1.
Antifungal agents

2.
Yeasts• Fungi may be classified as Moulds• Yeasts: Blastomyces, candida, histoplasma, coccidioides, cryptococcus.• Moulds: Aspergillus spp. Dermatophytes, mucor Superficial mycosis• Clinically classified as: Deep (systemic) mycosis

3.
• Systemic fungal infections: – Systemic candidiasis: RTI with progressive dimunition – Cryptococcal meningitis, endocarditis – Rhinocerebral mucormycosis – Pulmonary aspergillosis – Blastomycosis (pneumonitis, with dissemination) – Histoplasmosis(cough , fever, multiple pneumonic infiltrates) – Coccidiodomycosis – Pnemocystis carinii pneumonia

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Polyenes (Disrupt membrane structure & function)Azoles inhibit Flucytosine inhibits DNA synthesis

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Caspofungin inhibitscell wall synthesis

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Classification based on mechanism of action1. Fungal cell wall synthesis inhibition: Caspofungin.2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin.3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine, Butenafine.4. Inhibition of ergosterol synthesis: Azoles5. Inhibition of nucleic acid synthesis: 5–Flucytosine.6. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin.7. Miscellaneous: • Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.

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Classification based on structure• ANTIBIOTICS Polyene: Amphotericin, nystatin, hamycin Hetrocyclic benzofuran: griseofulvin• ANTIMETABOLITE : Flucytosine• AZOLES Imidazoles: Ketoconazole, clotrimazole, oxiconazole, miconazole, Triazoles: Fluconazole, itraconazole, voriconazole,

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Classification based on structure• ALLYLAMINES – Terbinafine, butenafine• ECHINOCANDINS – Caspofungin, anidulafungin, micafungin• OTHER TOPICAL AGENTS – Tolnaftate, Undecyclinic acid, benzoic acid

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Polyene antibiotics• Amphotericin B: – Obtained from Streptomyces Nodosus – Amphoteric in nature Hydrophilic part Lactone ring Lipophilic part

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Mechanism of action

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Mechanism of action Amphotericin BBinds ergosterol in fungal cell membrane Form pores in cell membrane Cell contents leak out Cell death

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Antifungal spectrum- Aspergillus- Blastomyces dermatitidis Broadest spectrum- Candida albicans of action- Cryptococcus neoformans- Coccidioides immitis Fungicidal at high & static at low conc.- Histoplasma capsulatum- Mucor spp.Also active against Leshmania

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Mechanism of resistance• Resistance: – Replacement of ergosterol by other sterols in fungal plasma membrane. – Resistance is not a problem clinically.

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Pharmacokinetics• Poorly absorbed orally• Insoluble in water so colloidal suspension prepared with sodium deoxycholate(1:1 complex)• 90% bound to plasma proteins• Metabolized in liver slowly excreted in urine• t ½ = 15 days

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Administration & dose• Systemic mycosis: IV – Available as 50mg vial – suspended in 10 ml water and then diluted with 500 ml glucose – 0.5mg/kg to 1 mg/kg – Total dose- 3-4 gm over 2-3 months• Intestinal Monoliasis: 50-100 mg QID Orally• Vaginitis: topical• Otomycosis: 3 % drops• Intrathecal: 0.5 mg BD in fungal meningitis

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Uses• Useful drug in nearly all life threatening mycotic infections• Treatment of invasive aspergillosis• Rapidly progressive Blastomycosis & Coccidiomycosis• Cryptococcus neoformans• Mucormycosis.• Disseminated rapidly progressing Histoplasmosis• Reserve drugs for resistant kala azar• Topical uses:

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• Adverse events: – Acute reaction: – Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNF – can be treated with hydrocortisone 0.6mg/kg – Long term toxicity: – Nephrotoxicity: Azotemia, Hypokalemia, acidosis, ↓ GFR – anemia – CNS toxicity : intrathecal administration, headache, vomiting, nerve palsies – Hepatotoxicity rarely

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Disadvantages of AMBSIDE AmphotericinAMB toxic EFFECTS OF B isNephrotoxicityAcute infusion related reactionsHypopotassemia, anemia, hepatic dysfunction..

