Proc. lndian Acad. Sci. (Plant Sci.), Vol. 94, Nos 2 & 3, April & May 19850 pp. 453-463. 9 Printr in India.

Drechslera longirostrata (Subramanian) and other Drechslera pathogenic to humans and animais

EDOUARD DROUHET, CLAUDE de BIEVRE and SEEMA WAHAB~ lnstitut Pasteur, Unit› de Mycologie, 75015 Paris, France

Abstrlet. Four species of Drechslera usually soil saprophytes or ptant parasites were recognized over tb.x last few years as agents of deep mycoses with subcutaneous, osteolytic, endocardic and pulmonary Iocalizations as well as superficial myr of cornea and skin. The key of the potentially pathogenic fungi Drechslera lom.jirostrata (agent of an endocarditis and spondylodiscitis), Drechslera hawaiensis (agent of a pulmonary mycosis) D. rostrata and D. spicifera (agents ofseveral c,ases of phaeohyphomycoses) is describe& The sensitivity of these species to actual systemic antifungal agents (amphotericin B, ketoconazole, itracoaazole) is reported.

Keywortls. Drechslera species; myco~s; antifungal agents; amphotericin B; ketoconazole; itraconazole.

1. lntroduetion

A great variety of fungŸ soil saprophytes or plant parasites usually considered as non- pathogenic to man may become pathogenic in humans and animals when the host conditions are favourable; these fungi are called opportunistic (Drouhet 1972) and may produce superficial or deep mycoses, sometimes very severe as we observe with Drechslera longirostrata (Subramanian) com& nova; this usuaLly isolated from dead leaves (Subramanian 1956; Subramanian and Jain 1966) rice and sorghum (Nath et al 1970) was recognized recently (Drouhet et al 1982) for the first time in literature as responsible of an endocarditis and spondylodiscitis in a young woman operated in Martinica for a cardiac valve prosthesis. Three other species of Drechslera chiefly Graminae pathogens or soil saprophytes were recognized during the last few years as responsible for various human and animal mycoses called phaeohyphomycoses (Ajello et al 1980) due to the dematiaceous characters of the filaments invading the deep tissues: Drechslera hawaiensis (Fuste et al 1973; Koenig et al 1984; Krachmer et al 1978; McAleer et al 1981; Young et al 1978), D. rostrata (Ajello et al 1980; Forster et al 1975; McKenzie and Connole 1977) and D. spicifera (Bridger et al 1960; Estes et al 1977; Kaplan et al 1975; Patton 1977; Sobol et al 1984; Zapater et al 1975)o In honour ofProf. C V Subramanian, whose work consecrated to the Hyphomycetes (Subramanian 1956; Subramanian and Jain 1966; Subramanian 1983) is internation- ally unanimously appreciated '~, we relate in this contribution the principal mycological and pathological characters of the Drechslera opportunistic species, pathogenic for o Post-doctoral fellow undcr Indo-Frcnch Scientific Cooperation * Prof. C V $ubramanian was elected President of the International Mycological Association and of the 3rd International Congress of Mycology held in Tokyo from 28th August- 3rd September t983.

453 454 Edouard Drouhet, Claude de Bievre and Seema Wahab

man and animals, as well their sensitivity to antifungal agents in view of an effective chemotherapy.

2. Mycological aspects

Drechslera Ito, Proc. Imp. Acad. Jpn 6: 355, 1930 noto. cons

2.1 General characters Taxonomic studies by Ito (1930) and Shoemaker (1957), showed that the genus Helminthosporium was a heterogeneous assemblage of species. This reatization led to the creation of 2 new genera--Drechslera Ito (1930) and Bipolaris Shoemaker (1959) to accommodate the anomalous species. The genus contains 40 to 45 species (Ellis 1971, 1976). Many of the species are cosmopolitan but are more frequent in tropical or subtropical countries. Most of the known host plants belong to the family Graminaceae. Drechslera may cause leaf spot, seedling blights or root rots. Several species are opportunistic and cause diseases in man and animals. On mar agar the colonies are fast to mild growing, velvety to cottony, grey, brown or blackish. Reverse is dark brown to black, hyphae are hyalin or pigrnented. Conidiophores are single or in small groups, generally unbranched, and geniculated due to sympodial elongation; spores are produced through a conspicuous pore (poroconidia) fusiform to ellipsoidal, pale to dark brown, smooth walled with several pseudoseptates (phragmospores) sometimes with end cells pale coloured. The relationship of Drechslera with other allied genera and connexious anamorph- teleomorph are discussed by Lutrell (1977). On the basis of the spore germination some authors maintain Bipolaris Shoemaker (1959) asa separate genus, the conidia of the Dreehslera sensu stricto germinate from any cell and those ofBipolaris by the end cells. Some species showing a protuberant hilum in conidia, iike Drechslera rostrata, ate placed in the new genus Exserohilum Leonard and Suggs (1974) but we do not follow this opinion.

