Antifungal drugs

Antifungal agents

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

• 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

Azoles inhibit

Polyenes (Disrupt membrane structure & function)

Flucytosine inhibits DNA synthesis

Caspofungin inhibits cell wall synthesis

Classification based on mechanism of action

1. 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: Azoles

5. 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.

Classification based on structure

• ANTIBIOTICS

Polyene: Amphotericin, nystatin, hamycin

Hetrocyclic benzofuran: griseofulvin

• ANTIMETABOLITE : Flucytosine

• AZOLES

Imidazoles: Ketoconazole, clotrimazole,

oxiconazole,

miconazole,

Triazoles: Fluconazole, itraconazole,

voriconazole,

• ALLYLAMINES

– Terbinafine, butenafine

• ECHINOCANDINS

– Caspofungin, anidulafungin, micafungin

• OTHER TOPICAL AGENTS

– Tolnaftate, Undecyclinic acid, benzoic acid

Classification based on structure

Polyene antibiotics • Amphotericin B:

– Obtained from Streptomyces Nodosus– Amphoteric in nature

Lactone ring

Lipophilic part

Hydrophilic part

Mechanism of action

Mechanism of action Amphotericin B

Binds ergosterol in fungal cell membrane

Form pores in cell membrane

Cell contents leak out

Cell death

Antifungal spectrum

- Aspergillus- Blastomyces dermatitidis- Candida albicans - Cryptococcus neoformans- Coccidioides immitis- Histoplasma capsulatum- Mucor spp.Also active against Leshmania

Broadest spectrum of action

Fungicidal at high & static at low conc.

Mechanism of resistance

• Resistance:– Replacement of ergosterol by other sterols in

fungal plasma membrane. – Resistance is not a problem clinically.

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

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

• 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:

Uses

• 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

Disadvantages of AMB

Amphotericin B is toxic SIDE EFFECTS OF AMB

Nephrotoxicity

Acute infusion related reactions

Hypopotassemia, anemia, hepatic dysfunction..

Lıpıd formulations of amphotericin B

(ABLC; Abelcet®)

(ABCD; Amphocil® or Amphotec®)

(L-AMB; Ambisome®)

Amphotericin B Lipid Complex

Amphotericin B Colloidal Dispersion

Liposomal Amphotericin B

ABLC

Ribbon-like particles

Carrier lipids: DMPC, DMPG

J Liposome Res 1993; 3: 451

AMB Lipid complex (ABLC):

35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids

ABCD

Disk-shaped particles

Carrier lipid: Cholesteryl sulfate

J Pharmaceutics 1991; 75: 45

AMB colloidal dispersion (ABCD):

Disc shaped particles containing 50% each of AMB & cholesteryl ester in aqueos dispersion

The ‘LIPOSOME’..

Hospital Practice 1992; 30: 53

• Liposomal AMB (Small unilamellar vesicles) :

10% AMB incorporated in SUV made up of lecithin

Lipid formulations:20-50 times more expensive than AmB-deoxycholate

Milder acute reaction Can be used in intolerance

to conventional preparationsLower nephrotoxicity &

anemiaDeliver AMB to RES of liver

speen so useful in leshmania & immunocompromised

Can be used in higher

doses

Major advantages of lipid AMB formulations

Liposomes in the therapy of infectious diseases and cancer 1989: 105

Release frommacrophage

MacrophageMacrophage

Release in bloodcompartment

Endocytosis

Liposome LysosomeFusion

Liposomedegradation

Endocyticvesicle

NystatinObtained from S.NourseiSimilar 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 TDS1 lac U in vaginitis Prevention of oral candidiasisCan be used in oral, cutaneous, conjunctival candidiasis

Adverse events: Gastointestinal disturbances with oral tablets

Hamycin:S. PimprinaHindustan antibiotics pimpri More water soluble, fraction absorbed orally but unreliable

in systemic infectionsTopical use in thrush, cutaneous candidiasis, trichomonas

& monilial vaginitis, otomycosis by aspergillusNatamycin:

Similar to nystatin, broad spectrum Used topically 1%, 3% ointmentFusarium solani keratitis, trichomonas & monilial vaginitis

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

• 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

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

• 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

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

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

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

• 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

• 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

• 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

Ergosterol

14 α demethylase Ѳ Azoles

squalene 2,3 epoxide Ѳ

Lanosterol

Squalene Terbinafine

Mechanism of action:

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

Ketoconazole

– First orally effective broad spectrum antifungal – Effective against

• Dermatophytosis, Deep mycosis , Candidiasis

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

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

Drug Interactions

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

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

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

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

UsesCandida:

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

Itraconazole

Broadest spectrum of activity also against aspergillus

Fungistatic but effective in immunocompromised

Does not inhibit steroid hormone synthesis and no serious hepatoxicity

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

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

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

Triazoles

Itraconazole- Varied absorption.

Metabolized by cyt P450

- less endocrine effects but occur at high doses

- Less penetration in CSF - Many drug interactions

(due to inhibition of CYT P450/ 3A4)

Fluconazole- Completely absorbed and

better tolerated, Renal excretion

- Less endocrine effects - Penetrates well into CSF- Drug Interactions

VoriconazoleII 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

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

TerbinafineOrally & 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 daysNegligible effect on CYP450

Adverse events and uses

Adverse events: Nausea , vomiting , Diarrhoea Taste disturbancesRarely 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

Caspofungin acetate

Semisynthetic antifungalMOA: 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

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

• 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

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)

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

Topical agents used in dermatophytosis

Systemic administration

Topical

Griseofulvin Ketoconazole

Ketoconazole Miconazole

Fluconazole Clotrimazole

Itraconazole Terbinafine

Terbinafine Nystatin

Spectrum of action

AMB 5FC KTZ FLU ITR

Aspergillus -- -- -- Y

Blastomycosis -- Y Y Y

cryptococcus Y -- Y Y

Coccidiodo -- Y Y Y

candida Y Y Y Y

Histoplasma -- Y Y Y

mucor -- -- -- --

Sporotrichosis -- -- Y Y

chromoblast dermatophyte Fusarium

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

Spectrum of action

• 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

Important characteristics