Fungal Infections & Treatment

• Human fungal infections have increased due to advances in surgery, cancer treatment, critical care, broad-spectrum antimicrobials, and the HIV epidemic.
• Fungal infections are harder to treat than bacterial infections because fungal organisms grow slowly.
• Fungal infections often occur in tissues poorly penetrated by antimicrobial agents - devitalized or avascular tissues.
• Fungal infection therapy usually requires prolonged treatment.
• Superficial fungal infections involve cutaneous (skin, nails, hair) and mucous membrane (oropharynx, vagina) surfaces.
• Deepseated/disseminated fungal infections, caused by dimorphic fungi and yeasts like Cryptococcus neoformans and Candida spp., respond to systemic agents.
• Responding systemic agents include amphotericin B (a polyene), flucytosine (a pyrimidine antimetabolite), azoles (ketoconazole, fluconazole, itraconazole, voriconazole), and caspofungin (an echinocandin).

Types of Fungal Infections

• Systemic: candidiasis, cryptococcal meningitis-endocarditis, cerebral and pulmonary aspergillosis, internal organs, inhalation of saprophytes-Aspergillosis.
• Subcutaneous: bone, connective tissue, skin, and subcutaneous tissues.
• Cutaneous: epidermis, hair, nails-dermatophytoses-Tinea (general name).
• Superficial: hair and epidermis.

Antifungal Classifications

• Antifungals damaging permeability of the cell membrane include Imidazoles, Triazoles, Allylamines, Morpholines, Thiocarbamates, Substituted pyridones, and Polyene antibiotics.
• Imidazoles: Bifonazole, Clotrimazole, Econazole, Ketoconazole, Miconazole.
• Triazoles: Fluconazole, Itraconazole, Voriconazole.
• Allylamines: Terbinafine, Naftifine.
• Morpholines: Amorolfine.
• Thiocarbamates: Tolciclate, Tolnaftate.
• Substituted pyridones: Ciclopirox.
• Polyene antibiotics: Amphotericin B, Nystatin.
• Antifungals inhibiting chitin synthesis in the cell wall: Caspofungin, Griseofulvin.
• Antifungals inhibiting synthesis of nucleic acids: Flucytosine.

Griseofulvin

• It is an antifungal isolated from Penicillium griseofulvum in 1939, used orally, and is fungistatic
• It binds to tubulin protein, inhibiting cell division and DNA replication
• It treats fungal infections of nails, scalp, and skin when antifungal creams don't work, and is taken by mouth

Polyenes

• Changes membrane permeability and leads to leakage of intercellular components
• Examples include Amphotericin and Nystatin
• May be -static, -cidal, and is dose dependant

Amphotericin (Ambisome IV)

• Used intravenously to treat meningitis
• Intravenous administration of amphotericin B is the preferred treatment for mucormycosis
• Used for initial treatment of cryptococcal meningitis, severe or rapidly progressing histoplasmosis, blastomycosis, and coccidioidomycosis.

Nystatin (Mikostatin, Fungostatin)

• Too toxic to be used systemically
• Only topical treatments of superficial infections caused by C. albicans
• Infections commonly treated: oral candidiasis (thrush), mild esophageal candidiasis, and vaginitis.

Echinocandins

• Cyclic peptides that carry long lipophilic side chains
• Cause the cell wall to weaken and inhibit synthesis of B-glucan in the fungal cell wall (B-1,3-glucan synthase inhibition)
• Capsofungin is an example that received FDA approval for use in Aspergillosis and Candida infections and is administered IV
• The only antifungal found in the last 30 years that acts with a different mechanism.

Antifungal Azoles

• Synthetic drugs with broad-spectrum fungistatic activity, divided into two groups:
• Older imidazole agents (clotrimazole, ketoconazole, miconazole) with two nitrogens in the five-member azole nucleus
• Newer triazole compounds (fluconazole, itraconazole, voriconazole) with three nitrogens in the azole nucleus
• Synthetic antifungals inhibits the synthesis of ergosterol which is a precursor of fungal cells

Clotrimazole (Canesten cream, imazol cream)

• An Imidazole
• Local use antibiotic
• Treats vaginal yeast infections, oral thrush, tinea versicolor, and types of ringworm including athlete's foot and jock itch and can be taken orally or applied to the skin or vagina as a cream.

Ketoconazole (Nizoral)

• Can be absorbed orally, but requires an acidic gastric environment
• Useful in treating cutaneous and mucous membrane dermatophyte and yeast infections
• Replaced by newer triazoles for serious Candida infections and disseminated mycoses
• Effective on thrush; fluconazole is superior for refractory thrush
• Treats widespread dermatophyte infections on skin surfaces easily with oral ketoconazole.

Butoconazole

• An imidazole antifungal and is used in gynecology
• Administered as a vaginal cream.

Econazole

• Treats skin infections like athlete's foot, tinea, pityriasis versicolor, ringworm, and jock itch
• Sold as Ecostatin in Canada as vaginal ovules to treat vaginal thrush

Isoconazole (Travogen sprey, Oly sprey)

• An azole antifungal drug and can inhibit gram-positive bacteria
• Similar effectiveness to clotrimazole for foot and vaginal infections
• Isoconazole nitrate may be used with corticosteroid diflucortolone to increase its bioavailability.

Miconazole (Nidazol vaginal tablet, Pres-Mant gel, Noe-pentoran vaginal ovul)

• Sold under the brand name Monistat
• Treats ringworm, pityriasis versicolor, and yeast infections of the skin or vagina as a cream or ointment.
• Treats ring worm of the body, groin (jock itch),and feet(athlete's foot)

Oxiconazole (Oceral cream, sprey)

• Market trade names include Oxistat in the US, Oxizole in Canada
• Antifungal medication typically administered in a cream or lotion.
• Treats skin infections like athlete's foot, jock itch, and ringworm.
• Treats skin rash known as tinea versicolor, caused by systemic yeast overgrowth (Candida spp.).