2.2 Key to the potentiall.v pathogenic species AII these species grow at 37~ which is an obligatory condition for human and animal pathogenicity. Drechslera tongirostrata Subramanian Conidiophores thick-walled, single of in groups of 2-5 bearing 2-6 poroconidia at their tip. Poroconidia have numerous septa (up to 24). The basal and rarely apical septum ate darker. Conidia with prominent hilum are mostly stout, sometimes abruptly bent. According to the medium the maximum length varies (as very often with other species) from 310 to 434#rn and the width from 12 to 20q This species is partly distinguished from the closely related Drechslera rostrata on the basis of the length and the arrangement ofconidia and top darker septum in Drechslera lonoirostrata. Groups of conidia, provided with a dark basal septum, give a palm tree like appearance. On the contrary in Drechslera rostrata, conidia provided with a dark basal and top septum ate Drechslera species pathogenic to human and animals 455

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Figure 1. Morphology of Drechstera tongirostrata strain lP 1229-80 from human en- docarditis. Malt extract agar (a,b), Sabouraud glucose agar (c,d) a. Multiseptated macroconidia (17 septa) (obj. x 100 HI oz• 10) b, Macroconidia up to 20 septa (obj. x 40 oc • 10). r Macroconidia (obj. • 40 oc • 10). 456 Edouard Drouhet, Claude de Bievre and Seema Wahab

arranged in an alternate fashion. Figure 1 illustrates the microscopic morphology of the strain isolated from mycotic endocarditis and osteoarthŸ Drechslera rostrata (Drechsler) Richardson and Fraser. Exserohilum rostratum-- (Drechsler) Leonard and Suggs. Teleomorph: Setospheria rostrata (Drechsler) Leonard (1976). Conidiophores single or in small clusters, generally flexuous or geniculate, dark brown, up to 200 q long and 6-8 la thick. Poroconidia stout, slightly curved to obclavate with 6 to 10 dark septa, end cells less pigmented, 40 to 180 la long and 14 to 22 ~ thick, with a prominent hilum. Figure 2 illustrates the microscopic morphology of some of the strains studied: IMl 76563--ex soil India, coll. R. Y. Roy, 1959 (in the catalogue of the Commonwealth Mycological lnstitute under D. halodes which is now considered conspecific with D. rostrata). IMI 136668 --- ex leal of Sorghum sp., Cairo, tJ,~R, Coll. O. Abdel-Azim-- CMI 1968. ~rai 197559-- ex Zea mays stalk, usA, 1972, coll. T A Kucharek (Luttrel18868)-- K J Leonard (rnating type a). IMl 197560--ex Hay 3 x ZMI 76563, USA, K Leonard (S~A 3 -mating type ,4). Drechslera hawaiensis (Bugnicourt) Subramanian and Jain ex Ellis 1966. Perfect state: hawaiensis. In 1966 Subramanian and Jain emended the genus Drechslera and transferred the species Helminthosporium hawaiensis to the genus Drechslera. Conidiophores solitary flexuous to geniculate wŸ several septa, brown coloured up to 100 to 120 #m Iong and 2-7 #m thick. Poroconidia ellipsoidal, oblong to cylindrical with rounded ends, pale to dark brown, mostly 5 septate, but varying from 3 to 7 septate. In some strain length varŸ from 12 to 37 ]ah. Thickness varies from 5 to 11 tzm; 5 septate poroconidia are mostly 9 • 25/~. Figures 3 a, b, c jllustrate the microscopic morphology of the strain isolated from the case reported by Koenig et al (1984). Drechslera spicifera Nelson. Teleomorph: Cochliobolus spicifer Nelson 1964. Conidiophores as in other species arise singly or in small clusters, repeatedly geniculate, with conspicuous scars giving a typical appearance, mid to dark brown, up to 300 la long and 4 to 9/~ thick. Poroconidia are oblong or cylindrical with rounded ends generally golden brown in colour, with 3 septa length varŸ from 20 to 40 q and thickness from 9 to 14 #m. Figure 3d illustrates the microscopic rnorphology of a human strain of D. spicifera.

