systemic fungal infections venkat

Wednesday 3 May 2023 Nandyala Venkateshwarlu SVS Medial College Mahabubnagar, Telangana India

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Systemic fungal infections

N Venkateshwarlu MBBS (Kurnool), MD(AIIMS/Lady Hardinge)

Systemic fungal infections N Venkateshwarlu MBBS (Kurnool), MD(AIIMS/Lady Hardinge)

Professor, Department of Internal Medicine SVS Medical College Mahabubnagar A.P.

Nandyala Venkateshwarlu SVS Medial College Mahabubnagar, Telangana India

Wednesday 3 May 2023 3

Fungi • Molds and yeasts are widely distributed in air, dust, fomites and normal flora.• Humans are relatively resistant.• Fungi are relatively nonpathogenic.• Of the 100,000 fungal species, only 300 have been linked to disease in animals.• Fungi are the most common plant pathogens.• Human mycoses are caused by true fungal pathogens and opportunistic

pathogens.


Wednesday 3 May 2023 4Nandyala Venkateshwarlu SVS Medial College Mahabubnagar, Telangana India

Fungi


Fungal infections1. Superficial 2. Cutaneous3. Subcutaneous 4. Systemic 5. Opportunistic



Systemic fungal infections • May result from breathing in the spores of fungi, which normally live in the soil or

rotting vegetation or as opportunistic disease in immune compromised individuals. A. Inhaled fungal infection (By True pathogens)• Although uncommon, some may infect healthy individuals. The result is most often

a mild infection and long lasting resistance to further attack, but occasionally these infections are more serious and chronic (especially in the immune suppressed). The organisms causing systemic fungal infections include:

1. Histoplasmosis2. Coccidioidomycosis (North and South America).3. Blasomycosis4. Para-coccidiodomycosis



Systemic fungal infections B. Fungal infections of intermediate virulence

1. Sporothrex schenckii – Sporotrichosis 2. Genera dermatophytes [Microsporan, Trichophoton, Epidedermophyton]



Systemic fungal infections C. Opportunistic infections• Other systemic mycoses only infect those who are already sick or with an

immunodeficiency disorder i.e. they are ‘opportunists’. Repeated infection may occur. Risks for systemic mycoses include:

1. Serious illness and debility 2. Cancer or leukemia 3. Diabetes mellitus 4. Transplant 5. Massive doses of antibiotics 6. Parenteral nutrition 7. Drug addiction 8. Infection with human immunodeficiency virus (HIV)



Systemic fungal infections C. Opportunistic infectionsOpportunistic fungal infections include:

1. Aspergillosis (found everywhere) 2. Zygomycosis 3. Cryptococcosis (where there are pigeon droppings) 4. Trichosporon beigelii 5. Pseudallescheria boydii



Opportunistic fungal diseases• Opportunistic mycosis a fungal or fungus-like disease occurring in an animal /

human’s with a compromised immune system. • Opportunistic organisms are normal resident flora that become pathogenic only

when the host's immune defences are altered, as in immunosuppressive therapy, in a chronic disease, such as diabetes mellitus, or during steroid or antibacterial therapy that upsets the balance of bacterial flora in the body.



Systemic fungal infections – clinical suspicion

1. Fever with severe neutropenia or immunosuppresion2. Fever resistant to broad spectrum antibiotics in neutropenic patient3. Symptoms and signs of new resistant or progressive lower

respiratory tract infection4. Prolonged severe lymphocytopenia in chronic graft versus host

disease [GVHD] and immunosuppression5. Periorbital or maxillary swelling with tenderness



Systemic fungal infections – clinical suspicion

6. Palatal necrosis or perforation7. Features of focal neurologic deficit or meningeal irritation

with fever8. Unexplained mental changes with fever9. Papular or nodular skin lesions10.Intra-ocular evidence of systemic fungal infection



Systemic Fungal infections• The highest frequency of opportunistic fungal infections come in the following

order:1.Candidiasis2.Aspergillosis3.Cryptococcosis

• Candidiasis• Deep fungal infections• Mucormycosis



Transmission • Portal of entry

– primary mycoses – respiratory portal; inhaled spores– subcutaneous - inoculated skin; trauma– cutaneous and superficial – contamination of skin surface

• Virulence factors – thermal dimorphism, toxin production, capsules and adhesion factors, hydrolytic enzymes, inflammatory stimulants

• Antifungal defenses are the integrity of the barriers and respiratory cilia.• Most important defenses are cell-mediated immunity, phagocytosis, and

inflammation.• Long-term immunity can only develop for some.



