Despite the remarkable progress of topical antimycotics, clinical efficacy is not necessarily parallel to their MICs. In this paper, problems apparently relating to the efficacy are discussed.
1. MIC: MIC of recent products has reached 0.00- (double 0), usually indicating an excellent product.
2. Fungicidal, static: Fungicidal capability may correlate to the elimination of causative fungi, but not necessarily correlate to clinical improvement.
3. Concentrations of drug: The higher the concentration, the higher may be the effectiveness if the substance is not stimulative. Two fold concentration may cause a nearly 10% rise in clinical efficacy.
4. Percutaneous absorption: Experimental tinea pedis of guinea pig requires two times the drug concentration and twice as many long treatment as tinea corporis. It is the most variable in efficacy on human athlete's foot on the sole, and experimental guinea pig athlete's foot is the best model for the evaluation.
5. Adsorption to horny material and release from it: Keratin is the most adsorptive substance, and is inactivated by binding; thus the characteristics of keratinophilic substance are active for a long time. If it is released within 2 to 4 days, and if sub MIC of the released drug is sufficiently effective.
6. Physiological fungicidal substances in the horny layer: Keratinophilic fungi are not necessarily pathogenic, because the horny layer contains potent fungicidal substances such as H1 histone. The drug should cooperate with them.

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The clinical course was investivated of patients suffering from tinea pedis who visited the Dermatology Clinic of Nagasaki Municipal Hospital between July and November, 1993. A complete cure was seen in only 27 of the 380 patients examined, less than 10%. Most patients were still receiving treatment by either topical and/or systemic antifungal drugs after several years because of repeated recurrence of lesions.
The treatment of tinea pedis lesions has two facets, one for efficacy in the short term and the other, complete cure of the lesions, i. e. eradication of dermatophytes from the body surface.
Many new antifungal drugs have recently been introduced on Japanese market. These drugs are greatly improved in minimal inhibitory concentration for dermatophytes, irritability and efficacy rate judged over four-weeks of observation. They focus primarily on short term treatment, but not on a complete cure of tinea pedis lesions. Data concerning long-term follow-up study of tinea pedis patients treated with these newly introduced antifungal drugs is still sparse.

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Griseofulvin therapy was reported to be effective in the treatment of tinea unguium, although a longer course of treatment was required than that suggested in earlier reports on the efficacy of the drug.
There are only a few reports on the clinical evaluation of griseofulvin for tinea unguium based on long-term follow -up studies.
To evaluate griseofulvin therapy, a retrospective survey was carried out on tinea unguium patients who visited Sakai Municipal Hospital in 1992. Three hundred and ten of these patients were treated with oral griseofulvin (0.5g/day). 161 patients dropped out before complete cure was achieved, and 31 currently remain under treatment. Complete cure was recorded in 19 individuals with tinea unguium of the fingernail and in 62 with the tinea unguium of the toenail.
Within one year, complete cure was recorded in nine patients with fingernail infection and in 26 with toenail infection, and within two years in 16 and 48, respectively.
Continued treatment with oral griseofulvin achieved an overall cure rate of about 80% within two years. No change in the liver function test was observed.
Treatment was stopped in eleven patients because of adverse reactions, namely headache, gastric distress or drug eruptions, which immediately ceased with when the drug was discontinued.
Treatment of tinea unguium with oral itraconazole, oral terbinafine and fulconazole were briefly reviewed. The efficacy of these newly developed oral antifungal agents has not yet been completely evaluated.
Mechanical and chemical avulsion, and topical agents are helpful in treatment of tinea unguim. Combination of topical and systemic therapy may raise the cure rate of this disease and make it one which is more frequently curable in future.

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Commercially available topical antifungal agents pose no serious safety problems, but no agent is free from side effects in all patients. Allergic contact dermatitis caused by an antifungal agent and/or vehicle has been reported and we have experienced some cases of this. However, it seems to us that primary skin irritation is caused mainly by the vehicle. Types of skin irritation are immediate, primary and dry skin irritation. In the new commercially available topical antifungal agents, primary skin irritation has been almost improved.