3. Parasitic and saprophytic life of Drechslera species potentŸ pathogens for man and animais

3.1 Drechslera ton#irostrata D. lvngirostrata was isolated by Subramanian (1956) from dead leaves of Borassus flabellifer and by Nath et al (1970) as seed-borne in rice and sorghum, as well as other seeds (wheat, pearl, millet). Experimental infections carried out at 2 stages ofgrowth of rice and sorghurn proved their plant pathogenicity but their role in growing crops remains to be established. The first human case of mycosis due to D. longirostrata was reported by Drouhet et Drechslera species pathogenic to human and antmals 457

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Figure 2. Macroconidia of Drechslera rostrata, a. strain iP 1260 t-MI 197560 b, c. strain li, 1263 CMI 76563 (obj. • 40 oc x 10). 458 Edouard Drouhet, Claude de Bievre and Seema Wahab

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Figure 3 a. Macroconidia and conidiophores of DrechMera hawaiensis strain 11, 15t 3-83 from a human pulmonary mycosis (obj. 40 oc • 10). b. Obj. / 100 cx~l oc • 10. c. Obj. 40 oc • 10. d. Macroconidia and conidiophores of D. spicifera (Obj. x 10(I oc x 10). Drechslera species pathogenic to human and animals 459

al (1982); the patient a young woman, 20 year old, operated at Fort de France (Martinica) with valvular prosthesis for a congenital heart defect, developed in the following 3 months a mycotic endocarditis diagnosed when she was reoperated in Paris. At surgery there was an aortic valvular vegetation in which hyphal elements were seen microscopically and from which D. longirostrata was isolated and identified. In spite of amphotericin B treatment followed by ketoconazole treatment, vertebral arthritis due to invasion of the fungus localized first at the intervertebral disc of 2 lumbar vertebral was extended to 3 lumbar segments. Only combination of the 2 antifungal agents, amphotericin B and ketoconazole, permitted the complete cure of this severe case.

3.2 Drechslera rostrata This species is cosmopolitan and common on Graminae and irregularly isolated from soil (Ellis 1971). Jones (1975) incriminated D. rostrata as an agent of oculomycosis. Ajello et al (1980) described this species as an agent of phaeohyphomycosis in a 12 year-old black boy from Bakers¡ (California); the severe chronic and progressive osteolytic infection in the foot of this boy was cured after six months of amphotericin B treatment. An experimental infection was obtained in some mice inoculated by intraperitoneally: a lesion noted in the liver of a mouse was found to contain dematiaceous mycelium. D. rostrata was observed as an agent ofmycoses in Australian bovines; Pritchard and Chick (1977) described multiple mycetoma in a cow with multiple lesions of the skin, nasal mucosa and lymph nodes and mycelial elements organized into granules; McKenzie and Connole (1977) observed also mycotic nasal granuloma due to D. rostrata in cattle.

3.3 Drechslera hawaiensis This species described by the French mycologist Bugnicourt in 1955 was first isolated from rice in Hawai and later from several other plants in many countries but particularly in the tropical and subtropical areas. D. hawaiensis was incriminated as the etiologic agent ofa fatal case of men- ingoencephalitis in Memphis, Tennessee (Fuste et al 1973); the victim was a 31 year old woman with ah underlying tymphocytic lymphosarcoma. Numerous hyphae, (2--4-2/~m dia.) bizarrely shaped and swollen fungal ceUs were observed during autopsy in the brain. Experimental infection in guinea pigs and mice were obtained with the human isolate as well as with plant isolates of D. hawaiensis. In France, D. hawaiensis has been isolated by Koenig et al (1984) from a pulmonary allergic bronchocele in a 12 year old hoy who lived in Tahiti. The septate, dematiaceous hyphae were observed in the pulmonary excised lesion. Eosinophilic infiltrative lesions accompanied the pulmonary granuloma; the child is still under ketoconazole treatment. A nasal obstruction with bone erosion caused by D. hawaiensis in a 15 year old hoy was reported by Young et al (1978). Several comeal ulcers due to a Helminthosporium sp. presumed to be D. hawaiensis aecording to de Hoog (1983) were reported by Krachmer et al (1978). In animals granulomatous proliferations of the nasal mucosa were described in cattle by Roberts and co-workers as due to

P,S. 48 460 Edouard Drouhet, Claude de Bievre and Seema Wahab

Helminthosporium anomah~m. Gilman and Abbott: according to de Hoog the fungus of this case is also recognized as D. hawaiensis.