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Diagnosis of invasive fungal infections

• High degree of suspicion depending upon 1. The risk factor2. Clinical situation3. Immune status of the patient4. Pneumonia5. Sinusitis6. Radiological and histological diagnosis7. Microbiological serological abnormality


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1. Microscopy 2. Culture3. Serology4. Histopathology5. Imaging


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Microscopy 1. Readily available easy, simple and cheap2. Respiratory secretions like sputum, broncho-alveolar lavage [BAL]

fluid 3. Microscopy differentiate septate and nonseptate molds 4. A positive India ink preparation of CSF – cryptococcal meningitis


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Culture• Samples can be Blood, CSF, Urine, sputum, Intracath tip, Endo-

tracheal tube tip, • Automated cultures • Candida species is most common organism – can be contamination


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Serology• A variety of serological tests are available with different degree of

specificity and sensitivity are available for example…1. Detection of Cryptococcal polysaccharide antigen in serum and CSF.

Positivity is >90% as against India ink preparation – 70% Culture in CSF – 50%

2. Detection of Histoplasma antigen in urine and serum3. Detection of antibodies to Coccidoides immitis and Histoplasma

capsulatum in serum and CSF


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Serology• Serological markers – Galactomannan and (1,3)-β-D-glucan [BG]• For diagnosis of IPA [invasive pulmonary Aspergillosis] in patients

with neutropenia • Galactomannan is released from Aspergillosis during growth• Multiple tests to be done in order to lessen the false positive results• Sensitivity is much higher if respiratory secretions are used in stead

of serum


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Histopathology• Definitive • Stained with Periodic acid Schiff [PAS] stain, Gomri methenamine

silver or fluroscent stain, • Candida is seen in Gram’s stain • Evidence of inflammatory cells along with fungus is highly

diagnostic as it eleminates contaminants


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Imaging 1. Pulmonary fungal infections2. Fungal sinusitis3. Fungal meningitis4. Fungal IE5. Disseminated candidiasis


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Imaging HRCT Scan of chest is diagnostic of IPA – Presence of halo-crescent sign

– a localized ground glass appearance representing hemorrhagic infarction surrounds a nodule suggestive of IPA

Immunocompramized patient with a new neurologic feature [ headache – new persistent, seizures, stroke or meningitis – MRI/CT BRAIN


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Systemic anti-fungal drugs1. Polyenes [Amphotericin B deoxycholate]2. Azoles [Flucanazole etc.]3. Echinocandins


Classification of antifungal infection according to site 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.



Site of action


FLUCYTOSINE

IMIDAZOLES

TRIAZOLES

POLYENES

CANDINS

GRISEOFULVIN

OTHERS

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ANTI FUNGAL DRUGS MECHANISAM



Classification of antifungal drugs – according to chemical structures

A. ANTIBIOTICS Polyene: Amphotericin, Nystatin, Hamycin Heterocyclic benzofuran: GriseofulvinB. ANTIMETABOLITE : Flucytosine C. AZOLES

1. Imidazoles: Ketoconazole, clotrimazole, oxiconazole, miconazole,

2. Triazoles: Fluconazole, itraconazole, voriconazole,



Classification of antifungal drugs

D. ALLYLAMINES• Terbinafine, Butenafine

E. ECHINOCANDINS• Caspofungin, Anidulafungin, Micafungin

F. OTHER TOPICAL AGENTS• Tolnaftate, Undecyclinic acid, Benzoic acid



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Polyenes


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Antibiotics1. Amphotericin B2. Liposomal Amphotericin B [LAB] 3. Nystatin 4. Hamycin5. Natamycin 6. Griseofulvin


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Polyenes • Fundamental prototype [Amphotericin B] for 1. Aspergillosis 2. Cryptococcosis3. Systemic candidiasis 4. Histoplasmosis 5. Blastomycosis 6. Coccidiodomycosis7. Zygomycosis


Site of action • Several amphotericin B molecules bind to

ergosterol in the plasma membranes of sensitive fungal cells.

• There, they form pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antibiotic and the sterol.

• The pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death.



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Amphotericin B • Late 1950’s • Amphoterecin deoxylate • Fungicidal • Acts on ergosterol of the fungal cell wall membrane • 0.6 – 1 mg/kg/day • Broad specrtum • Significant nephrotoxicity • No oral


Amphotericin B- 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 – Amphotericin

• 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



Amphotericin B• 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:



Amphotericin B• 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 Nandyala Venkateshwarlu SVS Medial College Mahabubnagar,

Telangana India


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Amphotericin B • Intravenous infusion related reactions – fever, chills, nausea and

vomiting, hypotension and hypoxemia – 4-6 hours• Rapid infusion – life threatening hyperkalemia and arrhythmias • Shock • Should not be administered simultaneously with leukocytes as this

may precipitate pulmonary toxicity• Infusion related reactions can be reduced by infusing for 24 hours

continuously with normal saline


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Amphotericin B • Risk factors for nephrotoxicity 1. Male 2. Body weight greater than 90 kg3. C.K.D.4. Treatment with aminoglycosides and cyclosporine5. Dose of Amphotericin B > 35 mg/ day