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Lıpıd formulations of amphotericin B Amphotericin B Lipid Complex(ABLC; Abelcet®) Amphotericin B Colloidal Dispersion(ABCD; Amphocil® or Amphotec®)Liposomal Amphotericin B(L-AMB; Ambisome®)

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ABLC AMB Lipid complex (ABLC):35% AMB incorporated inribbon like particles ofdimyristoyl phospholipids Ribbon-like particles Carrier lipids: DMPC, DMPG J Liposome Res 1993; 3: 451

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ABCDAMB colloidaldispersion (ABCD):Disc shapedparticlescontaining 50%each of AMB &cholesteryl ester in Disk-shapedaqueos dispersion particles Carrier lipid: Cholesteryl sulfate J Pharmaceutics 1991; 75: 45

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The ‘LIPOSOME’..•Liposomal AMB (Smallunilamellar vesicles) :10% AMBincorporated inSUV made up oflecithin Lipid formulations: 20-50 times more expensive than AmB-deoxycholate Hospital Practice 1992; 30: 53

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Major advantages of lipid AMB formulations Macrophage Milder acute reaction Liposome Lysosome Can be used in intolerance Fusion to conventional preparations Liposome degradation Lower nephrotoxicity & Endocytosis anemia Deliver AMB to RES of liver Endocytic vesicle speen so useful in leshmania Release in blood Release from & immunocompromised compartment macrophage Can be used in higher doses Liposomes in the therapy of infectious diseases and cancer 1989: 105

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Nystatin Obtained from S.Noursei Similar to AMB in antifungal properties, high systemic toxicity so used locally only Poorly absorbed from mucus membrane Available as ointment ,cream , powder, tablet Uses:  5 lac U in intestinal moniliasis TDS  1 lac U in vaginitis  Prevention of oral candidiasis  Can be used in oral, cutaneous, conjunctival candidiasis Adverse events:  Gastointestinal disturbances with oral tablets

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 Hamycin:  S. Pimprina  Hindustan antibiotics pimpri  More water soluble, fraction absorbed orally but unreliable in systemic infections  Topical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis, otomycosis by aspergillus Natamycin:  Similar to nystatin, broad spectrum  Used topically 1%, 3% ointment  Fusarium solani keratitis, trichomonas & monilial vaginitis

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Griseofulvin• One of early antibiotics from penicillium griseofulvum• Fungistatic, systemic drug for superficial fungal infections• Active against most dermatophytes• Dermatophytes concentrate it actively hence selective toxicity• Resistance: loss of concentrating ability

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• Mechanism of action: – Griseofulvin interacts with polymerized microtubules and disrupts the mitotic spindles thus arresting fungal mitosis• Pharmacokinetics: – Oral administration, irregular absorption, increased by fatty food and microfine particles – Gets conc in keratinized tissue – Metabolized in liver, excreted in urine,t1/2=24 hrs

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• Adverse events: – Headache most common – GIT disturbances – CNS symptoms: confusion, fatigue, vertigo – Peripheral neuritis – Rashes, photoallergy – Transient leukopenia, albuminuria

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• Uses: – Systemically only for dermatophytosis, ineffective topically• Systemic azoles more effective and preferred• Duration of treatment depends on site, thickness of keratin and turnover of keratin.• Treatment must be continued till infected tissue is completely replaced by normal skin,hair, nail.• Dose: 125-250 mg QID

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Duration of treatment• Body skin = 3 weeks• Palm, soles = 4- 6 weeks• Finger nails = 4- 6months• Toe nails = 8 – 12 months• Griseofulvin should be reserved for nail hair or larger body surface involvement• Interactions: – Warfarin , OCP – Phenobarbitone, Disulfiram like reaction

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5 flucytosine– Prodrug, pyrimidine analog, antimetabolite– Converted to 5 FU– Human cells cant convert it to 5FU– Adverse events: • Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis– Uses: in combination with AMB in cryptococcal meningitis– Narrow spectrum of action

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Advantages of combination:–Entry of 5 FC–Reduced toxicity–Rapid culture conversion–Reduced duration of therapy–Decreased resistance

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• Differences between AMB & 5 FC • AMB = Active drug, broad spectrum, antibiotic, fungicidal • Not absorbed, high protein binding, no BBB, metabolized in liver, highly efficacious, IV,Intrathecal,topical

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• Azoles: – Synthetic antifungals – Broad spectrum – Fungistatic or fungicidal depending on conc of drug – Most commonly used – Classified as imidazoles & triazoles• Imidazoles: Two nitrogen in structure – Topical: econazole, miconazole, clotrimazole – Systemic : ketoconazole – Newer : butaconazole, oxiconazole, sulconazole

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• Triazoles : Three nitrogen in structure – Fluconazole, itraconazole, voriconazole – Terconazole: Topical for superficial infections• Both these groups are – Structurally related compounds – Have same mechanism of action – Have similar antifungal spectrum