3.4 Drechslera spicifera (Bainer) Plant parasites, isolates from textiles, soil and air in all parts of the world, especially in the tropical and subtropical areas were identified as D. spicifera (Ellis 1971). In man, Zapater et al (1975) and Forster et al (1975) reported the first cases of corneal ulcers due to D. spicifera. A primary cutaneous phaeohyphomycosis in a 5 year old leukemic boy was reported by Estes et al (1977), Hyphae and swollen hyphal cells resembling chlamydospores were observed in the body specimens. Resolution of the infection occurred following excisional biopsy and systemic amphotericin B therapy. Two cases of chronic pneumonia caused by a Helrninthosporium sp that retrospectively seems to be close to D. spicifera (de Hoog 1983) were reported by Dolan et al (1970). In animals, phaeohyphomycoses due to D. spicifera was reported by Kaplan et al (I 975) in a young horse from Virginia, and by Muller et al (1975) in a cat. Clinically the horse had multiple black, pustulous and papular cutaneous plaques, 1-3 cm in diameter; within the tissues septate hyphae measuring 5 to 35 pro in diameter were observed. The cat also showed chronic granulomatous skin lesions as well as the cat mycetoma reported by Bridges and Beasley (I 960). A maduromycotic type mycetoma was also reported in ah aged mare due to a fungus close to D. spicifera (Schauffer 1972), in a dog (Hall 1965) and in a cow (Patton 1977), Recently Sobol et al (1984) reported a new case of phaeohyphomycosis of the maxilloethmoid sinus caused by Drechslera spicifera.

3.5 Sensitivity of Drechslera pathogenic strains to systemic antifungal agents The four species of Drechslera, potentially pathogenic for humans and animals D. longirostrata, D. rostrata, D. hawaiensis and D. spicifera are agents of deep mycoses with subcutaneous, osteoarticular, pulmonar or endocardic localisations; their severity of infection and chronicity necessitate systemic chemotherapy by intravenous amphotericin B and oral ketoconazole combined with surgical excision; for superficial cutaneous or ocular Iocalisations, topical treatment (iodide, amphotericin B, pima- ricin) showed some limited effects. The infection severity of the first reported case of D. longirostrata infection in man (Drouhet et al 1982), where a spondylodiscitis extended to 3 lumbar vertebrae asa complication of endocarditis from a valve prosthesis infection, was cured on/y after combined administration of i.v. amphotericin B and oral ketoconazole; both drugs have been proved unsuccessful when given alone. The minimal inhibitory concentration (MlC) ofeach individual tested antifungal agent in liquid casitone medium was 1/~g/rrd, while complete inhibition of the growth was recorded at 0.12/~g amphotericin B and 0.25/~g/ml ketoconazole, showing synergism which explains the excellent therapeutic effect when the two antifungal agents were used concomitantly. The strains ofD. hawaiensis, D. spicifera and D. rostrata reported from different cases by Young et al (1970), Estes et al (1977) and Ajello et al (1980) were found responsible for severe subcutaneous and osteolytic phoeohyphomycoses and showed their sensitivity to amphotericin B. Their prolonged treatment v,Sth this drug associated with surgery permitted complete cure but with sequelae. Among the new Drechslera species patho9enic to human and animals 461

Tible I. MIC of ketoconazole and itraconazole against Drechslera sp after 24 and 48 hr using casitone and YNe liquid media, employing microtiter technique.

