fungal infections

PEBC

fungals infections

dermatophyte (tinea infections)

• tinea barbae = on beard

  • on coarse beard hair

  • spread by animals to farm workers

  • unilateral lesions = scaly patches, follicular pustules

• tinea capitis = scalp

  • scalp hair follicles and adjacent skin

  • children = common

  • also common in low socioeconomic and crowded environments

  • through direct contact, animals, contaminated clothing

  • annular patch of scaling and itchy skin along with hair loss

• tinea corporis = ringworm

  • trunk or limbs excluding face, hands, feet, groin

  • flat, circular scaly spot with central clear portion with raised red border

  • common in athletes with skin-to-skin contact (wrestlers)

• tinea cruris = jock itch

  • groin area

  • scrotum and penis are spared

  • in men during summer months

  • often a reservoir for infection found on feet

  • bilateral, scaly, red-brown centers with clearly defined raised borders

• tinea pedia = athletes foot

  • white scaling between toes, skin maceration, odour present

  • late-teens, adults

  • in moist environments (swimming pools, occluded footwear and excessive sweating)

• tinea mannum = hand ringworm

  • not common

  • dorsal surface of hands

dermatophyte/ tinea infection treatment

non pharm:

• keep skin clean and dry to discourage fungal proliferation

• wear loose fitting clothing for ventilation

• nonmedicated powders can be used to absorb excess perspiration BUT AVOID CORNSTARCH b/c it promotes fungal proliferation

  • use talc with caution around neonates/ infants or those w respiratory conditions

topical treatment = clotrimazole 1%, ketoconazole 2%, Miconazole 2%, terbinafine 1%, ciclopirox 1%

• azoles:

  • tinea cruris (jock itch) = 2-4 weeks

  • corporis (ringworm), pedis (athletes foot) = 4 weeks

• terbinafine:

  • tinea cruris (jock itch) and corporis (ringworm) = 1 week

• tinea pedis = treatment should continue for at least 1 week after symptom resolution

candidiasis

• fungal infection or mycosis due to Candida sp

• most common cause is Candida albicans

• can cause oral or esophageal candidiasis

diagnosis:

• history and physical examination

• can do biopsy and endoscopy

oral candidiasis

Microbiology:

• Candida albicans = 70-80%

• non - albicans = 17% → increases to 50% in immunocompromised pts (c. glabrata, c. tropicalis, c. krusei, c. guilliermondi, c. paeapsilosis)

clinical presentation:

• pseudomembranous with “cottage cheese” appearance = thrush

• soft white plaques overlying areas of erythema (red) —> can be removed with vigorous rubbing but leave red/bleeding sites

• lesions on tongue, gums, throat

symptoms:

• cotton mouth

• loss of taste

• may have pain on eating and swallowing

• burning sensation on tongue

• metallic taste

• dysphagia

esophageal candidiasis

clinical presentation:

• extension of oral but esophagus can be the only site involved: distal 2/3 of esophagus (the lower part) rather than the proximal

symptoms:

• dysphagia (difficulty swallowing)

• odynophagia (pain on swallowing) = HALLMARK

• retrosternal chest pain

• epigastric pain (rare)

signs:

• fever

• plaques (can be ulcerated or edematous)

• advanced cases present with narrowing of lumen

local risk factors (for candida)

systemic risk factors (candida)

drug causes (candidiasis)

• steroids

• xerostomia inducing agents:

  • anticholinergics

  • radiation

• broad spectrum antibiotics = alter normal flora

  • decreased environmental and nutritional competition for Candida causes candidal overgrowth

• chemotherapy = altered rate of mucosal regeneration, xerostomia, neutropenia

• PPIs = inhibition of gastric acid allows overgrowth, decreased salivation

goals of therapy (candida)

1. cure fungal infections: eliminate signs and symptoms

2. prevent complications related to fungal infection

3. minimize adverse effects and manage drug-drug interactions

treatment (candidiasis)

topical agents:

• 1st line in uncomplicated oral candidiasis with no underlying conditions

• include oral rinses (suspensions) and troches (lozenges)

• need to be administered frequently with short contact time

• need enough saliva to dissolve troches (can be issue in dry mouths)

• irritating

suspensions

• can be better for patients with dry mouth but the contact time is short

systemic agents:

• needed for for esophageal candidiasis

• trouble swallowing = give IV formulations

• mucocutaneous candidiasis = fungal infection on mucous membranes:

  • Imidazole and triazole antifungals: fluconazole (IV, PO), itraconazole (po), voriconazole (IV, PO), Posaconazole (po)

• effective and more convenient and better tolerated vs topical

• preferred in:

  • patients at high risk for disseminated systemic or invasive candidiasis (ex. neutropenia due to leukemia and bone marrow transplantation)

  • who cant tolerate topical agents due to dry mouth or swallowing issues

  • refractory to topical treatment

  • severe odynophagia

treatment options (oropharyngeal candidiasis)

treatment options (esophageal candidiasis)

azoles

• 2 classes:

