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35 Cards in this Set

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Basic characteristics of Fungi
Fungi are eukaryotic organisms with rigid cells walls composed of mannan, glucan, and chitin. 2-300 of the 200,000 species casue human disease. They are more complex than bacteria, and exist as eithe unicellular or filamentous multicellular organisms. They reproduce either sexually or asexually. Their cell membranes differ from ours (they use ergosterol which is a drug target, as we use cholesterol, althugh there is just a little cross reactivity). Many plants need fungi to symbioticaly provide nutrients. They cause subacute and chronic infections (slow smouldering as opposed to bacteria).
Fungal Structures
There are 2 main varieties, yeasts and molds (dimorphic fungi can take either form.

Yeasts can appear as small spheres (blastocondida), spheres with invaginations (fission formation) or pseudohyphae (tubular aggregations of yeasts that pinch off. They often reproduce by budding, and may have pilli.

Molds can appear as coenocyclic hyphae (a long continuous tube as one giant cell), Septate hyphae (tubular/branching with compartmentalization), and septate hyphase wtih clamp connections (as before but with overlapping edges). A mycelium is the result of a mold shooting out many hyphae in a massive forest.
Dimorphic Fungi (genearl characteristics)
Grows as mold in the environment. Metabolic and temp signals cause it to convert its growth pattern to that of yeast. HSP's may be involved. Note that the shift causes it to become more pathogenic. This is demonstrable by splitting cultures. Grow one in environmental conditions (minimal nutrients, ambient temperature) and the other in rich media at 35-37 degrees. You should be able to observe the change. Note that this stuff can be seen in people with normal immune systems.
Identificaton of Fungi
Scrapings/K-OH test- 10% K-OH digests human cells however leaves fungus alone (as they have tough cell walls). Stains that work include- calcifluor white binds to chitin in cell wall and fluoresces under UV light. Gram stains also work, they appear gram + but far larger than bacteria. Lactophenol cotton blue stains hyphae, conidia, spores.

Biopsy- Allows us to view fungus colonization vs invastion. Wen can use H & E or Silver stains (fungal elemants turn black, few human tissues stain) to aid in visualization.

Culture- Gold standard for identification, but takes days to weeks, and bacteria may overgrow if not controlled. Sabouraud's agar is most commonly used, it is seletive (antibiotics to inhibit bacteria, promotes fungal growth). Most fungi prefer 25-30 degrees (except for dimorphic fungi which must be split, and note that they are contagious). Yeasts and molds are identified differently. The former is identified using biochemical tests and the latter is stained by lactophenol cotton blue after conidia formation [takes weeks])

Antigen Detection- Ex. Cryptococcus has a large polysacharide capsule that responds to enzyme immuno assat or latex agglutination. It is both sensitive and specific with the exception of capsule deficient mutants). Histoplasma capsulatum sheds polysaccharide antigen in serum and urine.

Additinally antibdy titers canbe taken, however these are difficult to interpret and may only be useful to detect trends. Delayed type hypersensitivity tests are also available 9Similar to PPD and are useful for epidemiologic purposes, most studies in Histoplasma capsulatum).
Factors influencing fungi pathogenesis
Adherence- ex. Candida Albicans can adhere to the vagina and GI tract making it pathogenic.

Invasion- Sporothrix scheneckii infects via direct inoculation (stabbed by rose thorn). Coccidioides immitis is small enough to evade lung defenses. Dimorphic fungi undergo metabolic/morphologic shift, Candida spp form hyphae

Tissue Injury- analogous to bacterial toxins but evidence of exotoxins is lacking. There are no endotoxins, but there is an equilivant in the fungal cell wall. Ex. aspergillus causes necrosis/infarction as it loves the little arteries.
Fungal Immunity
Phagocytosis is the mainly effective method. Neutrophils are the first line of defense, they kill hyphae (as killing aspergillus in the lungs), putting neutropenic patients at high risk. Some fungi can fight back such as candida albicans interfering with complement binding. Dimorphic fungi evade phagocyte killing (Coccidioides immitis has antiphagocytic properties, Histoplasma multiplies inside phagocytes).