Ketoconazole (#g/mi) ltraconazole (#g/mi)

Casitone Y~e Casitone YNs Strain (Nber) 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr 24 hr 48 hr

1 0"39 0"39 3"12 25 0.18 0"18 0.18 0"18 2 0-39 1"56 6"25 12"5 0"18 1"56 6-25 6"25 3 0"39 0-78 - 12"5 0"39 0'39 0-18 0'18 4 I"56 3'125 3"125 50 0.18 0"78 0-18 0"39 5 1"56 1-56 6"25 25 0'18 0-18 0-18 0"39

Concentratiorts tried: 100, 50, 25, 12.5, 6.25, 3"125, 1-56, 0-78, 0.39 and 0-18 #gJml. Media: Casitone complex medium (Drouhet and Dupont 1983) YNB (Difco)+ asparagine 1-5 g/l + glucose 10 g/l Strains: !: D. lon#irostrata lp 1229--80, 2: D. rostrata IP 1262-81 cuz 197559 3: D. rostrata II" 1263-81 CM• 75563, 4: D. rostrata lP 1260-80 CM91197568 5: D. hawaiensis lP 1503-83

imidazole derivatives two systemic antifungal agents, the ketoconazole (Drouhet and Dupont 1983) and itraconazole (R 5121 1) (Van Cutsem et al 1983) are promising drugs in systernic mycoses. The sensitivity of several strains of Drechslera species studied in our laboratory showed that these drugs are effective in vitro against these potentially pathogenic fungi for human and animals and may be used in vivo for the treatment of their mycotic infection.

4. Conclusions

Among the great variety of fungŸ soil saprophytes or plant parasites considered usually as non-pathogenic for human and animals, four species of Drechslera were recognized in recent years as agents of deep mycoses with subcutaneous, osteolytic, endocardic and pulmonary localizations as well as superficial mycoses of cornea and skin. The potential pathogenicity of species of Drechslera longirostrata (Subramanian) Nath, D. rostrata (Drechsler) Richardon and Fraser, D. hawaiensis (Bugnicourt) Subramanian and Jain and D. spicifera Nelson, is described as well the pathological manifestations in humans and animals have also been reviewed. D. longirostrata reported for the first time as an agent of endocarditis followed by vertebral localizations in a young women submitted to heart surgery. A pulmonary mycosis was also observed in France in a boy arriving from Tahiti. The other cases reported in literature ate particularly from tropical and subtropical countries. The above mentioned four species are sensitive to systemic antifungal agents (amphotericin B, ketoconazole and itraconazole) but the chemotherapy necessitates in some severe cases a prolonged treatment with combined surgery.

Acknowledgements

The authors express their thanks to Dr Phyllis Stockdale and Dr A Sivanesan (Commonwealth Mycological lnstitute Kew, VK) for help in identification of the strain

Po S. 49 462 Edouard Drouhet, Claude de Bievre and Seema Wahab of D. longirostrata and the cultures of various Drechslera species sent for comparison. They acknowledge Lvce Improvisi, O Ronin, A Piet froid and Mafie-Claire Thibovt for their excellent technical assistance and Dr J Van Cutsem (Jansen Pharmaceutica, Beerse, Belgium) for Ketoconazole and itraconazole samples.

References

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Pritchard D and Chick B F 1977 Mycotic mycetoma due to Drechslera rostrata infection in a cow; Aust. Vet. 53 241-244 Patton C S 1977 Helmmthosporium spiciferum as the cause of dermal and nasal maduromycosis in a cow; Cornell. Ver. 67 236-244 Schauffer A F 1972 Maduromycotic mycetoma in ah aged mare; J. Aro. Vet. Med. Assoc. 160 998-1000 Shoemaker R A 1959 Nomenclature of Drechslera and Bipolaria, parasites segregated from Helminthosporium; Can. J. Bot. 37 879-887 Subramanian C V 1956 Hyphomycetes II; 3. lndian Bot. Soc. 35 446-494 Subramanian C V and Jain B L 1966 A revision of some graminicolous Helminthosporia; Curr. Sci. 35 352-355 Subramanian C V 1983 Hyphomycetes. and biology (London: Academic Press) 502 pp Sobol S M, Love R G, Stutman H R and Pysher T Y 1984 Phaeohyphomycosis of the ma~lloethmoid sinus caused by Drechslera spidfera: a new fungal pathogen; Laryn#oscope 94 620-627 Van Cutsem J, Vangerven F and Zaman R 1983 Pharmacological and preclinical results with a new oral and topical broad spectum antifungal R 51211. Proc. 13th Int. Congress of Chemotherapy Vienna, August 28-Sept. 2, Abstract. Young C N, Swart G and Ackerman D 1978 Nasal obstruction and bone erosion caused by Drechslera hawaiensis; J. Larynyol. Otol. 92 137--143 Zapater R C, Albesi E J and GarcŸ G H 1975 Mycotic keratitis by Drechslera spicifera; Sabouraudia 13 295 -298