med chem of antifungals Flashcards
overview of fungi
Diverse group of eukaryotes** (> 1.5 million species): rigid cell wall, require organic compounds for both carbon and energy sources, obtain nutrients by absorption, live off decaying matter (saprophytes) or living matter (parasites)
Generally harmless for humans: relatively few are human pathogens (100’s), Most cannot infect humans with normal immune system
Two broad groups:
-Yeast
-Mold (mould)
increasing fungal infections
Parallels increase in number of people who:
-Have immunosuppressive infections
-Are taking immunosuppressive drugs
-Use implanted medical devices
Four species account for ~90% of deaths: Cryptococcus, Candida, Aspergillus, Pneumocystis
two broad groups of fungi
Yeast: Grow as single cells, Divide asexually by budding (fission)
Mold: Filamentous multicellular aggregates (hyphae), Hyphae grow by elongation at their tips, Usually separated into cell-like units by crosswalls called septa
dimorphic fungi
Grow as hyphae at room temperature
Grow as yeast in human tissue or on media at 37 C
Conversion to yeast form appears to be necessary for pathogenesis
characteristics of pathogenic fungi
Able to grow at high temperatures
Able to reach target tissues
-Dissemination in air (spores or similar)
-Penetration of host barriers
-Dissemination in body -Ability to change morphology is key, Many fungal pathogens are thermally dimorphic
Able to digest and absorb components of human tissues
Able to withstand/evade immune system
sporulation
Reproduction and spread in the environment
Source of infection
classification of fungal infections
True vs opportunistic
-True: cutaneous infective, subQ infective or systemic infective
Superficial and cutaneous - diseases are generally cosmetic, not life-threatening
Subcutaneous - fungi are generally implanted in skin, fungal growth produces a lesion
Systemic or invasive - Fungi have invaded the deep tissues, Can be self limiting or cause severe disease with high mortality rates
superficial and cutaneous infections
Dermatophytosis
-Classic skin and hair infections (ringworm, athlete’s foot, jock itch, etc.)
-Involve 3 genera of mold that grow on keratin on a living host (Epidermophyton, Trichophyton, and Microsporum)
-Cause a series of conditions referred to as tineas
—Tinea capitis = ringworm of the scalp
—Tinea pedis = athlete’s foot
Onchomycosis
-refers to non-dermatophyte nail infections or to any fungal nail infection caused by any fungus
systemic invasive infections
Examples: Coccidioides, Histoplasma, Blastomyces
Usually begin in lung – asymptomatic, influenza- like, or pneumonia
May disseminate to internal tissues or organs
-Blastomyces – bone, skin, joints
-Histoplasma – gastrointestinal tract, adrenals, bone and skin
Usually asymptomatic and self limiting, but may be severe and life threatening
Immune response is cell mediated
Infection is not communicable
Geographically restricted (endemic fungi)
histoplasmosis
Caused by dimorphic endemic fungi** Histoplasma capsulatum var. capsulatum Bat or bird droppings Spores! Lung is most frequent site of infection All stages of this disease may mimic tuberculosis People at risk for disseminated disease -Immunosuppressed individuals -children under 2 years old -elderly
blastomycosis
Caused by Blastomyces dermatitidis
-Endemic dimorphic fungi
-survives in soil that contains organic debris (rotting wood, animal droppings, plant material)
-infects people collecting firewood, tearing down old buildings, etc.