Humoral immunity has little effect. It helps a little with Coccidioides immitis, and perhaps some cryptococus and candida immunity. Ab titers are useful only to look at trends to detect dissiminated disease.

Cellular Immunity- T cell defects leave you vulnerable, such as results from Steroids, Hodgkins, AIDS, Chemotherapies. TCR recognize fungal antigens and upon activation secrete IL2 and IFN-G to activate macrophages, which are then able to kill invading fungi.
Fungal Skin Diseases
Candidal infections
Tinea infections (ringworm)
Pityriasis (tinea) versicolor
Candidal Skin Infections
Occur in crural folds, wet macerated skin such as diaper rash, diswasher hands, under breasts. It causes erythema and fissures, and spreads rapidly. Diagnosed via KOH prep, and Tx wtih topical antifungal (azole cream, nystatin). also keep area dry.
Tinea Infections (list)
3 main genera are the culprits- Microsporum, Trichophyton, Epidermophyton

Tinea Capitus- Head, patchy circular hair loss.

tinea barbae- Beard as above

Tinea Corporis (body ring with central clearing)

Tinea Cruris- groin jock itch

Tinea Pedis- Athletes foot, break in the skin can lead to other infectin including cellulitis.

Tinea unguium- Nail
Tinea Infections (characteristics)
(AKA Ringworm) Slowly progressing eruption of the skin, nails, and hair. Minimal mortality and moderate morbidity, however it is cosmetically displeasing.

Found in the environemnt, it is transmitted via close personal contact (barber shops, family, locker rooms, pets. environmental reservoirs). Low virulence/infectivity. Infective hyphae contact minor/micro skin breaks where surface fatty acids facilitate infection. When the stratum corneum is breached hyphae proliferate through keratinized skin. (Proteases, moisture, skin turnover, desquamation, and steroid use are risk factors.

Immunity: most spontaneously heal once inflamation kicks in (increases desquamation). neutrophils can kill dermatophytes, and the T cell response if important (however humeral immunity is not as important and it is unknown weather or not lasting immunity occurs. Half of the patients already have T-cell dysfunction, and some of the possible culprits do not trigger the immune system.

Tinea Capitus- erythema about hair shaft, progressive scalp desquamation and hair breaks as hyphae penetrate the shaft (shafe exclusively = endothrix, inside and out = ectothrix. The hair breaks off.

Tinea corporus- begins as erythmatous scaly patch and spreads in a ring. predilection for moist areas of skin-skin contact.

Onychomycosis/Tinea Unguim- Fungal nail bed infections (rare to infect the nail itself). Causes hyperkerototic reaction

Diagnosis- If fungi, bacteria, and non-infections are all partof the DDX, we need a conformation. Scrapings of the advancing edge examined (broken hairs) microscopically wtih KOH. Note that some species fluoresce under UV. Send cultures as well.

Tx- Often self limited. Topical tolnaftate, Nystatin, 'Azoles in general. For nail beds/hair infection systemic meds may be required.
Malassezia furfur
causes Tinea Versicolor (AKA pityriasis versicolor) Core common in tropical and temparate climates. Patchy areas of hyper/hypopigmentation. A pustular rash can result. Fungemia can occurin neonates, or persons on TPN (it is all the lipids). Skin scrapings/KOH reveal budding yeast and hyphae (meatballs and spaghetti). Culture requires high lipids. Rhumatoid arthritis is a risk factor (over steroid use casues problems)
Sporothrix Schenckii
A dimorphic fungus in the environment, often gowing on plants (rose growers disease). Thorns directly innoculate hosts, after which fungi spread via lymphatics and casues nodular ulcerations. Papule develops at the innoculate site in weeks to months, ulcerates, and then satellite nodules develop along lymphatic drainage routs. Deeper tissuse ifections are rare, but occur in immunocompromised individuals.

