Medical Mycology 2024 Lecture Notes PDF

Patrick J. McDonnell, Pharm.D., FASHP Professor of Clinical Pharmacy Fall 2024 MEDICAL MYCOLOGY Objectives  Describe the types of infections in humans caused by fungi  Compare and contrast molds and yeast  Identify common super...

Patrick J. McDonnell, Pharm.D., FASHP Professor of Clinical Pharmacy Fall 2024 MEDICAL MYCOLOGY Objectives  Describe the types of infections in humans caused by fungi  Compare and contrast molds and yeast  Identify common superficial and subcutaneous mycoses  Differentiate between the types of endemic mycological infections  Identify the most common opportunistic fungal infections in humans  Recognize basic therapeutic options in the treatment of common mycotic infections Mycology  The study of fungi  Eukaryotic organisms: they contain a true nuclei  Nuclear membrane  Endoplasmic reticulum  Mitochondria  Secretory apparatus  Are they animal, mineral or vegetable???  Unlike plants, fungi are devoid of chlorophyll and non- photosynthetic ○ They absorb all nutrients from the environment  Unlike animals they are non-motile, and possess a rigid cell wall Medical mycoses  80,000 species of fungi have been described  Less than 50 cause more than 90% of fungal infections in humans and other animals  They can also be phytopathogens  Fungal infections are called mycoses  Most pathogenic fungal infections are from exogenous sources—water, soil, organic debri  Other infections in humans are caused by fungi that are part of the normal human flora Blight Irish famine 1844-1851 1 million died of starvation 2 million emigrated Infections from fungi  Types of infections Superficial Cutaneous Subcutaneous Systemic (that is invading the internal organs) ○ Opportunistic  Patients that are immunocompromised Superficial infections Superficial infections Cutaneous Infections What is this medically What is this medically known as? known as? Cutaneous infections What is this medically known as? Cutaneous Mycoses: Thrush Subcutaneous mycoses Subcutaneous Endemic (and incidentally dimorphic) These tend to be Systemic Infections mainly in patients with weakened immune systems  Histoplasmosis  Coccidioidomycosis  Blastomycosis  Paracoccidioidomycosis Systemic and Opportunistic Mycoses Systemic and Opportunistic Mycoses Systemic and Opportunistic Mycoses General Classification of Fungi  Yeast  Molds  Unicellular  Multiple identical nuclei; consist of branching cylindric  Appearance: white tubules called hyphae. and thready; usually Hyphae bear reproductive structures, anchor the colony oval in shape. (mycelium) and absorb  Reproduction: nutrients  Fuzzy appearance and can be Asexually via mitosis various colors orange, green, in a process called black, brown, pink or purple. budding  Reproduction: via small spores, which can be sexual or asexual Reproductive Structures of Fungi Conidia: asexual reproductive structures produced either from the transformation of a vegetative yeast or hyphal cell from a mold. The cell wall of fungi  Fungi have an essential rigid cell wall  Determines its shape  Protects from osmotic and environmental stress  Composed of long chains of carbohydrates, glycoproteins and lipids ○ Certain polymers are unique to certain fungi  Cell walls may also release immunodominant antigens activate the complement cascade and provoke an inflammatory reaction  In some cell walls brown or black melanin can be protective from host defenses and is associated with virulence: dematiaceous Superficial Mycoses  Pityriasis Versicolor  Chronic mild superficial infection of the stratum corneum caused by the mold genus Malassezia.  Discrete hyper- or hypopigmented maculae occur on the skin, generally of the upper torso and arms  More cosmetic then a serious infection  Malassezia species are lipophilic and if being culture require higher amount of lipid in culture media  However can be confirmed on direct microscopy with scrapings of the skin treated with KOH.  Generally self-limiting  Rx: topical or oral antifungal “azoles” or even topical selenium sulfide  Rarely serious since these molds are considered to be part of the normal skin flora.  ? Implicated in dandruff Malassezia furfur complex Cutaneous Mycoses: Dermatophytosis  These are fungal infections that infect only the keratinized tissue Skin, hair, and nails.  