1-2 cases per 100,000 in endemic areas
50% of primary infections are asymptomatic
Acute pulmonary disease indistinguishable from bacterial pneumonia
Permanent lung damage with chronic disease
Mortality rate is about 5%
Coccidioidomycosis
Dimorphic fungus Coccidioides immitis
Endemic** in southwest US
Infection begins in lungs after inhaling spores
50% of infections are asymptomatic
Symptoms are flu-like
Severe pulmonary disease may develop in HIV-infected persons
Opportunistic fungal infections
Not considered true pathogens - do not cause disease in immunocompetent people; low virulence
Most common: Candida, Cryptococcus, Pneumocyctis, Aspergillus, Mucomorales
Risk factors: immunosuppression, major burn wounds or trauma, central venous catheters, broad-spectrum antibiotics, Diabetes, renal insufficiency requiring dialysis
Candidiasis
Caused by Candida albicans and other species of Candida
Classified as a yeast
Part of the normal human flora
Occurs when: members of the normal flora are suppressed, host immune response is diminished, especially neutrophil function
Can be localized to mucous membrane or may be invasive
-Candidemia – blood stream infection
-visceral infections
scope of the problem
Most common fungal pathogens - 8 cases per 100,000 in the general population
75% of women have at least one bout of vulvovaginal candidiasis (VVC)
> 90% of people infected with HIV who are not receiving therapy develop oropharyngeal candidiasis
4th most common bloodstream infection among hospitalized patients in the U.S.
diseases caused by candida
Can infect healthy and immunocompromised people
Cutaneous candidiasis
-diaper rash, jock itch, athlete’s foot
-key factor: prolonged exposure of normally dry skin to moisture
Esophagitis - HIV patients
Onchomycosis (nail)
Oropharyngeal (thrush)
Vulvovaginitis: Women treated with broad-spectrum antibiotics, Pregnancy, Diabetes
Candidemia and invasive (Systemic) infections
-Not typically diseases of healthy individuals
-Can involve virtually any organ
-Mortality ranges from 30-40%
-Responsible for the largest number of deaths from fungal infections
Most Candida infections are mucocutaneous and do not cause mortality
aspergillosis
Large spectrum of diseases caused by many species of Aspergillus
Hyphal growth
Three disease states:
-Opportunistic infections (inhaled into the respiratory tract, characterized by angioinvasion, hemorrhage and tissue infarction, especially in the lungs)
-Allergic states
-Toxicoses** - some species produce toxins (aflatoxin)
Risk factors
-Prolonged granulocytopenia & organ transplant
-Not HIV
High mortality rate
Cryptococcosis
Most cases caused by Cryptococcus neoformans
-Exists only as a yeast
-Found in soil worldwide - usually with bird droppings (especially pigeons)
-Cryptococcus gattii outbreak in NW
Wide polysaccharide capsule*
Acquired by inhalation
Presents most commonly as chronic meningitis
85% of cases occur in HIV-infected persons (2-7 cases per 1000 AIDS patients)
12 % fatality rate in AIDS patients
antifungal drugs: polyenes
i.e. amphotericin B
Main features
-natural product - produced by Streptomyces nodus
-Amphoteric - has both an acidic and basic groups
-Contains a lipophilic polyene region (bottom) and a hydrophilic polyalcohol region (top) - amphiphilic
-Macrolide ring
-Fungicidal
amphotericin B MOA
Amphotericin B binds to ergosterol in cell membrane - predominant sterol in fungal cell membranes - leakage of intracellular cations and proteins
Reason for specificity: mammalian and bacterial cell membranes contain cholesterol
amphotericin B - PKs
Poorly absorbed from GI tract
Oral amphotericin B only effective for GI infections
Intravenous injection required for systemic infection
Cerebrospinal levels 2-3% of blood levels
-intrathecal therapy needed for fungal meningitis
amphotericin B AEs
Toxicity is low enough to allow use, but still very toxic
Infusion-related
-Fever, chills, muscle spasms, vomiting, headache and hypotension
-Can be ameliorated by reducing rate of infusion
-Premedication with diphenhydramine and/or acetaminophen
Renal damage
-Occurs in nearly all patients
-Reversible component - reduced renal perfusion
-Irreversible component - renal tubular injury - Usually occurs after prolonged (>4 g) administration
Liver abnormalities occasionally observed
therapeutic applications
Systemic infections
-Amphotericin B
—broad spectrum antimycotic (Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Aspergillus fumigatus)
—Some fungi are naturally resistant
—Drug of choice for life-threatening fungal infections
-Intravenous administration over 1-4 hours
• Superficial fungal infections
-Nystatin - polyene drug similar to amphotericin B
—Too toxic for systemic administration