Sporotrichosis- may disseminate in T-cell immunosupressed individuals (may cause meningitis). Melanin production decreases susceptability to oxidative killing. Scrapings/KOH is unrevealing (low number of organisms, and asteroid bodies). Culture is the gold standard, requires 2-5 days, and we need to see conidia and/or dimorphism. Tx was oral Saturated solution potassium iodide (SSKI), itraconazole, amphotericin B (for disseminated infection).
Tropical disease caused by Phialophora, cladosporium, and Fonsecaea. causes papules on legs/feet that develop into fungating mass. KOH prep may show branching septate hyphae. Rx includes surgery and antifungals, however the cure rate is poor in advanced disease. Use flucytosine or itraconazole. May predispose to squamous cell carcinoma.
clinical term for when trauma introduces fungal (or actinomycete) infection. Most often occurs in the tropics, due to barefoot movement. Causes massive induration, draining sinuses, and is difficult to treat.
Histoplasma capsulatum
Histoplasma is a dimorphic fungus growing in the yeast phase in tissues and in temps over 37 Celsius. The yeast forms are small (diagnostic) and reproduce by budding.
The mycelia are septate and produce microconidia. Histoplasma grows in soil under humid conditions, mainly concentrated in the Ohio and Mississippi River areas. It is also found in Puerto Rico and spelunkers are at risk as it can be aerosolized from bat feces.

Virulence- The microconidia are inhaled and reach the alveoli where they convert to yeasts and are readily phagocytosed. However they are not readily oxidized, surviving by capturing iron and calcium from the macrophage to modulate pH which leads to ineffective killing. They then grow within the macrophages and neutrophils. The Histoplasma continue to grow in the lung leading to lesions similar to tuberculosis. It can Disseminate to the Reticuloendothelial system (bone marrow, Lymh Nodes, Liver, Spleen) where granulomas with necrosis occurs (similar to TB again)

Disease- Usually asymptomatic or short lived respiratory syndrome occurs. The organism may be contained and then cleared or contained within granulomas and calcify. A progressive pulmonary disease with cavitation, sputum production, night sweats and weight loss similar to tuberculosis is possible. With dissemination to the RES symptoms include fevers, sweats, weight loss, skin & subcutaneous nodules and mucous membrane ulcerations are not unusual (tongue, larynx- biopsy for exam). Adrenal involvement and endocardial and pericardial infections reported

Dx- Recognize the epidemiology and environmental conditions makind infection likely. Sputum sulture is not effective BCX may Id dessiminated disease. The diagnostic structure is the tuberculate macroconidium hyphal form with thick walls, and radial finger-like projections. Growth occurs @ room temp on blood, chocolate and Sabouraud's agar but takes weeks. Dx via examination of white cells to visualize the organisms inside, possible isolate via RES biopsy. Fungal stains such as methenamine silver may be helpful. The most reliable non culture method is urine enzyme immunoassay (EIA) of the polysaccharide antigen of histoplasma. This is 90% sensitive in disseminated disease, but still takes a week.

Immunity/Tx- Control is via cell mediated immunity (T cell activation of macrophages). Neither B cells nor antibodies have a significant role. If Tx is required, Itraconazole is the drug of choice.
Coccidioides Immitis
Dimorphi Fungus. In the soil, it exists as septated hyphae which can fragment into separate arthroconidia.
They are barrel shaped and easily aerosolized. The fungus is present in the southwestern US and Northern Mexico deserts (the Sonoran Desert, and specifically the Lower Sonoran Life Zone). It requires alkaline soil. Infection cannot be acquired without visiting the area X/c for ocupational exposure (it is very easily aerosolized in the lab).

Virulence- The arthroconidia are inhaled and brought into the airway
Once inside the host, the arthroconidia change into spherules due to increased temperatures, lower pH and interactions with phagocytes
The spherule is a “sac” of endospores which are released and lead to new spherules
Proteases released by the spherule are virulence factors
They destroy collagen, elastin and immunoglobulins

