Volume: 3: Issue-4: October-2014

Research Article ISSN:2278-0246

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ANTIFUNGALS AND THEIR ROLE IN THE MANAGEMENT OF ORAL MYCOSES: A REVIEW Ananya Madiyal1, Vidya Ajila2, G. Subhas Babu3, Shruthi Hegde4, Priyadharshini Alva5 1

Post-graduate student, Department of Oral Medicine and Radiology, A. B. Shetty Memorial Institute of Dental Sciences, Nitte University, Deralakatte, Mangalore-575018, Email: [email protected], Contact number: +919538840189 2 Reader 3 Professor and Head of the department. 4 Reader. 5 Post-graduate student, Department of Oral Medicine and Radiology, A. B. Shetty Memorial Institute of Dental Sciences, Nitte University. ABSTRACT: Candida species are common commensals of the oral cavity. Increase in the number of immunocompromised patients and patients with severe debilitating diseases has caused a rise in the emergence of fungal diseases caused by organisms that had previously co-existed harmlessly in the human body. Management of these fungal diseases has always been a challenge to the general practitioner due to the growing rates of fungal resistance and toxicity of antifungal drugs. Classes of drugs like polyenes, azoles and antimetabolites are frequently used in the battle against mycoses. Adverse effects like gastrointestinal distress, nausea, vomiting, hepatotoxicity and renal toxicity as well as the patient’s underlying systemic problem have to be borne in mind before deciding the course of antifungals to be given. Keywords: Antifungal, Antimycotic, Candida, Polyenes, Azoles, Antimetabolites.

INTRODUCTION Colonization of the oral cavity by Candida has been recorded throughout history. Hippocrates in 377 BC reported the presence of Candida causing oral lesions in a patient.[1] Oral candidiasis is often regarded as a commensal in the oral cavity with the development of opportunistic infections in case of presence of favourable predisposing factors. It can also be a marker for systemic diseases like diabetes mellitus and may commonly be seen in the immunocompromised. Of the 150 species of candida, only a few (C. albicans, C. tropicallis, C. parapsilosis, C. krusei, C. kyfyr, C. glabrata, C. guilliermondii) are recognised as medically important pathogens.[2] The increased incidence of patients contacting Human Immunodeficiency Virus (HIV) has shown an increase in the prevalence of oral candidiasis which was usually seen in the very young, very old and the very sick.[3] Candida species are also frequent causes for an increasing number of nosocomial infections.[4] Although these organisms typically colonise mucosal surfaces, they gain entry into deeper tissues when host immunity is compromised. Candidiasis is the most common fungal infection of the oral cavity.Other fungal diseases include Histoplasmosis caused by Histoplasma capsulatum, Blastomycosis caused by Blastomyces dermatitidis, Paracoccidiodomycosis caused by Paracoccidiodes brasiliencis,, Coccidiodomycosis caused by Coccidiodes immitis, Cryptococcosis caused by Cryptococcus neoformans, Zygomycosis caused by Z. absida, Z. mucor, Z. rhizomucor and Z. rhizopus, Aspergillosis caused by A. flavis and A. fumigatus and Toxoplasmosis caused by Toxoplasma gondii.[5] Various fungal lesions and the treatment for them have been shown in Table 1.[5] Although these mycoses cause diseases usually when the host immunity is compromised, candidiasis is seen in clinically healthy

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individuals if there is a presence of local predisposing factors. Table 2 [5, 6] gives a comprehensive enumeration of various types of oral candidiasis and the clinical features as well as the treatment to be implemented for them. To date, 3 classes of antifungals have been available for systemic mycotic infections like polyenes (amphotericin B), azoles (ketoconazole, itraconazole) and antimetabolites (flucytosine).[7] Even though there have been an increasing development in these classes of drugs, failure of treatment and development of fungal resistance poses a challenge to the clinician. Through this review we aim to shed a light on the efficacy of various antifungals that can be used in the treatment of mycoses.