Key Dermatophytes species are: Trichophyton Epidermophyton Microsporum  Dermatophytes are unable to grown at 37° C or in the presence of serum, hence they are primarily restricted to the non-viable skin tissue Dermatophytosis  Among the most prevalent infections in the world  Can be persistent and bothersome but generally are not debilitation or life- threatening  These fungi are acquired by contact with contaminated soil, infect animals or humans (or surfaces in which contain these contaminants) Clinical Features of Dermatophyte Infections Skin Disease Location of Lesions Clinical Features Tinea corporis (ringworm) Non-hairy, smooth skin Circular patches with advancing red, vesiculated border & central scaling; pruritic Tinea pedis Interdigital spaces on feet Acute; itching red vesicular. Chronic: itching, scales, fissures Tinea cruris Groin Red scaling lesions in the groin area; pruritic Tinea capitis Scalp hair: either inside the Circular bald patches with hair shaft (endothrix) or short hair stubs or broken outside (ectothrix) hair within follicles Tinea barbae Beard hair Edematous red lesions Tinea unguium Nail Nails thickened or crumbling distally; discolored; lusterless. Usually associated with tinea pedis Onychomycosis  Nail physiology Nails develop from cells in the basal layer of the epidermis Nail surface: densely compacted heavily keratinized, dead skin cells….virtually impossible to penetrate Nails replacement ○ Fingernails: 6-9 month ○ Toenails: 12-18 month Onychomycosis: Pathology  Infection begins as a primary fungal invasion of the health nail plate and hyponychium (skin under the distal end of the nail)  Nail plate appearance Thickened Distorted Opaque, white or yellow Crumbly Treatments  Surgical/mechanical: removal of the nail  Nonprescription: basically not efficacious….never cure and not FDA approved for treatment for onychmycosis  Prescription Therapies Oral ○ Griseofulvin (not used anymore) ○ Ketoconazole (not used; very toxic) ○ Itraconazole (toxic; select patients) ○ Terbinafine Topical: ciclopirox 8%; efinaconazole 10% Subcutaneous Mycoses  May be caused by dozens of environmental molds associated with vegetation and soil  Infections are usually acquired when minor cuts and scrapes introduce soil or plant debris containing the pathogenic fungus  Ensuing infections can be chronic Sporotrichosis  Caused by Sporothrix schenckii  Dimorphic fungus Outside environment: exist as mold Inside the body/host: exist as yeast cells Sporotrichosis  Rose bushes, grasses, trees, sphagnum moss  Conidia are introduced into the skin by trauma  Patients recall a history of trauma with outdoor exposure  May be a chronic misdiagnosed granulomatous infections  Spreads to lymphatic systemic  Most reliable way to diagnose is culture on proper media  Incubated at both 25-30°C and 35-37°C  Treatment with oral azole antifungals; systemic disease treated with amphotercin Mycetoma  Cause by soil dwelling fungi  Madura foot (maduromycosis) also called eumycetoma  Primarily in tropical areas  Diagnosis by culture of pustular material  Treatment: debridement, draining  Antifungals  May lead to secondary superinfection with staphylococci or streptococci Endemic Mycoses  Infections generally GEOGRAPHICALLY restricted to specific areas  Exist in nature in soil  Sometimes with guano (bird and/or bat droppings)  Fungi leading to these infections are DIMORPHIC MOLDS  Many infections are asymptomatic and self resolving  Systemic tend to be LUNG infections  Systemic infections more so in immunocompromised hosts  Mycosis Etiology Ecology Geography Histoplasmosis Histoplasma Avian and bat guano; Ohio, Missouri & capsulatum alkaline soil Mississippi River Valleys; Most mycologist feel it’s entire continental US today Coccidioidomycosis Coccidioides immitis Soil, rodents Desert Southwest US; Mexico; Central and South America Blastomycosis Blastomyces ?riverbank soil SE US; St. Lawrence, dermatitidis Mississippi, and Ohio River Valleys Paracoccidioido- Paracoccidioides Soil? Central and South mycosis brasilensis America Histoplasmosis  Caused by Histoplasma capsulatum  In US most common in the Ohio and Mississippi River valleys  However most clinicians/ID specialist feel