Disease- Once the Coccidioides is inhaled, it can lead to similar types of disease as Histoplasma
It can be contained, lead to a limited pulmonary disease or active pneumonia
Valley Fever
It can also disseminate, but dissemination leads to meningitis or osteomyelitis
More than half those infected are asymptomatic.
Others develop “valley fever” which is
Chest pain
The disease lasts 2-6 weeks
Chest x-rays are usually clear or have hilar adenopathy (or may have an associated pneumonia)
Resolution is spontaneous in over 90%
Dissemination occurs in <1% including the skin, bone, meninges
African or Filipino ancestry
Pregnant women
T-cell number / functional abnormalities
The most important site of dissemination is the meninges
Symptoms include fever, headache, neck stiffness

Dx- The spherules on KOH preparation or biopsy are diagnostic
Culture is not difficult but infection of laboratory staff is quite a concern
Complement fixation may be helpful to assess the extent of the diseases
IgM is present for the first 3 weeks and IgG is present somewhat later. The characteristic mold grows on enriched Sabouraud’s medium at room temperature
Usually after a period of 3-4 days

Tx/Immunity- Life long immunity does develop
Arthroconidia can be phagocytosed and killed by PMNs
The endospores cannot be handled until macrophages are activated by T-cells (Th1 subset)
Humoral immunity does not play a role
Complement is not effective at opsonizing C. immitis. Primary disease is self limiting and no therapy is indicated
The drug of choice in the treatment of disseminated Coccidioidosis is fluconazole (fluconizole is active against the C's...Cocci only...)
Amphotericin B also has activity and is considered second line
Blastomyces Dermatitidis
Dimorphic Fungus. Yeast phase at 37 degrees
The yeast are larger than Histoplasma
They broad based bud and have a thick wall
Mold phase at 25 degrees
The hyphae are septate and produce round to oval conidia. Geographic distribution includes the middle (Ohio and Mississippi valley)and south east part of the US (Virginia and the Carolinas)
Also southeastern Canada (Quebec and Nova Scotia)
Much less common than Histoplasma and Coccidioides.

Virulence- Primary infection is by inhalation of the conidia
A mixed inflammatory response occurs
The organism then starts to grow as large yeasts with thick double walls
Unlike Histoplasma, these yeasts are extracellular and much larger

Disease- Similar to Histoplasmosis and Coccidioidomycosis, pulmonary findings are the most common manifestations
Usually limited or it may progress
Dissemination occurs but rarely
Involvement of the skin is common by direct inoculation or dissemination from the lung
These lesions can lead to extensive necrosis and fibrosis

Dx- For skin infections, direct demonstration of the yeast with broad based budding is diagnostic
Conidia are not distinctive
Serologic tests may be helpful, but are not sensitive

Tx/Imunity- Not clear what the predominant host response is. Complement, antibody and cell mediated immunity are all involved. Itraconazole is the Tx of choice, followed by Amphotericin B.
Paracoccidioides brasiliensis
Dimorhic Fungus, least common. Limited to Central and South America, 80% of all cases are in Brazil.

Virulence- Microconidis are inhales and usually contained and cleared. Pulmonary or lymoh node involvement leads to chronic disease.

Disease- Pulmonary infection includes cough, fever, malaise, and weight loss. The mucus membranes of the mouth and pharyns are often involved lesions are progressive and destructive. Skin and lymph nodes are affected in a smaller %age of cases.

Dx- Visualization of yeast with multiple blastoconidia (looks like a ship's steering wheel). Antibody measurement has a 95% sensitivity.

Tx/immunity- The drug of choice is TMP-Sulfa. Alternates include itraconazole and amphotericin B.
Penicillium Marneffei
Important in HIV infected patients in Southeast Asia and China
Dimorph Epidemiology
Thie is the most common the the 3 we cover (They are the most common fungal infection). They can form chlamydoconidia and pseudohyphae which are actually buds that elongate(hyphae like extensions, like a mold/yeast combo). They grow as round or budding yeasts (looks like bowling pin), with mannan, glucan, and chitin in the cell wall. It is important to tell C. albicans from other candida as they differ in antifungal susceptability. Albicans is over 50% of fungemia, and UTI, and >90% of mucocutaneous. C. glabrata is tne 2nd most common form of fungemia, up to 1/3 resistant to fluconazole. C. Tropicalis is possible. C. parapsilosis is an exogenous cause of fungemia. C. Krusei is uncommon in infection but fully resistant to fluconazole.

