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Introduction Fungi and Diseases Caused by Them

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Introduction Fungi and Diseases Caused by Them INTRODUCTION FUNGI AND DISEASES CAUSED BY THEM : Fungi have been recognised as etiologic agents of diseases in man and animals since time immemorial. The prevelence i,sr recorded during the vedic periods (1). Since 1950's there has been a dramatic increase in the number of cases of human diseases attributable to pathogenic fungi (2) . This is Due to a) increase in number of reported mycosis because of increased awareness on the part of clinicians b) improved diagnostic practices c) prolonged life span of patients in whom opportunistic fungal infections are becoming increasingly frequent. Normally in group of patients with naturally induced immuno suppression (as in the case of malignant diseases and diabetes) as well as those individuals with artificially induced immuno suppression (caused by transplantation, chemotherapy), fungal infections becomes life threatening situation (3). Fungal infections in man can be classed as follows :- a) SUPERFICIAL MYCOSIS :- They involve skin, hair and nails. They may not be of serious consequences except being of temporary nuisrfnce. The causative agents include dermatophytes like Epidermophyton, Microsporium. Trichophyton, hair infections by Tri chosporon cutaneum and skin infections by Cladosporium werneckii. b) SUBCUTANEOUS MYCOSIS :- It is caused by agents of sporotrichosis, chromomycosis, phaeomycotic cysts etc. c) SYSTEMIC MYCOSIS :- They are deep mycosis involving internal organs. The deep mycosis might get widely disseminated in the various organs and on occasions, can even prove fatal. The fungi and their spores are also capable of causing allergic conditions in man. The systemic infections can be caused by . (i) Primary Pathogens :- eg. Hist oplasma capsulaturn, Coccidioides immi t i s, Blast omy ces dermat i t idi s etc. (ii) Opportunistic Pathogens :- eg. Aspergillus fumigatus. Candida albi cans, Crypt ococcus neof orman s and Mucor species. These opportunistic pathogens initiate infection only when host's resistance is impaired (4). Aspergillus fumigatus is common in decaying vegetation. Its spores reach the respiratory tract, sinuses and ear canals. Massive spore inhalation can cause acute allergic pulmonary diseases (5). Candida albi cans is a normal inhabitant of mouth, intestine and vagina. Established infections may involve the mouth, skin, nails and many parts of the body. Otomycosis is O chronic or subacute infections of the external auditory meatus and ear canals characterised by exudative inflammation. The aetiologic agents include Pseudomonus aeruginosa, Prot eus, Mi crococcus, Streptococcus, Tri chophyt on, Vi olaceum, Epidermophyt on f1occosum etc. Dermatomycosis refers to fungus infection of skin caused by dermatophytes (6). They account for 8-10% of total attendances in the skin clinics in various parts of India. The current estimate of world wide antifungal market is 3 billion U.S. dollars and represent 6% of total antiinfective agents (7) . (Figure (i) and Table I.) Sources of the skin infections include Tri chophyt on rubrum, Tri chophyt on mentagrophyt es, Mi crosporeum gypseum. PERCENTAGE OE TOTAL PHARMACEUTICALS SALES IN INDIA Topical antibiotics (8.0%) Other antifungals (10%) 9ynaeco antilnfectlves(2.0%)) Antifungal dermatologies (90.0%) Flg.l ANTIFUNGALS REPRESENT 9% OF TOTAL PHARMACEUTICAL SALES IN INDIA. OUT OF WHICH ANTIFUNGAL DEMATOLOGICALS REPRESENT 9 0%. OF THE TOTAL ANTIFUIIGAL SALES. TOPICAL ANTIBIOTICS REPRESENT 8 %. GYNAECO ANT I INFECTIVE 2% AND OTHER ANT I- ' FUNGALS 10% OF TOTAL ANTIFUNGAL SALES. TABLE I TOTAL ANTIFUNGAL SALES AS PER LATEST OPERATIONAL RESEARCH GROUP, BARODA. (ORG, AUG 1995) . Product Company Value of Monthly P:r i ce product sal es (OOORs.) % of total 1 ANTIFUNGAL DERMATOLOGIC 1. Tinaderm Fulford 1629.5 21 .3 2. Tolnaftate Soln.lO mg Cream 0.5 gm 222.5 2.9 6 .37 Sol. 10 ml 1407.0 18.4 9 .69 3. Derobin Oint 25 g Allenbury 834.9 10.9 7 . 12 4. Daktarin Mlconlzole Ethnor 758. 7 9.9 - Nitrate 2% Gel 20 g 724.5 9.5 13 .58 P owd e r 10 g 34.2 0.4 11 . 25 5. Grisactin CFL - - - Gri si ofulvin Tablet 125 mg 250.5 3.5 5,. 15 6. Multifungln Boehringer 203. 1 2.6 — Knoll Oint 30 g 99.5 1.3 6,.8 4 Oint 15 g 16.3 0.2 3 .03 Powder 30 g 52.9 0.7 6,.8 4 Sol 30 ml 34.4 0.4 7 .86 7. Hamycin H.A. 64. 7 0.8 6..7 6 suspn-lOml GYNAECO ANTINFECTIVE 1. Nystatin (mycostatin) Sarabhai 482. 1 16. 4 - (Vag.tabs) 338. 9 11 . 5 - 2. Econazole Tabs 150 mg 82. 7 2.8 6. 22 3. Canesten(CIotrimazole) Bayer 262.5 8.9 6. 4 4. Surfaz Franco Indian 101.5 3.4 6. 69 5. Hamycin H.A. 79.2 1.3 7. 56 TOPICAL ANTIBIOTICS 1. Sof ramycin Roussel 5967.6 47.2 - 2. Neosporin Burroughs 4519.4 35.8 - oint - 5 gms 2904.6 23. 0 - powder 10 gms 1614.8 12.8 3. Pragmatar SKF 720.6 85.2 - 4. Hamycin H.A. 13.9 0. 