it’s the entire continental US  Most common of the endemic mycoses Histoplasmosis Clinical Presentation  Pneumonia with mediastinal lymphadenopathy  Mediastinal or hilar masses  Pulmonary nodules  Cavitary lung disease  Pericarditis with mediastinal lymphadenopathy  Dysphagia cause by esophageal narrowing  Often mimics a condition call sarcoidosis Histoplasmosis  Diagnosis confirmed with histopathology using stains for fungi  Cultures  Antigen testing and other erologic tests for Histoplasma-specific antibodies  Treatment  Most resolve on their own  Rx for: ○ Exposure to large inoculum ○ Immunocompromised ○ Drugs: itraconazole; amphotercin B for severe disease Question???  What are some drugs that are used in the treatment of rheumatoid arthritis that may make someone prone to Histoplasmosis and why? Endemic mycoses  In their endemic areas, the rates of infections can be very high but keep in mind that the infections are self-limited and asymptomatic  90% of identifiable and treatable infections are found in immunocompetent individuals  Patients with compromised cell-mediated immune defenses (Th1) have significantly great risk of developing disseminated disease Systemic Mycoses  Patients with compromised host defenses are susceptible to ubiquitous fungi to which healthy people are exposed but usually resistant  In patients with HIV/AIDS, the incidence of opportunistic mycoses are inversely correlated with the CD4 lymphocyte count.  Patients with CD4 counts less than 200 cells/µl are highly susceptible to infection with opportunistic fungi  Candidiasis: Yeast from the Candida genus is an endogenous opportunists  Exogenous: from soil, water and air ○ Cryptococcosis ○ Aspergillosis ○ Pneumocystis pneumonia ○ Mucormycosis Mucormycosis  Caused by the Mucorales Phylum of molds Rhizopus ○ Most prevalent is Rhizopus oryzae ○ Rhizomucor ○ Lichthemia ○ Cunninghamella Mucormycosis  Ubiquitous  Patients at risk Acidotic conditions (especially with diabetes in crisis) Leukemias and lymphomas Chronic steroid treatment Severe burns Immunodeficiencies Mucormycosis  Major clinical form is a rhinocerebral mucormycosis.  Germination of sporangiospores in the nasal passages ○ Hyphae invade blood vessels causing thrombosis, infarction, and necrosis  Can progress to sinuses, eyes, cranial bones and brain Candida Candidiasis  Members of the yeast genus Candida are capable of causing candidiasis  They are members of the NORMAL FLORA of the skin, mucous membranes, and GI tract.  Candidiasis is the most prevalent systemic mycosis  Common yeast species  C. albicans  C. glabrata  C. parapsilosis  C. tropicalis  C. guilliermondii  C. krusei  C. lusitaniae  C. aureus (resistant to almost all antifungals) ○ The widespread use of the common antifungal agent fluconazole has lead to azole- resistances in these two species.  Most of these Candida species have been renamed into new genera, but for this course, we will still refer to them as the Candida genus. Candidiasis  In culture or tissue, Candida species grow as ova, budding yeast cells (3-6 micron in size).  Pseudohyphae: buts continue to grow but fail to detach producing chains of elongated cells that are pinched at the septations between cells.  On agar media and within 24 hours at 37° C or room temperature Candida species produce soft, cream-colored colonies with a yeasty odor Candida in the Micro Lab Only species Candida albicans will produce a germ tube Sugar fermentation differences will help to differentiate other Candida species. Candidiasis: Pathogenesis  Cutaneous or mucosal candidiasis is established by an increase in the local population of Candida  And damage to the skin or epithelium that permits local invasion  Systemic candidiasis occurs when the yeast enters the bloodstream and the phagocytic host defenses are inadequate to contain the growth of yeast.  