Virulence- C. Albicans is normal flora of the Gi and Female Genital tract. Infections commonly result from invasive procedures like indwelling catheterization and parenteral nutrition (rich in fats and SUGAR which candida loves), the organism hithing a ride on the device. HIV, steroids (esp oral/inhaled steroids not washed out of the mouth), Transplant, and cancer patients are immunocompromised and susceptable. The change from the yeast form to pseudo-hyphal happens when candida starts to invade tissue, and is associated with enhanced pathogenesis (forms a strong attachment to epithelial cells allowing entry and infection)

Cutaneous-Skin, esp in crural folds. Will grow in wet macerated areas (diaper rash, breasts, fingers of dishwashers). Common in diabetics and obeise, causing red papules (raised lesions) or macular (not raised) lesions associated with tenderness and fissures. vaery puritic and has characteristic satellite lesions.

Mucocutaneous- superficial invasion of mucus membranes. Usually appear as white cheesy plaques easily removed. Thrush is the oral versoin, on buccal mucosa, palate, and tongue. Esophageal is usually an extension of thrush resulting in odynohagia and dysphagia. **if there are no known risk factors we need to search for them as this is abnormal. Vaginal lesions are similar to thrush resulting in itching burning, and white discharge. Chronic mucocutaneous is seen in T cell immunodeficiency and causes significant disfigurement and discomfort.

Fungemia- candida gets into blood stream through indwelling catheters.

UTI- candida gets in via foley cath, Common esp in those in the ICU on antibiotics/Steroids/TPN/Neutropenia/etc. The predilection is to involve the eye (Travels to eye via blood causing endophtlalmitis), so an eye exam within a few weeks is strongly recommended.

Disseminated candidiasis- Invasion of visceral organs. Happens 2ndary to long term fungemia, or by extension from the GI tract. Organs may include the liver, spleen, kidneys brain, eye, and heart. Esp in immunosupression without adequate prophylaxis.

Dx. They grow on sabouraud's agar and blood agar forming smooth colonies overnight (resembles staph). Id is based on carbohydrate assimilation, fermentation, and most of all on the chlamydoconidia, germ tube and hyphae/pseudohyphae. It is important to diff C. albicans from other Candida. Only Albicans forms germ tubes, which happens after a few hours of incubation. Scrapig of the lesions can be diagnostic via KOH. Fungemia Dx is via BCX (70% effective so do at least 2 concurrently). Ucx for UTI, and Biopsy/culture for Disseminated candidiasis.

Tx/Immunity- C. Albicans requires long duration Tx with broad spectrum antibiotics. The new Iconacandins (Fungins) are used for non-albicans. Nystatin swish and swallor, Clotrimazole lozenges, of fluconazole for thrush (longer for esophogeal/vaginal yeast). Fluconazole for mucocutaneous. Amphoteracin B kills all of them but is very toxic, last resort. Humeral and cell mediated immunity play an important role. Neutrohils are the first line of defense (they yeast are phagocytosed and killed when opsonized by Ab and complement). In the absence of antibodies, natural anti-Mannan IgG opsonizes. A balanced cytokine response is important which is why immunocompromise is bad.
Cryptococus Neoformans
Yeast that produces a capsule, the only pathogenig fungus that does. The capsuel is a complex polysaharide(glucuronoxylamannan). It is ubiquitous in soil contaminated with pigeon/bird droppings. Inhalation is the mode of transmission. Mainly afects immunocompromised hosts.

Virulence- after inhalation the capsule is formed. It is antiphagocytic by inhibiting complement binding. It also produces melanin (anti-oxidation). Then it mutiplies and spreads into pneumonia and the blood. It likes the CNS causing meningitis. In the immunocompromised host it sets up shop in the lung, get missed, and then into blood, meninges, and skin.