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This study discusses the role of new systemic antifungal drugs (new azoles such as fluconazole and itraconazole) in the treatment of subcutaneous mycoses. The new azoles may be able to replace griseofulvin for treating dermatophytoses, and outstanding progress has made in the treatment of chronic mucocutaneous candidiasis, but it is hoped that even better results can be obtained by treatment of the latter with other new antifungal drugs, imcluding cytokines. For the management of sporotrichosis cases, itraconazole probably of primary importance, but a more potent antifungal agent to combat the extracutaneous form of this disease is required. Chromomycosis does not respond well to drug therapy, and cases that are unresponsive to the new azoles necessitate consideration of their combined use with treatments like hyperthermia or oral flucytosine administration, or of a surgical approach. In progressive or systemic chromomycosis infections, there is a need for studies of the immunological mechanisms involved. Cases of primary or localized cutaneous cryptococcosis in which the new azoles have been effective have been reported, there is no doubt that, with introduction of new antifungals, further developments will be made in medical mycology.

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Visceral mycosis has become a worldwide problem recently, and many important problems in it's diagnosis, treatment and control are towering before us.
Several strains of Candida albicans and Aspergillus fumigatus kuboyama strain were examined for their susceptibility to five antifungal agents separately and in combination using an in vitro agar dilution or microdilution assay. Media were Sabouraud dextrose agar and yeast nitrogen base supplemented with 1% glucose and 0.25% K₂HPO₄. The antifungal agents were amphotericin B (AMPH), 5-fluorocytosine (5-FC), miconazole, fluconazole and itraconazole. The cumulative mortality rate and histopathological findings in experimental candidiasis and the experimental pulmonary aspergillosis using a newly devised aerosol exposure apparatus treated with each of the five drugs were studied.
Determinations were made of intracellular concentrations of 5-FC of C. albicans in yeast nitrogen base with or without AMPH. The levels of the antifungal agents in serum of human and mouse were also calculated.
Synergistic effect of 5-FC and AMPH was found not only in vitro but in vivo. No significant difference in pharmacokinetics of 5-FC by single or combined administration was observed and Candida intracellular levels of 5-FC increased in parallel with the concentration of AMPH.
No significant effects were noted in combinations with other drugs, but we must be very much aware that a precise method for evaluation of susceptibility in vitro has not yet been developed and the pharmacokinetics differ between human and animals. Detailed analysis of this point would be matter for further research.

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The in vitro and in vivo combination effect of antifungal agents was investigated. The combination of amphotericin B (AMPH) plus fluconazole (FLCZ) had a synergistic effect against Candida spp. The combination of flucytosine (5-FC) plus FLCZ had a synergistic effect against Cryptococcus neoformans isolated clinically, and the combination of AMPH plus miconazole (MCZ) was synergistic against Aspergillus fumigatus. Treatment of FLCZ plus 5-FC was shown efficacious in three cases of pulmonary cryptococcosis. Twenty cases of deep-seated mycosis were treated by the combination of MCZ plus 5-FC: seven cases showed improvement, in six cases fungi were eradicated, and side effects occurred in ten cases.

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The emergence of Candida albicans resistant to fluconazole (FLCZ) because of long-term treatment in AIDS patients and the increase of infections with C. krusei and C. glabrata poorly sensitive to FLCZ have attracted attention in other countries. This study examined the possibility of a tendency toward azole-resistance among fungal isolates in Japan and the effect of antifungal agent treatment of infections by resistant fungi. The following results were obtained:
1. The sensitivity to FLCZ and ketoconazole was determined on eight species of yeast-like fungi, including 122 strains isolated before marketing of FLCZ (up to December 1987) and 138 strains isolated afterward (July 1991 to October 1992). No significant differences in sensitivity were detected, which suggests the absence of a tendency toward azole resistance among the fungal strains.
2. Among the clinical isolates tested, C. albicans, C. parapsilosis and C. tropicalis were highly sensitive to FLCZ (IC₉₉≤0.78μg/ml), C. guilliermondii, Cr. neoformans and T. cutaneum were moderately sensitive (1.56 to 6.25μg/ml) and C. krusei and C. glabrata were poorly sensitive (up to 25μg/ml).
3. An experimental model of lethal C. glabrata infection in mice was established. Using this model and comparing it with C. albicans infection, the relationship between the effectiveness of FLCZ treatment and the drug sensitivity of the challenged fungi to FLCZ were examined. A good correlation was obtained depending on the serum drug level.