Lipid formulations of Amphotericin B• Amphotericin B Lipid Complex

• Amphotericin B Colloidal Dispersion

• Liposomal Amphotericin B



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Amphotericin B Lipid Complex [ABLC]

• Amphotericin B Lipid Complex [ABLC]

• 35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids


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Amphotericin B Colloidal Dispersion [ ABCD]• Amphotericin B Colloidal

Dispersion [ABCD]

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


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Liposomal Amphotericin B [LAB]• Liposomal Amphotericin B

[LAB] ( Small unilamellar vesicles)• 10% AMB

incorporated in SUV made up of lecithin


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Major advantages of lipid amphotericin B

Milder acute reaction Can be used in intolerance to conventional preparationsLower nephrotoxicity & anemiaDeliver AMB to RES of liver spleen so useful in leshmania & immuno-

compromised

Can be used in higher doses

20 – 50 times costlier than Amphotericin B


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Antibiotics – Nystatin Obtained 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


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Antibiotics 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 aspergillus


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Antibiotics Natamycin:

Similar to nystatin, broad spectrum Used topically 1%, 3% ointmentFusarium 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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Griseofuvin • 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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Griseofulvin


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Griseofulvin • Adverse events:

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


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Griseofulvin • 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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Griseofulvin • 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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Imidazoles


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Triazole Allymines


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β-1-3-Glucan symthase inhibitors


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GrisofulvinFlucytosine


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Azoles • Azoles:

• Synthetic antifungals• Broad spectrum • Fungistatic or fungicidal depending on concentration of

drug • Most commonly used • Classified as imidazoles & triazoles


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Azoles • 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:


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Micanazole 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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Ketaconazole – First orally effective broad spectrum antifungal – Effective against

• Dermatophytosis, Deep mycosis , Candidiasis

• Most toxic among azoles so not used so much triazoles preferred

• Acidic environment favours absorption so orange juice increases absorption and proton pump inhibitors decrease absorption.

• But saturation of metabolism occurs shortly which prolongs the its half life and permits once daily dosing , since small amount of drug appears in urine.


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Ketaconazole – 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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Ketaconazole – Adverse effects • 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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Ketaconazole – Drug reactions


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Ketaconazole • Dermatophytosis: concentrated in stratum corneum • Monilial vaginitis : 5-7 days • Systemic mycosis: blastomycosis, histoplasmosis, coccidiodomycosis

• Less efficacy than AMB & slower response• ↓Efficacy in immuno-compromized and meningitis• Lower toxicity than AMB higher than triazoles

• High dose used in Cushing’s 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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Fluconazole 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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Fluconazole Adverse effects

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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Fluconazole – 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


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Itraconazole – 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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Itraconazole 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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Itraconazole – Uses • Capsule form of drug better absorbed in fed state , invasive

aspergillosis outside the CNS• In treating deep mycosis two 100 mg capsules given twice daily with

food , divided doses increase the AUC • WHY PULSE THERAPY: retention of active drug in nail keratin . Daily

therapy preferred for recurring infection. • Terbinbafine 250 mg OD better in onychomycosis than itraconazole


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Itraconazole – Adverse effects • 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

- 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


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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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Voriconazole • 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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Posaconazole • Broad spectrum antifungal 1. Candida2. Aspergillosis 3. Zygomycetes 4. Fusarium • Oral preparation• Variable bioavailabilty • Better after food


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Posaconazole • Prophylaxis against aspergillosis [200mg t.i.d PO]• Prophylaxis against candidiasis [ 100 – 400 mg PO q12 –

q24h]; in severely immunocompramized individuals • Treatment of oropharyngeal candidiasis refractory to

flucanazole and itraconazole • In combination therapy in Mucor mycosis – 400 mg b.i.d PO• As a salvage therapy in severely immuno-compramized

patients in refractory patients with aspergillosis


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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 daysNegligible effect on CYP450


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Terbinafine 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


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Spectrum of azoles


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Echinocandins • New parenteral antifungal agents• Mechanism of action: Inhibits B (1,3) D glucan an

essential component of fungal cell wall1. Capsofungin 2. Micafungin3. Anidulafungin


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Echinocandins Pharmacokinetics

• No renal or hepatic toxicity • Do not cross B.B.B • Fungicidal against Candida albicans and non-albicans

Candida species • Fungistatic against Aspergillus species • Greatest use against Candida infection• No cross resistance with Azoles


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Capsofungin acetate Semisynthetic antifungalMOA: Inhibits B (1,3) D glucan an essential component of fungal cell

wall Uses: Treatment of 1. Refractory Invasive aspergillosis 2. Candidiasis (esophageal, intraperitoneal), 3. Empiric therapy in neutropenic patients