Disease- Initial pulmonary infection may be mild and not diagnosed. Then it leaves the longs and enters the blood, meninges (most common clinical manifestation), skin and bone. Meningitis has slow onset of Headache, fever, nuchal rigidity, and photophobia. Rarely also seizures and CN abnormalities. Skin infection is common in disseminated disease with maculopapular umbilicated lesions (red bumpy with raised center). Osteomyelitis is occationally seen.

Dx- Forms mucoid colonies on blood, Chocolate, or sabouradi's agar at 35 degress. This is nto sensitive however. It is Urea +, assimilates inositol by way of Creatine assimilatin, and turns bird seed agar black. Antigen tests (serum/CSF) is the best. India Ink is only + in half of cases. For bone and skin pathological exam is helpful with staining of the capsule (turns mucicarmine red)

Tx/Immunity- Alternate complement pathway is important. Antibodies are not usually detected, but T cell responses are crucial. Tx meningitis via Amphoteracin B + Flucytosine until asymptomatic, then indefinite fluconazole. Also repeat lumbar punctures to decrease pressure may be indicates as it can plug draingae and cause hydrocephalis. Other forms of crypto care tx'd with flucoazole during and after symptomology.
Pneumocystis Jiroveci
(AKA pneumocyatis carinii, PCP, PJP). Has been confused as a protozoan, characterised as a fungus based on genetics. Exists as a sporocyte. Cell wall lacks rigidity in spite of glucan and chitin. It exists world wide and all kids by the age of 4 have antibodies. Reservoir is unclear, but infection is likely by inhalation. Seldom produces disease in a normal host.

Virulence- Major surface glycoprotein (MSG) serves as attachment ligand. It remains extracellular in the lung leading to accumulation of mnocytes and fluid (hyaline membrane formation) The disease is due to rxn to the organism, not the organism itself.

Disease- Pneumonia which progresses over 3-4 weeks including non-productive cough, dyspnea on exertion, and only very rarely extrapulmonary findings (it does not disseminate)

Dx- Butterfly patterned infiltrate sparing the bases and apices. Sputum, or better induces sputum, or best Bronchial Alveolar Lavage is stained (with methenamine silver) and examined.

Tx/Immunity- Alveolar macrophages are front line, activated macrophages and CD4 lymphocytes play an essential role. Humeral immunity may have a role, it is unclear. Drug of choice is TMP/Sulfa in HUGE doses (3 TID - 4 QID)
Many forms including fumigatus (most common and virulent), flavus (2nd most), niger, terreus, and versicolor (don't sweat the last 3). Mold that grows rapidly with septate hyphae branching at acute angles (<90 degrees). The finger like conidial extensions are characteristic. Ubiquitous in soil, pepper, bread, in air etc. Heat resistant and easily aerosolized, it is inhaled leading to infection. lab sample may be contaminated by aspergillus. Note that you can get pulmonary aspergillus form marijuana.

Virulene- Proteins on teh surface adhere to laminin and fibrinogen, multiple enzymes cause injury to the lung. If they survive and germinate into hyphae, they can invade vasculature and lead to infarction (angioninvasive, findings similar to embolism or other infarction).

Allergic bronchopulmonary aspergillosis (ABPA)- a Ture allergic rxn when a hypersensitized individual inhales spores, and they settle in the mid-sized bronchi. Rxns may be manifested as acute asthma, cough, SOB. Bronchiectasis (fibrous thickening of bronchi) can result.

Aspergilloma- Growth in an avascular lung cavity present from previous lung disease (cavitary TB or COPD). Hemoptysis can result when it rubs on the epithelum an exposes a blood vessel (dormant otherwise). It does not invade, so antifungals are not effective, and as the rest of the lung is immunocompetant, the infection is contained.

Invasive aspergillosis (AKA IPA-invasive pulmonary aspergillosis)- Invades the tissue, mostly in immunosupressed individuals, leading to vascular invastion, infarction, and dissemination. Can present with non-specific chronic non-productive cough leading to hemoptysis and pleuritic chest pain (a result of angioinvasiveness leading to symptoms similar to pulmonary embolism). Dissemination allows seeding of brain, heart, liver, spleen, kidneys, skin, etc, at which point it carries nearly 100% mortality. Note that once it invades it is no longer found in the sputum.