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The occurrence of fungal opportunistic pathogens and fungal allergens in indoor environments and their potential hazards to human health are discussed. Epidemiologically domestic molds have recently been associated with allergic symptoms in Japan. Fungal flora in the dust samples collected from carpets and the internal air of domestic dwellings including the indoor environments of patients who have developed allergic asthma are summarized. In measuring by cultivation on low water activity medium (DG 18 agar), dry areas such as living and bedrooms contain large numbers of the xerophilic fungi, Aspergillus restrictus, Eurotium spp. and Wallemia sebi. Modern air conditioning systems and the westernized life style in Japanese dwellings are consistently involved with mold development in all seasons. The effect of some antifungal treatments on commercial household utensils is also described.

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The ecology of pathogenic dematiaceous fungi in natural and living environments in Colombia, Venezuela, Brazil, China and Japan was investigated, and the relationship between their ecology and epidemiology of dematiaceous fungal infections was discussed.

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Cryptococcus neoformans was isolated from 13 of 22 samples of pigeon droppings and one of flitter mouse dung collected in Kobe city, Japan. This finding in the flitter mouse dung was the first recorded in Japan. Twenty-six samples of the above substrates were also examined for their mycoflora.
To determine the best method for routine clinical examination for C. neoformans, various identification techniques were compared morphologically and physiologically, using 10 isolates from the clinical sources and 249 from the pigeon droppings. The phenol oxidase reaction may serve as a simplified identification method of C. neoformans.
The physiological characteristics were tested for the effects of temperature and pH concentration on their growth. The tested isolates grew within the range of 6-37°C, the optimum temperature for growth being 25°C. No growth was observed at 43.5°C. Heat treatment at 50°C for 5min effectively sterilized the cell suspensions. Measurements of the tolerance of the isolates for UV irradiation and common disinfectants showed that all isolates were strongly resistant to UV irradiation. With the exception of 0.02-0.5% chlorohexidine gluconate, common disinfectants were found to be effective in vitro for the sterilization of the isolates.

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Geophilic dermatophytes (Microsporum gypseum, etc.) are often isolated from soil. For human beings, however, the existence of anthrophophilic and zoophilic dermatophytes in their residence is more important.
Dermatophytes are often isolated from normal healthy skin of not only patients but also their family memmbers. Zoophilic dermatophytes (Microsporum canis, etc.) exist in most cases as saprophytes, but anthrophophilic fungi (Tricophyton rubrum, T. mentagrophytes and T. violaceum) present at the stage of subclinical infection, not merely in saprophytic growth.
It was proved that patients with Tinea pedis disseminated fungi in the environment, and neither the frequency nor the degree of dissemination differed significantly in relation to species in studies using the foot-press method and the cellophane tape method of slippers on bare feet for 10 minutes.
There are several reports in Japan of dermatophytes having been isolated from inside a residence, for example, from mats, slippers, bathtubs, and floors. Recent reports stated that dermatophytes were easily isolated from the housedust of patients' residences. This suggests that housedust should be considered a significiant source of dermatophyte infection.

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There are many kinds of fungi related to allergies in different environments. The authors have worked on fungal distribution and biological findings of allergenic fungi in the home for the past decade. This paper describes the distribution of fungi related to allergy in the air (outdoor and indoor), housedust, air conditioning filters and fungi contaminating households such as in the bathroom, kitchen and damp areas. Airborne fungi in the home peaked in spring and autumn in most years in Japan, while house dust fungi did not change year-round. The dominant fungi were mostly Cladosporium, Penicillium and Aspergillus in those environments and other predominant fungi differed depending on the surroundings. Their distribution is determined by the lifestyle of each household.