May be a “super-infection” with the administration of antibiotics Candidiasis: Pathogenesis  Candida cells elaborate polysaccharides, proteins, and glycoproteins Stimulate host defenses Facilitate the attachment and invasion of host cells Thrush  Risk factors associated with thrush include:  HIV/AIDS  Cellular immunodeficieny (other than AIDS)  Pregnancy  Diabetes  Young or old age  Oral contraceptives  Treatment with antibiotics  Steroids  Genital thrush: SGLT-2 Inhibitors: Common oral drugs for diabetes Thrush Treatments for Oral Thrush  Topical Nystatin Liquid: Squish and Spit Troches  Clotrimazole troches  Oral Fluconazole  Treatment may need to be escalated with esophageal thrush and topical treatments are not recommended as monotherapy Thrush  Vulvovaginitis  Second most common cause of infectious vaginitis  Candida species part of the normal flora  Highest incidence in a woman’s reproductive years Risk factors similar to other forms of thrush Include also ○ Contraceptive devices ○ Sexual behavior Vaginal thrush  Clinical presentation  Vulvular pruritus is the dominant feature  Burning, soreness, irritation  +/- dysuria  Symptoms worse the week prior to menses  On physical exam: ○ Erythema ○ If discharge presents classically white, thick, clumpy with no or minimal odor ○ Cervix appear normal ○ Vaginal pH is normal at a range of 4 to 4.5 that distinguishes it from other forms of infectious vaginitis (where the pH is > 5.0) ○ Candida budding yeast can be seen on a wet mount preparation; culture not routinely recommended Vaginal Wet Mount Candida yeast cells. Trichomonas Vaginal thrush  Treatment  One time dose of fluconazole of 150 mg  Topical ○ Clotrimazole (Gyne- Lotrimin) ○ Miconazole (Monistat) ○ Nystatin (as a vaginal troche) ○ Tioconazole (Vagistat- 1) ○ Butoconazole (Gynazole) Systemic Candidiasis  Candiduria  Foley catheters, diabetes, pregnancy, antibiotic use. SGLT-2 inhibitors for diabetes  Candidemia  Indwelling catheters  Surgery  IVDA  Aspiration  Damage to skin or GI Tract  Treatment will be systemic antifungals  Duration dependent on the site/severity of infection  Agent dependent on the species of Candida ○ Speciation will be done for yeast isolated from blood or spinal fluids Cryptococcosis  Cryptococcus neoformans  Occurs in 6-10% of AIDS patients  Generally occurs in patients with CD4 < 100  Acute mortality: 10- 25%  Ubiquitous: Cryptococcus found commonly in the environment C. neoformans in the CSF Skin Lesions of C. neoformans Infection Cryptococcosis  Insidious onset with low grade fever, headaches, altered sensorium  Minimal nuchal rigidity, photophobia  Almost always presents as meningitis  Initial mortality ~ 25%  Relapse 50-90%  Severity of illness indicated by ○ Altered mental status ○ CSF antigen titer > 1:1024 ○ CSF WBC count < 20 cells/mm3 Cryptococcal meningitis  Treatment Amphotericin B 0.7-1 mg/kg daily +/- Flucytosine 50-150 mg/kg daily in divided doses every 6 hours 2 weeks) THEN Often followed by fluconazole 400 mg daily for 8 to 10 weeks Fluconazole 400 daily for 6 to 8 weeks for a more mild presentation Aspergillosis Stain of Aspergillus fumigatus Aspergillus fumigatus culture Aspergillosis  Aspergillus mold species are ubiquitous  Aspergillus fumigatus is the most commonly human pathogen but other species have been identified  A. niger  A. flavus  Aspergillus mold produces abundant small conidia that are easily aerosolized  Following inhalation of these conidia in atopic individuals they can often develop severe allergic ore respiratory reactions  “Bronchopulmonary aspergillosis”  Development of IgE antibodies to the surface antigens of Aspergillus conidia  In immunocompromised patients particularly  Leukemia/lymphoma  Stem cell (bone marrow) transplant  Lung transplant  Long term steroid use ○ Conidia from Aspergillus may germinate to produce hyphae that invade the lungs and other tissues  In the lungs, alveolar macrophages are able to engulf and destroy the conidia; this is not the case in patients with diminished immune systems Invasive Aspergillosis  Occurs in 1-15% of solid organ transplant recipients  Currently reported mortality rate is 22%  Greatest incidence of infection in lung transplant patients (4%-23.3% of patients)  Infection rate, severity, and mortality rate differ depending on the organ transplanted Invasive Aspergillosis Clinical Presentation  Immunocompromised patients experience vascular invasion leading to thrombosis, infarction, tissue necrosis, and dissemination to other organs Present with s/sx of acute pulmonary embolus: pleuritic chest pain, fever, hemoptysis and friction rubs  Neutropenic patients present with a necrotizing pyogenic pneumonitis