Dx- ABPA-the organism is cultured from lungs via coughing. The person has eosinophilia and elevated IgE, as well as fleeting lung infiltrates (can move up/down, and left/right) on CXR. In aspergilloma Sputum CX is used, or noting a cavity with fungus ball on CT or CXR. Invasice aspergillosis is tough, isolation from sputum does not indicate invasivement, and it is harder to grow once it is invading in its hyphal form. One needs a biopsy demonstrating the presense in the tisse in addition to culture. On visualization, note the septate hyphae and acute angles.

Tx-immunity- Macrohages are the first lines fo defense, then PMN's destroy hyphae. The role of humoral immunity is not clear. ABPA is treated with steroids/albuterol, antifungal are not indicated. For Aspergillosis we do not treat unless we see hemoptysis, after which we consider lobectomy, removal of the cavity, or sclerosis of the bleeding vessel. Antifungals are ineffective as it is non-invasive. Invasice aspergillosis is tx'd with voriconazole, with alternatives including itraconazole, or a lipid formulation of amphoteracin B. Surgial debulking is almost always neessary.
Group includes rhizopus and mucor (another name for the whole group). Asexual spres in sporangium with aseptate 90 degree branching hyphae. They are ubiquitous and are found in the soil.

Virulence- enter via inhalation OR direct cutaneous entry. They have a predeliction for low pH and are seen in pt's with acidosis (DKA or Lactic acidosis). They also sequester Iron (major virulence factor). Susceptable pt's include acidtics, Pt's getting Fr Chelating drugs, Pt's that are on steroids or neutropenics.

Disease- If inhaled the resultis pulmonary/rhinocerebral (most common form) infection. If the organism enters through the skin it can lead to cutaneous infetion followed by dissemination. When it invases tissue it destroys blood vessels leading to necrosis, and can be quite lethal.

Dx- Biopsy demonstrating the organism invading the tissue is important. It does not grow well, but is worth a try.

Tx/Immunity- Macrophages ingest spores but cannot kill the organism unless the host cellular immune system is intact. Humeral immunity may not have a specific role. Control of risk factors/underlying conditions is essential including correction of acidosis and stop the iron/chelator. Tx includes surgical debulking and use of amphotericin B or a lipid formulation of the same. New azoles are soon to be available that may also be effective, but none for now.
Anti-fungal methods of attack.
Note modes of attack.
Drug List for Dermatophytic infections

Griseogulvin- 1st oral drug for dermatophytes

Ketoconazole- replaces griseofulvin


Terbinafine- Oral and Topical.

Infections of skin, nails, and scalp inluding athletes foot, groin infections, ringworm, etc...are mostly treated with topical agents purchased OTC
Drug List for mucocutaneous infections
Amphotericin B- topical
Nystasin- topical
Natamycin- topical

Izole derivitives available ropially, orally, or IV for immunocompromised pt's include


Infections of moist skin and mucus membranes, eyes, ears, oraly/by dentists, vaginal yeast infections, perianal infection.
Drug List for Systemic Infections
Amphotericin B- First one for systemics.

Flucytosine- used only in combo

Ketoconazole - mostly replaced by newer izoles including :
and Caspofungin (newest class that is fairly selective)

These are more difficult to Dx and more serious. The infection site is often not very accessable so we need high concentrations of drugs leading to adverse reactions.
Polyene Antifungal Drugs
Polyene='s double bonds. They are bulky and work by binding to ergosterol to make pores. They work quickly as they do not have to wait for fungi to divide etc. As they bind ergosterol, they are fairly selective for fungal cells.

Amphotericin B- Has been around for a long time, and is used to tx life threatening infections. Available orally, topically (including eye prep), and via IV/catheter. It is often used IV as it is too bulky to be well absorbed GI, or via catheter directly to tx UTI. Binding tightly to tissues, it is present for 7 weeks after Tx. It does cross the BBB if it is enflamed enough so is usable for meningitis. fairly broad spectrum with out too much resistance.. Adverse reactions include hypersensitivity (attenuated by concurrent use of steroids), nephrotoxic (so preload pt with Na, and thrombophlebitis (so infuse slowly). Newer lipid prps may decrease the former 2.