POLYENES Polyenes act by binding to sterols incorporated into ergosterol of fungal cell membranes and cholesterol of mammalian cell membranes. They have more avid binding to ergosterol than to cholesterol thus sparing the mammalian cells from toxicity.[8] They interact with sterols with the participation of H2O to form a ‘cage’ resulting from hydrogen bonds. The functional groups involved in the hydrogen bonds are the hydroxyl group of the sterols and carboxyl group of the drug molecule. This binding is strengthened by the participation of the amino group of the amino sugars.[9] Amphotericin B, the most widely used antifugal drug for invasive or life threatening mycoses has a high rate of toxicity but for majority of patients with systemic candidiasis and endemic mycoses conventional amphotericin B or an azole derivative remains the first line of treatment. Three new formulations of amphotericin B have been developed namely amphotericin B lipid complex (ABCL), amphotericin B cholesteryl sulfate and liposomal amphotericin B. These lipid formulations offer various advantages over the conventional amphotericin B like increased daily dosing, high tissue concentration in primary reticuloendothelial organs, decrease in infusionassociated side effects and marked decrease in nephrotoxicity.[10] In regard to candida infection, 1-1.5 mg/kg/d amphotericin deoxycholate remains the standard of therapy. Patients who are intolerant to the drug or are refractory to treatment or have severe renal dysfunction can be prescribed with 5mg/kg/d of ABLC (paediatric dosage of 2-5 mg/kg/d) or 3-6 mg/kg/d of amphotericin B colloidal dispersion or 3-5 mg/kg/d of liposomal amphotericin B infused over 30-60 minutes.[11,12] Nephrotoxicity can be avoided by saline loading with 5001000 ml normal saline before infusion of the drug and avoidance of concurrent diuretics or nephrotoxic drugs like nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, radiocontrast dyes and immunosuppressive agents.[9] One of the major drawbacks of polyenes apart from nephrotoxicity is the development of resistance. Nystatin can be given as suspension 106 U every 6 hours for 4 weeks.[13] Liposomal nystatin (L-nystatin) can be given in a dose of 5 mg/kg/day for a period of 7 days.[14] All polyenes show gastrointestinal disturbances like nausea, vomiting and diarrhoea.[15] Griseofulvin can be given as 5 g/d with good results.[16] Nyawalo et al[17] conducted a study that showed that 2-3 g/d of griseofulvin showed significant reduction in the disease if given over the course of 4 weeks. Giving further dose after 8 weeks increased the cure rate to 91.2%.

AZOLES One of the potential measures to overcome fungal resistance is the development of newer drugs with better antifungal activity. Among the newer drugs, inhibitors of beta glucan synthesis and second generation azoles and triazole derivatives have characteristics that render them suitable agents against resistant fungi.[18] One of the newer members of the imidazole series, ketoconazole has a broad spectrum antifungal profile. It has good oral absorption and low degree of inactivation once absorbed. Its selective toxicity for yeasts and fungi is found to be primarily linked to the inhibition of ergosterol biosynthesis and interference with other membrane lipids. The synergistic action with host defence mechanism is an important part of its action that helps in the eradication of the disease.[19] The drug shows effectiveness against paracoccidiodomycosis, chronic mucocutaneous candidiasis, oral thrush, coccidiodomycosis, blastomycosis and histoplasmosis. A study conducted by Craven et al[20] showed the efficacy of ketoconazole at 800-1200 mg/d. Therapeutic dose of 160 mg/kg/d showed the same effectiveness as amphotericin B given intravenously. Combined treatment of ketoconazole with amphotericin B showed better efficacy in reducing mortality.[21] Clotrimazole is a synthetic azole antifungal drug developed in Germany. It is given as 1.5-3 mg every 6 hourly for a period of 8 days. It reaches a peak

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serum concentration in 1-8 hours.[15] Main toxic effects are gastrointestinal and rare side effects like gynecomastia and liver toxicity also appear.[22] Triazole antifungals are currently showing an increased efficacy against fungal infections as an alternate to amphotericin B. Itraconazole has a broad spectrum of activity against both Aspergillus species and Candida species. It is well tolerated and has a high safety profile. Oral itraconazole capsules 400 mg/d for 2 days followed by 200 mg/d for 12 days with a maintenance dose of 400 mg/d for a period of 12 weeks shows remarkable reduction in oral fungal infections.[23] Sharkey et al[24] found good efficacy of itraconazole at dosage of 600mg/d for a mean period of 5.5 months with a maintenance dose of 400 mg/d. Fluconazole is a relatively newer drug used in the treatment of fungal diseases which falls under the classification of triazoles. Daily dosage of 50 mg/d for 20 days and a single oral dosage of 400 mg have been reported to be effective.[25] Balachandran et al[25] conducted a study which showed that 2 doses of 200 mg each divided over 2 weeks showed better efficacy than a single oral dose of 400 mg. Ramesh et al[26] showed that using 2mg/ml of fluconazole in distilled water that is taken 5 ml and swished for 2 minutes and spit out 3 times a day for a period of 2 weeks to achieve a total daily dosing of 30 mg showed positive results in the resolution of oral candidiasis.