Invasive Aspergillosis Diagnosis  Culture – low sensitivity and specificity  If recovered on culture, consider clinical syndrome as well as a bronchoscopy  Galactomannan assay  Can be influenced by medications that cause false positives  CT findings  “Halo sign”  Nodules http://www.pedsoncologyeducation.com/ Pneumocystis jiroveci Pneumonia  Opportunistic fungal pulmonary pathogen  One of the most common opportunistic infections HIV patients  Incidence in solid organ transplant is highest in lung and heart-lung recipients, with incidences of 10-40% in patients not receiving adequate prophylaxis Pneumocystis jiroveci Pneumonia Risk Factors for Infection  High-dose or long-term  Low CD4 counts (HIV) corticosteroid use  Antilymphocyte therapy  Infection with CMV  Calcineurin inhibitor use  Prolonged neutropenia (tacrolimus, cyclosporine)  Exposure of a patient  Frequent organ rejection/ with inadequate treatment of organ prophylaxis to a patient rejection with PCP Pneumocystis jiroveci Pneumonia Clinical Presentation and Diagnosis  Marked hypoxemia out of proportion to clinical findings  Patients may present with fever, abnormal radiographs, cough, hypoxemia, dyspnea, or chest pain Pneumocystis Pneumonia  Therapy Antibiotics: Note the term---not typical antifungals being used. Oxygen Corticosteroids ○ Methyprednisolone or prednisone  indicated if paO2 < 70  shown to decrease length of stay (both total and ICU), duration of fever, need to ventilate, duration of ventilation, need to admit to an ICU, and mortality Summary of Human Fungal Disease Superficial Cutaneous Subcutaneous Systemic Mycoses Mycoses Mycoses Mycoses Affects hair & Affects skin and Affects Affects Organs: skin epidermis nails subcutaneous Lungs; (stratum tissue lymphactics, corneum) brain, meninges Tinea versicolor; Athlete’s foot, Candiadisis Aspergillosis Tinea corporis jock itch, (thrush, Histoplasmosis (ringworm) Onychomycosis invasive); Some Coccioides skin infections Cryptococcus Pneumocystis Can affect Can affect Skin: anyone Usually marked anyone anyone Candiadisis: some immunosuppression degree of immunosuppression A 60 yo male living in Tuscon Arizona is started on Humira (adalimumab) for his rheumatoid arthritis. What endemic systemic fungal infection may be prone to contracting while on this drug therapy?  A: Cryptococcus  B: Histoplasmosis  C: Coccioidomycosis  D: Candidiasis Which is NOT a characteristic of a yeast?  A: Unicellular  B: Prokaryotic  C: Reproduce by a process known as budding  D: Conidia are yeast’s main reproductive structures Select all that apply: Which of the following statements is/are TRUE regarding onychomycosis?  A: Molds cause this infection more than yeast do.  B: Non-prescription OTC therapy are quite curative for this infection.  Very often this infection is an offshoot of tinea cruris.  Nails that are infected can appear thickened, distorted, crumbly and yellowed. Select all that apply: Which of the following is/are true regarding Sporotrichosis?  A: Common antibiotics like vancomycin and cefazolin will cure skin infections.  B: The causative organism of this infection is a dimorphic mold.  C: Conidia can be introduced into the skin via injury from rose thorns.  D: It’s a subcutaneous skin infection that can also spread through the lymphatics. I am a common yeast which can be identified in the microbiology lab by identifying the germ tube that I produce. Who am I?  A: Candida aureus  B: Candida albicans  C: Malasezzia furfur  D: Trichomonas vaginalis  E: Aspergillus fumigatus What type of infection has the highest mortality in immunocompromised patients due to Crytococcus neoformans?  A: necrotizing fasciitis  B: pneumonia  C: meningitis  D:urosepsis Aspergillosis presents as what significant type of infection in markedly immunocompromised patients?  A: pneumonia  B: meningitis  C: Abdominal abscesses  D: Cellulitis  E: Urinary tract infections Select all that apply: What type of patients are at risk for Pneumocystis jiroveci (aka: carinii) pneumonia?  A: HIV infected patients with CD4 Counts > 1500  B: Patients on long term systemic corticosteroid use.  C: Transplant patients treated with frequent organ rejection drug therapies  Patients on diabetic drugs called SGLT2 inhibitors that lead to glycosuria