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Capsofungin acetate Pharmacokinetics: It is metabolized in liver and is slowly degraded

by hydrolysis and N-acetylation

Dose: IV 70 mg slowly [Loading dose] then 50 mg daily infusion Dose should be reduced to 35 mg/day in hepatic dysfunction Dose adjustment is not advised in renal insufficiency


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Capsofungin acetate Adverse events: safe medicine

1. Flushing rashes, 2. Nausea and/or vomiting, 3. Phlebitis, 4. Elevation of transaminases5. Histamine like reaction

Drug – Drug interaction with Rifampicin, Anticonvulsants, Tarcolimus, Cyclosporine, Protease inhibitors, NNRTI


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Micafungin • Approved for treatment of esophageal candidiasis•Prophylaxis in patients with hematopoetic stem cell transplant [HSCT] •Simultaneous administration of Micafungin and Cyclosporin do not require any dose adjusted for either drug •As or more effacacious as flucanazole•Indicated in deep seated Aspergillosis and candidiasis


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Anidulafungin 1. Indicated in candidemia2. Candida esophagitis 3. Candida peritonitis and deep seated candidiasis4. Refractory to flucanazole 5. H I V positive patients


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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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5 flucytosine


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Amphotericin B & 5 flucytosine

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


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Amphotericine and 5 flucytosine combination

• 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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Systemic administration

Topical

Griseofulvin Ketoconazole

Ketoconazole Miconazole

Fluconazole Clotrimazole

Itraconazole Terbinafine

Terbinafine Nystatin


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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


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Source 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


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Therapeutic options for invasive Cadidiasis

• Flucanazole is DOC for empirical therapy in patients with candidemia without sepsis or septic shock or recent exposure to azoles

• Amphotericin B or Capsofungin in patients with previous exposure to azoles and in patients with Neutropenia

• In severe sepsis and septic shock Capsofungin is DOC.• Microbiologically documented candidiasis [ C. Albicans, C. Tropicalis,

C. Parapsiliosis] Flucanazole is DOC• C glabrata or C krusei – Capsofungin or Amphorecin B are DOC


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Therapeutic options for invasive Aspergillosis

• Primary therapy – Voriconazole • Salvage therapy – Capsofungin, Voriconazole [if not used earlier]

liposomal Amphoterecin B – refractory cases • Combination therapy – Capsofungin + Voriconazole or liposomal

Amphoterecin B – critically ill patients • Empirical therapy – Amphotericin B deoxylate – patients with

neutropenia and persistent fever


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Therapeutic options for cryptococcosis

• CNS /disseminated Cryptococcosis in HIV patients: Amphotericin B 0.7-1.0 mg/KG/ + Flucytosine 100mg /KG/day PO for 2 weeks; followed by Flucanazole or Itraconazole 400mg PO for 8 weeks; followed by secondary prophylaxis with 200 mg of Flucanazole. Flucanazole prophylaxis is discontinued after starting of HAART, Symptom free, and CD count > 200/cu.mm.

• Asymptomatic or mild disease: Flucanazole 400mg/d or Itraconazole 400 mg/d for 6 – 12 months followed by secondary prophylaxis


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Therapeutic options for Mucor mycosis

• Surgical resection and debridement • Followed by high doses of Liposomal Amphotericin B 5-10 mg/KG/d

or Amphotricin B deoxylate 0.7-1.0mg/KG/day for 6 months• In patients who can not tolerate are refractory – Poscanazole 200 mg

PO four times a day • Prognosis is poor


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INDICATION PRIMARY THERAPY SECONDARY THERAPYDisseminated candidiasis Flucanazole or Voricanazole Amphotericin B, Capsofungin Invasive Aspergillosis Voricanazole Itraconazole, Amphotericin B,

Capsofungin, Poscanazole CNS Apergillosis Voricanazole Amphotericin BCryptococcal meningitis Liposomal Amphotericin B +

Flucytosin Flucanazole

Mucor mycosisPersistent neutropenic patient not responding to antibiotics

Amphotericin B, Capsofungin Poscanizole, Amphotericin B


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Antifungal prophylaxis NAME of DRUG DOSE for PROPHYLAXIS ROUTE of ADMINISTRATION

Flucanazole 50 – 400 mg / day PO

Itraconizole 10 mg / KG/ day PO

Voriconazole 200 mg B.I.D. PO

Posaconazole 200 mg T.I.D. PO

Micafungin 50 mg/day Intravenous

Capsofungin 50 mg/ day Intravenous


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Think a while • Each patient is a Book !• Each Day is a Learning Opportunity!!• Learning has More Relevance

today than ever !!!Wards are temples of MEDICINE


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Take home message

Eyes see only what brain

thinks

Common things are common

Think “horses” not “zebras”

Analysis improves

patient care


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systemic fungal infections venkat

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