  • Imidazoles = 2-N azole ring

    • clotrimazole, ketoconazole

  • Triazoles = 3-N azole ring, better pharmacokinetic properties

    • fluconazole = older

    • itraconazole = older

    • voriconazole, posaconazole

• voriconazole, isavuconazole and posaconazole = newer and made to:

  • overcome limited efficacy of fluconazole against Aspergillus and other non-albicans Candida sp

  • improve absorption, tolerability and safety vs itraconazole

• interactions:

  • CYP3A4 inhibitors = itraconazole, posaconazole, voriconazole

  • CYP3A4, 2C9/19 = Fluconazole

    • increased: cyclosporines, tacrolimus, sirolimus, CCBs, most BDZ, statins, steroids, warfarin, rifampin

  • itraconazole and posaconazole = inhibitors of PgP (EFFLUX PUMP)

  • CYP450 inducers (CBZ, Phenytoin, Phenobarbital, rifampin and rifabutin) = decreases azoles

• s/e:

  • N/V

  • LFTs increase

  • gynecomastia (at high doses, longer duration except fluconazole)

fluconazole

• not affected by food or GI pH

• dose adjust for renal dysfunction

• Hepatic CYP2C9 = metabolism

• penetrates into body fluids and CSF

• s/e:

  • GI upset

  • hepatitis

  • increased LFTs

• interactions (least drug interacting azole) = CYP3A4 / 2C9/ 19 inhibitor

  • rifampin = decreases its efficacy

  • increases toxicity of cyclosporin, contraceptives, prednisone, sulfonylureas, theophylline and warfarin

itraconazole

• capsule= best absorbed with food

• oral solution = best absorbed on empty stomach

• metabolized by liver

• interactions= Strong inhibitor of CYP3A4

• does NOT penetrate CSF

• s/e:

  • N/V

  • hepatotoxicity

  • Congestive heart failure , pulmonary edema = Black box warning!

voriconazole

• more efficacious vs fluconazole for invasive aspergillosis and non-albicans Candida

• oral= tablet or solution

• metabolized in liver by CYP2C19, 3A4 and less 2C9

• affected by CYP2C19 genetic variability (19% asians and 2% caucasians are poor metbaolizers)

• interactions:

  • sirolimus, tacrolimus, cyclosporine, midazolam, ributamin/rifampin, ergots

  • levels are decreased by: CBZ, Rifampin, barbiturats and phenytoin

• s/e = mainly eye disturbances and hepatitis

  • visual field disturbances = altered perception, acuity, photophobia

  • visual and auditory hallucinations

  • hepatitis

posaconazole

• only as a suspension for oral use

• for invasive aspergillosis prevention and treatment

• absorption is increased by food, esp fatty meals

• not affected by antacids

• metabolized by liver

• moderate inhibitor of CYP3A4

• s/e:

  • Diarrhea, headache, nausea

ketoconazole

• least effective of all azoles due to poor bioavailability

• low pH is needed for absorption = acid suppression decreases absorption

• not used systemically bc = greater toxicity, lower efficacy, drug interactions

  • replaced by fluconazole and itraconazole

• interactions = most interacting of ALL azoles —> potent 3A4 inhibitor

• s/e:

  • gynecomastia

  • N/V

  • abdominal pain

  • itching

  • headache

  • hepatotoxicity

  • endocrine effects

  • lichenoid mucosa reactions

echinocandins

• include: Caspofungin and Micafungin

• as efficacious as fluconazole, amphotericin B or lipid amphotericin B against candidemia

• resistance is infrequent

• only available as parenteral formulations

• effective against candida and Aspergillus

• drug interactions = none are major inducers, substrates or inhibitors of CYP450 or PgP

caspofungin and micafungin

• used in combo w azoles and polyenes (these are echinocandins)

• can be used more in immunocompromised patients

• narrow spectrum of activity

• Fungicidal against Candida spp

• s/e:

  • very few toxic s/e bc their MOA is not found in mammalian cells

  • increase LFTs

  • HA

  • histamine release (rash)

  • phlebitis (due to IV administration)

  • fever

• advantages:

  • extremely safe antifungals, relative to other antifungal classes

  • do not need dose adjustments

• disadvantages:

  • high cost

  • IV

nystatin

• polyene antifungal

• only non-absorbable topical form

• effective in oral candidiasis but less effective vs oral azoles

• produces channels through fungal membranes = leakage of essential cell contents

amphotericin b

• widest spectrum of activity among all antifungals

• polyene antifungal

• lipid based formulation = better safety profile (less nephrotoxic) and better PK parameters

• s/e:

  • N/V

  • diarrhea

  • infusion related s/e

• monitor electrolytes due to occurrence of hypokalemia, hypomagnesia, hypophosphatemia

• monitor renal function = nephrotoxic drug