1 — Trichomonas vaqini t i s and Vaginal moni1iasi s are common causes of leucorrhoea in women. The wide spread use of steroids, oral contraceptives, immuno supjressive agentsand broad spectrum antibiotics have definitely contributed toincreased incidences of mycotic infections. These potent therapeutic agents have brought down the fatalities due to bacterial infections considerably, leaving more and more of us to become victims of fungal infections. In fact, wide spread use oflcertain antibiotics seems to have resulted in a real increase in the incidence of certain intercurrent fungal infectionf In spite of the impressive advances in antimicrobial therapy, there is a need for additional potent antifungal agents to fill the gaps in the currently available armamentorium or to supplement the use of drugs already in existence. DRUG SELECTION FOR FUNGAL INFECTIONS : New agents are needed to combat refractory gram negative bacteria especially strains of Pseudomonas, Proteus, Aerobacter and Salmonella. Many mycobacteria, including the atypical ones, resist treatment with available drugs. Many fungi also ellicit the same response. Certain antibiotics have limited usefulness because of their toxicity. Finally, there is always a problem of development of resistant strains, some of which succumb to the newer antibiotics only to have other resistant strains to appear. Amphotericin B is the drug of choice for most of the systemic mycosis. But Amphotericin B has limited utility because of its toxicity and hence is used only in deep mycosis 1^ h particularly r^orth American blastomycosis, histoplasmosis, coccidioidomycosis, cryptococcosis and candidiasis. Most experts prefer combination of Amphotericin B and Flucytosine for cryptococcal meningitis (8). Flucytosine is used alone sometimes for chromomycosis but resistance develops rapidly. Ketaconazole is effective in patients with localised, non life threatening extra meningeal blastomycosis, histoplasmosis and cryptococcosis. Ketoconazole is the drug of choice for chronic mucocutaneous candidiasis and paracoccidioidomycosis, but prolonged therapy is required to avoid relapses. The important antifungal antibiotic griseofulvin was isolated from Peni cillium gri seofulvum in 1939 (9) . Thus, started the era of antifungal antibiotics of '"l^atural origin. Griseofulvin is effective in many superficial infections caused by some species of trichophyton, microsporum & epidermophyton. Candida infections of alimentary tract or localised vaginal or skin infections usually respond to nystatin (10). C PRESENT DAY ^NERIO OF ANTIFUNGAL THERAPY AND ITS DRAW BACKS : Dermatophytic infections involving skin hair, nails etc. require prolonged administration of griseofulvin or ketoconazole. (fig(i)). For mild to moderate fungal infections of skin or nails, miconazole i.e. a broad spectrum imidazole is effective when applied for 14-28 days depending on the extent and degree of involvement, Limited clinical studies suggest that even ticonazole is equally effective (11,12). Candidiasis limited to the skin does not respond to topical undecylenic acid, topical >H Ol l< Pi w S • M H > In < o Q w H 1/1 O H W o D u Q w 1=) in < O M H < w o tn W cc! H O D H to 0; W In H u o ^^2 H >^ U l=> CU Q W E lO o SD n •w in • HJ 4-> < C o 2o D ^—iu* ta M >< H CU S < < oc! W 5 K H taw >H fa< o Q Ul H W S « D ff!w H cr: U D D U « H 2 to l-H fa I S M u w H O tolnaftate or oral griseofulvin. Clioquinor (iodochlorhydroxyquin) also has only limited antifungal activity. Vaginal preparations of nystatin, clotrimazole, hamycin, miconazole etc are available to treat vaginal candidasis. Oral ketoconazole has been used investigationally in candidiasis. However, in view of its great potential for serious systemic adverse reactions, its use should be restricted to patients with chronic recurrent severe infections that do not respond to conventional topical therapy. Intravenous amphotericin B (8) is effective in chronic mucocutaneous candidAiisi s, however, relapse rate is very high when the drug is stopped. Prolonged use can even cause severe adverse reactions. Topical antiinfective agents are also used for local application in case of skin infections namely pyodermas and cellulitis. The most common serious secondary pyodermas are observed in patients with second or third degree burns, eczematous dermatitis, dermal stasis ulcers and in _^c t ' '(f '^ ^"'- £- i it debilitated or immunocompromised patients. Bacteriacin, gramicidin, neomycin and polymyxin B are especially useful in limited pyodermas. Cutaneous candidiasis responds to topical preparations of polyene antibiotics namely Hamycin, Amphotericin B (Fungizone), Nystatin (Mycostatin, Nilsat), Haloprogin (Halotex), Ciclopirox, (Loprox), Imidazoles (Clotrimazole, Lotrimin, Mycelex), Econazole (Spectrazole), Ketoconazole (Nizoral), Miconazole (Micatin). since there Is a regular thrust for an Ideal, potent and effective antifungal antibiotic, the efforts In the present study were directed to explore the possibility of developing a novel antifungal antibiotic. In search of an Ideal antifungal agent, the investigators attempted to isolate the cultures which were then subjected to screening procedures designed to detect antibiotic activity.
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