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Mechanism of action: Terbinafine Squalene Ѳ squalene 2,3 epoxide Lanosterol Ѳ Azoles 14 α demethylaseErgosterol

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Miconazole & clotrimazole• Topical use: – Miconazole 2 % and clotrimazole 1 % applied BD for 2 weeks in pityriasis versicolor, 4 weeks in cruris, capitis and corporis• Uses: – Dermatophyte infections – Candida: oral pharyngeal, vaginal, cutaneous• Adverse events: – Local irritation , itching or burning – Miconazole shows higher incidence of vaginal irritation & pelvic cramps

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Ketoconazole– First orally effective broad spectrum antifungal– Effective against • Dermatophytosis, Deep mycosis , Candidiasis

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Pharmacokinetics• Effective orally• acidic environment favours absorption• High protein binding• Readily distributed, not to BBB• Metabolized in liver, excreted in bile• t1/2 = 8- 10 hrs• Dose : 200 mg OD or BD

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Adverse events• Nausea , vomiting , anorexia• Headache , paresthesia, alopecia• ↓ steroid, testosterone & estrogen synthesis – Gynaecomastia, oligospermia , loss of libido & impotence in males – Menstrual irregularities & amenorrhoea in females• Elevation of liver enzymes• Hypersensitivity reaction - skin rashes, itching

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Drug Interactions

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Uses• Dermatophytosis: conc in stratum corneum• Monilial vaginitis : 5-7 days• Systemic mycosis: blastomycosis, histoplasmosis, coccidiodomycosis – Less efficacy than AMB & slower response – ↓Efficacy in immunocompromized and meningitis – Lower toxicity than AMB higher than triazoles• High dose used in cushings syndrome• Topical: T.pedis, cruris, corporis, versicolor

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Fluconazole• Newer water soluble triazole – Oral, IV as well as topical – Broad spectrum antifungal activity • Candida, cryptococcosis, coccidiodomycosis • Dermatophytosis • Blastomycosis • Histoplasmosis • Sporotrichosis • Not effective against aspergillosis & mucormycosis

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Pharmacokinetics94% oral bioavailabilityNot affected by food or gastric pHPrimarily excreted unchanged in urine t1/2 = 25 -30 hrsPoor protein bindingWidely distributed crosses BBB

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Adverse events GIT upset Headache, alopecia, skin rashes, hepatic necrosis Teratogenic effect CYP450 Enzyme inhibiting property less Interactions:  Effects hepatic drug metabolism to lesser extent than Ketoconazole  H2 blockers & PPI do not effect its absorption No anti androgenic & other endocrine effects

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UsesCandida:  150 mg oral dose can cure vaginal candidiasis with few relapse  Oral candidiasis- 2 weeks treatment requiredTinea infections & cutaneous candidiasis: 150 mg weekly for 4 weeks, tinea unguim : 12 monthssystemic fungal infections: Disseminated candidiasis, cryptococcal, coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longerMeningitis: preferred drugEye drops for fungal keratitis

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ItraconazoleBroadest spectrum of activity also against aspergillusFungistatic but effective in immunocompromisedDoes not inhibit steroid hormone synthesis and no serious hepatoxicity

48.
Pharmacokinetics50-60% bioavailability, absorption is variable, enhanced by food & gastric acidityHigh protein binding 99 %Well distributed accumulates in vaginal mucosa, skin, nails but CNS penetration is poorMetabolized in liver CYP3A4 excreted in feces t1/2= 30- 64hr

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Uses DOC for paracoccidomycosis & chromoblastomycosis DOC for histoplasmosis & blastomycosis Esophageal, oropharyngeal vaginal candidiasis  Not superior to fluconazole : 200 mg OD X 3 days Dermatophytosis: less effective than fluconazole  100- 200 mg OD X 15 days Onychomycosis : 200 mg / day for 3 months  Intermittent pulse regime 200 BD once a week / month for 3 months equally effective Aspergillosis: 200 mg OD/ BD with meals for 3 months or more

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Adverse events• GI Intolerance• Dizziness, pruritis , headache , hypokalemia• Increase plasma transaminase• Rarely hepatotoxicity• Drug interactions: – Oral absorption ↓by antacids, H2 blockers – Rifampicin, phenytoin induce metabolism – Inhibits CYP3A4 drug interaction profile similar to ketoconazole