Tioconazole

• An antifungal medication of the imidazole class used to treat infections caused by a fungus or yeast.
• Marketed under the brand names Trosyd and Gyno-Trosyd.
• Treats women's vaginal yeast infections in one-day doses.
• Treats ringworm, jock itch, athlete's foot, and tinea versicolor or "sun fungus".

Fluconazole (Candimax, Flucan, Fungan; kandizol, Triflucan, zolax, Fluzamed)

• Can be taken orally or IV (water soluble)
• Does not require an acidic environment
• About 80-90% of an orally administered dose is absorbed
• Very effective in the treatment of infections with most Candida spp
• Thrush in end-stage AIDS patients, often refractory to nystatin, clotrimazole, and ketoconazole
• Can usually be suppressed with oral flucanazole
• AIDS patients with esophageal candidiasis respond to fluconazole
• Used for vaginal candidiasis and candida urinary tract infections

Itraconazole (Funit, Itraspor, Sporanox)

• Lipophilic and water insoluble and a low gastric pH for absorption
• Oral bioavailability is variable (20 to 60%)
• Useful in the long-term suppressive treatment of disseminated histoplasmosis in AIDS.

Voriconazole (Vorzol, vorigen, vfend)

• Treats invasive aspergillosis, candidiasis, and fungal infections caused by Scedosporium and Fusarium species.
• Occurs in immunocompromised patients, including people undergoing allogeneic bone marrow transplant (BMT) or hematologic cancers, or organ transplants
• Acts more powerfully against Aspergillus and candida than itraconazole

Flucytosine

• Analog of cytosine
• Antineoplastic agent
• Converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase
• The active metabolite 5-fluorouracil interferes with fungal DNA synthesis, inhibiting thymidylate synthetase.
• Metabolites incorporated into fungal RNA inhibit protein synthesis
• Significant antifungal activity against Candida spp. and fungal organisms responsible for chromomycosis.

Allylamines

• Reversible noncompetitive inhibitors of the fungal enzyme squalene monooxygenase.
• Diminishes fungal cell membrane synthesis and function
• Exhibit fungicidal activity against dermatophytes and fungistatic activity against yeasts.
• Terbinafine(Lamisil) is available for topical and systemic use to treat dermatophyte skin and nail infections.

Tolnaftate

• Inhibitor of scualen epoksidase
• Less effective than azoles when used to treat tinea pedis (athlete's foot)
• Effective with ringworm; especially when passed from pets to humans

Haloprogin

• Previously used in 1% topical creams as an antifungal agent
• Marketed over-the-counter to treat tinea infections of the skin.
• Should be protected from light
• The mechanism of action is unknown

Undecylenic Acid

• Active ingredient in medications for skin infections
• Relieves itching, burning, and irritation associated with skin problems
• Treats fungal skin infections such as athlete's foot, ringworm, tinea cruris, or other generalized infections by Candida albicans
• If used for tinea cruris, leads to extreme burning
• Precursor to antidandruff shampoos and antimicrobial powders

Antihelminthic Drugs

• Tapeworms (cestodes) use Niclosamide or Praziquantel or Albendazole
• Roundworms (nematodes):
• Enterobius vermicularis (pinworm): Mebendazole or Pyrantel
• Ascaris lumbricoides: Mebendazole or Pyrantel
• Trichuris trichiura (whipworm): Mebendazole or Albendazole
• Trichinella spiralis (trichinellosis): Mebendazole and Thiabendazole OR Thiabendazole
• Strongyloides stercoralis: Mebendazole or Pyrantel
• Necator americanus (hookworm): Mebendazole, Pyrantel, or Albendazole
• Ancylostoma duodenale: Ivermectin of Diethylcarbamazine
• Onchocerca volvulus (Onchocercosis)
• Wuchereria bancrofti (Elephantiasis)
• Flukes (trematodes): schistszoma (Schistozomes) use Praziquantel

Mebendazole (Vermazol)

• Blocks glucose uptake by nematodes
• Causes mild Gl disturbances
• Not used in pregnancy or in kids under 2

Albendazole

• Similar to Mebendazole

Thiabendazole

• Inhibits cellular enzymes of susceptible helminths
• Leads to gastrointestinal, neurological, and hypersensitivity reactions, liver damage, and crystallauria

Levamisole

• Paralyzes the musculature of sensitive nematodes, which are expelled by normal peristalsis
• May cause abdominal pain, nausea, vomiting, headache, and dizziness.

Niclosamide

• Blocks glucose uptake by intestinal tapeworms
• May cause some mild Gl symptoms

Piperazine

• Causes hypersensitivity reactions, neurological symptoms ("worm wobble," neurotoxicity of piperazine) and may precipitate epilepsy

Praziquantel

• Paralyzes both adult worms and larvae.
• May cause nausea, headache, dizziness, drowsiness and cures with a single dose (or divided doses in one day).

Pyrantel

• Depolarises neuromuscular junctions of susceptible nematodes that are expelled in the feces
• Gl disturbance, headache, dizziness, drowsiness, and insomnia may be induced by this drug

Insecticides

• Chlorphenothane (DDT – Dichlor-Diphenyl-Trichlorethan) kills insects after absorption of a small amount, e.g., foot contact.
• Effects of DDT includes nervous system damage and seizures
• DDT causes acute neurotoxicity only after absorption of very large amounts
• DDT is chemically stable and degraded in the environment and body at extremely slow rates
• It accumulates in fat tissues
• Banned in many countries to prevent accumulating in food chains to alarming levels