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Food spoilage fungi are classified into three types by source: plant pathogenic field fungi, storage fungi and soil-borne storage fungi. Some mycotoxin-producing fungi are reported to be pathogenic for humans and domestic animals. Some of the fungi from the fields are Alternaria spp., Fusarium spp. and Trichoderma spp., The storage fungi are primarily Aspergillus spp., Eurotium spp., Penicillium spp. and Wallemia sebi. The soil-borne storage are Aspergillus flavus, A. fumigatus, A. niger, A. parasiticus, A. terreus, Emericella spp., Neosartorya spp., Penicillium chrysogenum, P. expansum and P. verrucosum.
Among them, Alternaria alternata, Aspergillus flavus, A. fumigatus, A. ochraceus, A. parasiticus, A. terreus, Emericella nidulans, E. rugulosa, Neosartorya fischeri, N. glabra, Fusarium graminearum, F. moniliforme, F. oxysporum, F. solani, Penicillium chrysogenum, P. citrinum, P. expansum and P. verrucosum are important mycotoxin-producing fungi. Aspergillus fumigatus, A. neoellipticus, N. fischeri and N. glabra produce tremorgenic mycotoxins such as fumitremorgins A, B and verruculogen, while Aspergillus flavus, A. parasiticus, A. versicolor and Emericella spp. produce carcinogenic mycotoxins, aflatoxins and sterigmatocystin.

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Changes in incorporation of [¹⁴C] acetate into lipid fractions were examined in Cryptococcus neoformans during growth and were compared with those in Candida albicans. The uptake of [¹⁴C] acetate in the total lipids of Cr. neoformans gradually increased following the growth phase and then decreased at the stationary phase. The hydrolysis of triacylglycerol (TG), the main lipid in Cr. neoformans, was considered to be accelerated as the radioactivity in TG decreased with a concomitant increase of radioactivity in free fatty acid (FFA) in the stationary phase. In contrast, in C. albicans, phosphatidylcholine (PC), the major component of cell membrane, increased during the growth phase and decreased in the stationary phase. It was also observed that the biosynthesis of acidic phospholipids, PI and PS, was enhanced during the growth phase in both types of fungi.

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A new rat model of recurrent pulmonary aspergillosis using cyclophosphamide (CPM) for re-institution of immunosuppression was established. The recurrence induced by CPM was rapid and pulmonary lesions were uniform in all animals. It is therefore considered to be a good model for evaluation of the mechanisms of recurrence and methods of early diagnosis by antigen detection in sera and urine. Galactomannan antigen of aspergilli in sera was examined by PASTOREX Aspergillus, and a very low positive rate was observed instead of the of severe pulmonary infection confirmed by histopathological study. However, antigen in urine detected by immunoblotting showed a relatively high positive rate from the early stage of the recurrence. Based on these findings, it can be concluded that the recognition of antigenuria is useful for early diagnosis of Aspergillus infection.

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To elucidate the mechanism in the dimorphic transition in Sporothrix schenckii at a molecular level, we investigated the proteins synthesized by yeast form (Y) cells and mycelial form (M) cells, and the proteins translated by the RNAs isolated from each cell form. Y cells cultured on BHI agar at 37°C were incubated in Sabouraud dextrose broth at 25°C. An intermediate form of cells between Y and M was obtained after 1, 3 and 5 days of incubation. The morphology of the cells obtained after 7 days (M' cells) was very similar to that of M cells. A major and unique 45kd polypeptide was found to be synthesized exclusively by M' and M cells, and a protein specific to M' and M cells was detected in the translated products by the RNA isolated from these two cell types. Both polypeptides gave an identical peptide mapping pattern with V8 protease digestion.
These findings strongly suggest that the morphological and biosynthetic phenotypes of M' cells are similar to those of M cells and that the gene expression of the 45kd protein expressed by M cells could be, at least in part, involved in the transition from Y cells to M cells in S. schenckii.

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