ANTIMETABOLITES Flucytosine is a synthetic antimycotic compound first synthesised in 1957.[25] It has no intrinsic antifungal effects. But after it is taken up by the fungal cells it is converted into 5-fluorouracil which is further converted into active metabolites that inhibit fungal RNA and DNA synthesis.[27] Fungi lacking cystosine deaminase are not susceptible to flucytosine since no conversion of active metabolite takes place.[28] The drug is effective against a wide variety of mycoses including Candida, Torulopsis, Cryptococcus spp., dermatiaceous fungi and Aspergillus spp. It is also active against protozoa including Acanthamoeba culbertsoni and Leishmania spp.[29] Flucytosine can be given at a dosage of 50 mg/d for a period of 2 weeks for systemic mycoses.[30] Bicanic et al[31] conducted a study which had concurrent use of amphotericin B 7 mg/kg/d along with flucytosine at 25 mg/kg/d four times per day for a period of 2 weeks followed by a maintenance dose of oral flucytosine 400 mg/d for 8 weeks and 200 mg/d thereafter. Larsen et al[32] used a combination of fluconazole 400 mg/d combined with flucytosine 150 mg/d for a period of 10 weeks with good efficacy. The occurrence of resistance to flucytosine precludes its use as a single agent. Certain mutations can occur in the enzymes necessary for cellular transport and uptake of the drug and its metabolism or resistance can occur from increased synthesis of pyrimidine which selectively competes with fluorinated antimetabolites of 5-fluorocytosine thus diminishing its antimycotic activity.[28] Flucytosine readily penetrates into most body sites like peritoneal, cerebrospinal and vitreous fluids and into inflamed joints.[33] But it is known to have common side effects like diffuse abdominal pain, nausea, vomiting and diarrhoea occurring in 6% of the patients and more severe side effects like hepatotoxicity and bone marrow depression.[30] Antimycotic activity of flucytosine is reduced if co-administered with cytosine arabinoside since they both use the same transport system.[34] Concomitant administration of aluminium hydroxide or magnesium hydroxide suspension delays absorption.[35] Drugs which are known to be myelosuppressive, cause bone marrow depression, hepatotoxicity or reduce glomerular filteration rate should be used sparingly with the use of flucytosine.[30]

CONCLUSION With the increased availability and use of various classes of antifungals, it is inevitable that we see a development of fungal species that are resistant to these agents. The availability of molecular genetic tools has led to a rapid improvement in our knowledge and understanding of the mechanism by which these fungal resistances occur. Continued efforts to study antifungal resistance and development of safer and more potent compounds are necessary to combat the growing threat of mycoses in the community. Table 1 [5]: Table showing various mycotic infections and their treatment with antifungal drugs

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Aspergillosis

Invasive type: Surgical debridement Itraconazole: 10 mg capsules taken daily after meals for 2 weeks Amphotericin-B: 1mg/kg/d

Blastomycosis

Subclinical infections: No treatment Acute phase: Amphotericin B initial dose of 10-20 mg in 300-500 ml of 5% glucose given slow infusion over 3-6 hours , then dose is increased to 10-20 mg/d Ketoconazole: 400mg/d after food for 2 weeks

Paracoccidioidomycosis

Sulfadiazene: 5mg/100ml Amphotericin B: 0.25-1.2 mg/kg/d dissolved in 5% glucose Ketoconazole: 200mg/d after food for 2 weeks

Sporotrichosis

Iodides: 5 drops/d Relapse: Amphotericin B 1mg/kg/d

Rhinosporidiosis

Surgical removal + Amphotericin B 1 mg/kg/d

Cryptococcosis

Amphotericin B: 1 mg/kg/d for 12 weeks

Coccidioidomycosis

Amphotericin B: 0.6 mg/kg body wt/day in 500 ml of 5% dextrose for 4-6 hrs Ketoconazole: 200 mg/d after food for 2 weeks

Table 2[5, 6]: Table showing various forms of candidiasis, clinical appearance and their treatment CLINICAL TYPE CLINICAL TREATMENT APPEARANCE / SYMPTOMS Pseudomembranous (thrush) Creamy-white plaque, Nystatin: 1-2 pastilles (200,000removable 400,000units) dissolved slowly in Burning sensation, foul mouth 4-5 times daily for 14 days taste Amphotericin B: 1 ml (100mg) rinse and hold in mouth for as long as possible four times daily after meal and at bed time for 2 weeks Clotrimazole: Trouche: Dissolve 1 troche (10 mg) in the mouth 5 times daily for 10-14 days 1 % Gel: apply 10-20 drops gently onto the lesion, preferably with a cotton bud 3-4 times per day Fluconazole: 2 tablets (200 mg) on day 1 and then 1 tablet (100 mg) daily for 1-2 weeks Itraconazole: 10 ml (100 mg) vigorously swished in the mouth and swallowed twice daily for 1-2 weeks Erythematous Red macules Local therapy same as for thrush

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Central papillary atrophy (median rhomboid glossitis, kissing lesion)

IJAPBS Burning sensation Red atrophic mucosal areas Asymptomatic

Angular cheilitis

Red fissured lesions Irritated, raw feeling

Denture stomatitis (chronic atrophic candidiasis, denture sore mouth)

Red denture bearing tissue surface Asymptomatic

Hyperplastic (candidal leukoplakia)

White plaques that are not removable Asymptomatic White plaques, some of which may be removable Red areas White plaques, some of which are not removable

Mucocutaneous

Endocrine-candidiasis syndrome

ISSN: 2278-0246

Asymptomatic type: No treatment required Symptomatic type: Local therapy same as that for thrush Local therapy same as for thrush along with correction of predisposing factors such as: Correction of vertical height of dentures Nutritional supplements Local therapy same as that for thrush along with treatment of denture such as: Soak the denture in 10 % solution of household bleach or Soak the denture in boric acid or Apply nystatin cream over the tissue bearing surface. Removal of soft liners Local therapy same as for thrush. Biopsy of the lesion to confirm diagnosis Local therapy same as for thrush along with systemic antifungal therapy Treatment of underlying conditions along with treatment of candidiasis with local and systemic antifungal therapy

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