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Triazoles Itraconazole Fluconazole- Varied absorption. - Completely absorbed and Metabolized by cyt P450 better tolerated, Renal excretion- less endocrine effects but - Less endocrine effects occur at high doses - Penetrates well into CSF- Less penetration in CSF- Many drug interactions - Drug Interactions (due to inhibition of CYT P450/ 3A4)

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VoriconazoleII generation triazoleHigh oral bioavailability, low protein bindingGood CSF penetrationMetabolized by CYP2C19Doesn’t require gastric acidity for absorptionT1/2= 6 hrs Uses:  DOC for invasive aspergillosis  Most useful for esophageal candidiasis  First line for moulds like fusarium  Useful in resistant candida infections

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Dose and Adverse effects• Dose : 200 mg BD• Adverse events: – Transient visual changes like blurred vision , altered color perception & photophobia – Rashes in 5 -6 % – Elevated hepatic enzymes – Prolongation of QT

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TerbinafineOrally & topically effective drug against candida & dermatophytesFungicidal : shorter courses of therapy required & low relapse rates Mechanism of action: Pharmacokinetics:  Well absorbed orally 75%  Highly keratophilic & lipophilic  High protein bound , poor BBB permeability  t1/2- 15 days  Negligible effect on CYP450

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Adverse events and uses Adverse events:  Nausea , vomiting , Diarrhoea  Taste disturbances  Rarely hepatic dysfunction  Topical: erythema , itching , dryness , urticaria, rashes Uses:  Dermatophytosis: topically/ orally 2- 6 weeks  Onychomycosis: first line drug 3- 12 months  Candidiasis: less effective 2- 4 weeks therapy may be used as alternative 250 mg OD

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Caspofungin acetateSemisynthetic antifungalMOA: Inhibits B (1,3) D glucan an essential component of fungal cell wallUses: Treatment of invasive aspergillosis & candidiasis (esophageal, intraperitoneal)Dose: IV 70 mg slowly then 50 mg daily infusionAdverse events:  Flushing rashes , nausea, vomiting, phlebitis

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Topical agents used in dermatophytosis Tolnaftate:  Tinea, cruris, corporis, 1- 3 weeks treatment  Not effective in hyperkeratinized lesions  Salicylic acid aids its effect by keratolysis Ciclopirox olamine:  Tinea infections, pitryasis versicolor ,dermal candidiasis, vaginal candidiasis  Penetrates superficial layers  Acts by inhibiting membrane uptake of precursors of macromolecules needed for fungal growth

58.
Topical agents used in dermatophytosis• Undecyclenic acid: 5% (Tineafax) – Generally combined with zinc (20%) – Requires prolonged treatment has high relapse rate – Weaker antifungal action used in tinea cruris and nappy rash• Sodium thiosulfate: (Karpin lotion) – Reducing agent known as hypo – Effective in pitryasis versicolor only 20 % solution for 3-4 weeks

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Topical agents used in dermatophytosis• Benzoic acid: – Used in combination with salicylic acid – Whitfields ointment: ( benzoic acid 6% + salicyclic acid 3 %) – Salicyclic acid due to its keratolytic action helps to remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion – Adverse events: irritation & burning sensation (Ring cutter ointment)

60.
Topical agents used in dermatophytosis• Quinidiochlor; – Luminal amoebicide – Weak antifungal & antibacterial – External application : dermatophytosis , mycosis barbae, pitryasis versicolor• Selenium sulfide: T versicolor• Potassium iodide: Dermatophytic infection

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Systemic TopicaladministrationGriseofulvin KetoconazoleKetoconazole MiconazoleFluconazole ClotrimazoleItraconazole TerbinafineTerbinafine Nystatin

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Spectrum of actionAMB 5FC KTZ FLU ITRAspergillus -- -- -- YBlastomycosis -- Y Y Ycryptococcus Y -- Y YCoccidiodo -- Y Y Ycandida Y Y Y YHistoplasma -- Y Y Y mucor -- -- -- --Sporotrichosis -- -- Y Y chromoblast dermatophyte Fusarium

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Spectrum of action• Nystatin: Candidiasis only• Griseofulvin: Dermatophytosis only• Terbinafine : Dermatophytosis & candidiasis• Caspofungin: Aspergillosis & candidiasis

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Important characteristics• Broad spectrum: AMB, KTZ, FLU, ITR• Resistance: 5 FC• Nephrotoxic/ Anemia: AMB• Leucopenia: 5 FC• GIT upset: All• Over all toxicity: highest for AMB lowest for fluconazole, itraconazole