, changing mycin and are less active; amphotericin from deterioration to resolution when antifungal drops are active, but toxic for the cornea (Fig. 1). For chemotherapy guided by sensitivity tests has been severe or deep intra-ocular yeast infections flucy- adequately implemented, makes a strong presump- tosine should also be given orally 200 mg/kg/day, tive case. However, the imidazole antifungal drugs, and intravenous amphotericin B may be required in especially econazole, clotrimazole and miconazole, addition; but its successful use requires meticulous become -bound. All antifungal chemotherapy precautions (Jones, 1975). Either the imidazoles: should, if possible, commence intensively and be clotrimazole, miconazole or econazole; or the continued at reduced levels for a long time. The polyenes: amphotericin B, candicidin, natamycin or regimen of 'topical saturation therapy' using chosen nystatin can be usefully combined with flucytosine. imidazoles in 1-2% oily solution, with or without But imidazoles should not be given in combination 1.5% flucytosine aqueous drops, is as follows: with polyenes because of antagonistic drug inter- every 15 min 1st day; every 30 min 1st night; action (Wingfield, 1974). every 15-30 min 2nd-4th day; 1-4 hourly 2nd-4th night; TABLE 2. every 60 min 5th-20th day; 2-4 hourly 10th-60th day; Filamentous ocular fungi: 119 isolates tested 4-8 hourly 20th-90th day. Aspergillus fumigatus and other spp. Allescheria Two specific and 3 general points deserve men- Alternaria tion: econazole is somewhat irritant in the eye and Cephalosporium may not be tolerated by certain individuals; thia-

Fusarium solani and other spp. Chaetomium Protected by copyright. Dreschlera bendazole is best administered as an aqueous 4%° Echinobotyrum suspension and is known to penetrate the eye well by Penicillium lilacinium and other spp. Epicoccum this route (Robinson et al., 1966); where available, Mucor administration should be combined with Nigrospora systemic Cladosporium herbarum and other spp. Paecilomyces topical during the initial phase of therapy of deep Phoma intra-ocular mycoses; anti-inflammatory therapy Sporodonema Econozole (N=91) The in vitro susceptibilities of some commoner 1ooI- ocular fungal isolates are shown in Table 1. C. albi- Miconazole cans represents the commonest yeast but if smears (N=105) _ suggest a filamentous fungus this may be one of more 80 than 100 species (Table 1). The fungus should be / *' - Clotrimozole isolated, identified and its sensitivity tested. ~~/ ~~~~/ ~(N=115) http://pmj.bmj.com/ For blind treatment of the entire range of 119 ocular filamentous fungal isolates tested (Table 2), 60 Fusarium and spp., but / including spp. Aspergillus E / Thiabendozole Candida spp. and other the of I / < (N =44) O excluding yeasts, drug c o choice was econazole (Fig. 2). Econazole was the 40 most active drug for 90°4 of the isolates; for 94°% it o / Amphotericin -/ had a MIC* of 6.25 mg/l or less (for 90/91 GMt MIC (N =119) on September 26, 2021 by guest. = 1 3 mg/l). Clotrimazole was the most active for 4Y4: Notamycin GM MIC = 2-9 mg/l for 111/115. Miconazole was 20 H / // (N=ll9) the most active for 2%: GM MIC = 2.2 mg/l for 104/105. Thiabendazole was the most active for 2%/: Flucytosine GM MIC = 2.9 mg/l for 34/44. Natamycin was the ;"I (N=72) most active for the remaining 2%: GM MIC- 9 7.8 mg/l for 107/119. 3 5 7 The evidence for efficacy in oculomycosis of each Antifungal minimal inhibitory concentrational (mg/litre) of these imidazole as for flucytosine, FIG. 2. Cumulative percentage sensitivity distribution , curves, for various antifungal drugs, for ocular isolates *MIC, minimal innibitory concentration of all filamentous fungi shown in Table 1, i.e. excluding tGM, geometric mean Candida albicans and other dimorphic fungi. Postgrad Med J: first published as 10.1136/pgmj.55.647.625 on 1 September 1979. Downloaded from 628 B. R. Jones, Y. M. Clayton and E. 0. Oji with prostaglandin synthetase inhibitors or corti- use in the eye at identifiable times of high risk, such costeroids can be beneficially combined with effective as following all eye injuries, no matter how trivial specific antifungal chemotherapy (Jones, 1975); (Jones and Clayton, 1978). In this field there are combinations of antifungal drugs should be used in important challenges that should be overcome by accordance with the following principles derived appropriate international co-operation in field and from unpublished in vitro work (Wingfield, 1974): laboratory studies. Polyene/polyene combinations, polyene/flucyto- sine, flucytosine/imidazole, and imidazole/imidazole References combinations have each been additive when tested. CULBERTSON, C.G. (1961) Pathogenic Acanthamoeba (Hart- On the other hand polyene/imidazole combinations monella). American Journal of Clinical Pathology, 5, 195. CULBERTSON, C.G., ENSMINGER, P.W. & OVERTON, W.M. have been antagonistic in respect of amphotericin B, (1965) Isolation of additional strains of pathogenic natamycin, nystatin, etruscomycin, and clotrimazole Hartmonella sp. (Acanthamoeba). American Journal of or miconazole. The clinical course ofeyes responding Clinical Pathology, 43, 383. only to a limited degree on natamycin therapy have JONES, B.R. (1975) Principles in the management of oculo- mycosis. XXXI Edward Jackson Memorial Lecture. very commonly shown a delay of 2 or more days American Journal of Ophthalmology, 79, 719. before showing a striking improvement on changing JONES, B.R. & CLAYTON, Y.M. (1978) Fungal infection of the to more active imidazole therapy. cornea. In: Proceedings ofthe XXIII International Congress Guided by these principles, is now of Ophthalmology, Kyoto, May, 1978. Excerpta Medica, oculomycosis Amsterdam. curable and vision can often be preserved or restored, JONES, B.R., JONES, D.B., LIM, A.S.M., BRON, A.J., MORGAN, given that the patient can remain under intensive G. & CLAYTON, Y.M. (1969) Corneal and intra-ocular medical and surgical care in the hands of a team that infection due to Fusarium solani. Transactions of the is experienced in such problems. There is thus a Ophthalmological Society of the United Kingdom, 89, 758. JONES, B.R., RICHARDS, A.B. & MORGAN, G. (1969) Direct strong case for referral of oculomycosis to a few such fungal infection of the eye in Britain. Transactions of the centres. Ophthalmological Society of the United Kingdom, 89, 727. Protected by copyright. Unfortunately, in the humid tropical rural world, JONES, D.B., SEXTON, R. & REBELL, G. (1969) Mycotic where fungal infection is most prevalent and keratitis in South Florida: a review of thirty-nine cases. Transactions of the Ophthalmological Society of the United probably plays an important role along with bacteria Kingdom, 89, 781. in septic loss of eyes, it is not practicable to provide ROBINSON, H.J., GRAESSLE, O.E., LEHMAN, E.G., KELLEY, this specialized and prolonged intensive care. The K.L., GEOFFROY, R.F. & ROSENBLUM, C. (1966) Ocular remaining big challenge in oculomycosis is therefore absorption of thiabendazole-14C by the rabbit. American Journal of Ophthalmology, 62, 710. to develop effective prophylaxis and to distribute WINGFIELD, H. (1974) Laboratory studies of some fungi prophylactic preparations efficiently for immediate incriminated as opportunistic pathogens. F.I.M.L.S. thesis. http://pmj.bmj.com/ on September 26, 2021 by guest.