Nystatin- Too toxic for systemic use. Discovered in NY STATE. Used for mucoutaneous/topical/oral infections when the pt is not immunocompromised. Used alot by dentists and for yeast infections, however it is only 60% effective so it is 2ndary to the azoles. With topical use side effects include burning and itching. Note that even with ingestion it is not always absorbed systemically (hence swish and swallow).

Compound to use opthalmically, may cause photosensitivity.
Fluorinated pyrimidine analog. Can be taken orally, however many fungi are now resistant so the spectrum is decreasing. Mostly used in combo with amphoteracin B or itroconazole. Excreted unchanged in urine 80%, and 20% uptaken by fungi thanks the fungal permease (until it mutates). When in the fungal cell it is converted to 5-fleurouracil (chemotherapeudic), and from there to FUTP which inhibits RNA synthesis, or 5-fluorodeoxyuridylate (Fdump) which inhibits thymidylate synthetase/impairs DNA synthesis.
Imidizole/Triazole derivitives.
Original drugs were imidizole dervitives, but the newer ones are tirazoles which are stronger and more selective. In the cell, lanosterol has a 14-A methyl group that gets knocked off to form zymosterol, which goes no to form ergosterol to make nice membranes (see chart). The enzyme 914-A demythylase) is blocked by the azoles which are used for chronic supressive therapy (less toxic than amphoterrible B).

Imidazoles (2N, 5 member ring):
Miconazole- Topical for athletes foot, groin, yeast (90% effective). Availabl IV but not used that way, too many adverse rxns including anaphylxis.

Clotrimazole- similar to miconazole, but also a lozenge (oral topical) form for thrush. Not available systemically in USA, too toxic.

Ketoconazole- 1st available for oral admin (subject of many studies). Available topically, shampoo, oral (requires stomach acid for absorption so beware tums, proton pump inhibitor etc...). reduces ergosterolsynthesis, but also steroid synthesis so adrenal/gonadal insufficiency is a danger. Approved for BPH to reduce testosterone, but may also effect labido. it inhibits P450, and has some hepatotoxicity. Today it is used more topically.

Triazole derivitives (3 N rings, more for systemic use):
Fluconazole- major drug for mucocutaneous candidiasis, also yeast infections (oral dose). Used also for UTI's. Side effects include inhibition of P450, hepatotoxicity etc, but not as bad as imidazoles.

Itraconazole- For onacomycosis. Replaced Ketoconazole alot. IV use for aspergillus, Orally for candidal

Voriconazole- Most potent of both classes. Used for aspergillus and candidal infections.

Posaconazole- newest of all, same general uses.
Derived from penicillium (natural compound). Not antibacterial, but efective against dermatophytes with oral dose. It binds to keratin, localizing to the skin and inhibits division causing multinucleated defective cells. Thus it takes a long time to work. Side effects include GI upset, nausea, mental confision, lethargy, hepatotoxicity. It is still approved but is not used as much cliniclly. Can be used in kids as it is not as hepatotoxic for them. The newer drugs are more effective and not as toxic, but this one has a unique mechanism of blocking microtubles.
Tx of Dermatophytic infections
All of these are available topially, but we are not sure how all of them work.


Ciclopirox- (AKA Penlac) topical lacquer painted on once per day for 48 weeks for onychomycosis (less then 10% effective)



terbinafine- taken orally for Onychomycosis for 12 weeks. 50% effective. The pt will need blood work at the start and 1/2 way to check for hepatotoxicity in spit eof low incidence. Some nausea as well.

caspofungin- newer group inhibiting the synthesis of B-Glucans. Released only as Iv so far and are more for Pt's who do not respond to amphoteracin for aspergillus, systemic candidal infection, micafungin and anidulafungin

Itraconazole- Oral Triazole derivitive taken for 12 weeks for Onychomycosis, 50% effective. Pt will need blood work at start and 1/2 way to measure hepatotoxicity in spite of low incidence. Some nausea and inhibition of P-450