Fungal & Viral Infections: Etiology and Pathogenesis

• Study notes for Infection & Infectious Diseases-2: Fungal & Viral Infections

Etiology: Fungus

• Fungi have thick, rigid cell walls with multiple protective layers, making them harder to kill and penetrate.
• Some fungi are part of the normal human flora.
• Yeast is unicellular, white, and microscopic, while mold is multicellular, multi-colored, and visible, can also grow in the environment

Systemic Fungal Infection Pathogenesis

• An immunocompromised host from cancer, glucocorticoids or organ transplant from HIV/AIDS comes into contact with environmental fungal spores or an overgrowth of normal flora.
• Host defenses are then invaded, which will result in a systemic fungal infection.

Fungal Clinical Manifestations

• Superficial fungal infections cause localized inflammation and itching.
• Subcutaneous infections have localized or widespread inflammation, resulting in ulcers and abscesses.
• Systemic fungal infections cause pain/discomfort, malaise, possible fever, and increased neutrophils in early infection.

Treatment Implications

• Antifungals can be administered systemically or topically.
• Difficult to deliver, requiring long duration of use, 6-12 months.
• Topical antifungals Systemic antifungals can stress or damage the liver.

Systemic Mycoses

• Fungal infections, treatment can be difficult because of thick cell walls.
• Infections often resist treatment, requiring prolonged therapy with drugs that are frequently more toxic than effective.

Major Groups of Antifungal Agents

• Drugs for systemic mycoses/infections.
• Drugs for superficial mycoses/infections.
• Note that a few drugs are used for both.

Drugs for Systemic Mycoses

• Opportunistic fungal infections can go systemic in immunocompromised hosts and are non-communicable, candidiasis, aspergillosis, cryptococcosis, and mucormycosis.
• Non-opportunistic: Farmers' Lung Disease, usually located in the lungs, as well as sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis, valley fever.

Four Classes of Antifungal Drugs

• Polyene - nystatin and amphotericin B
• Azoles - many types with this ending
• Echinocandins
• Pyrimidine analogs

Amphotericin B

• A polyene agent used only for systemic infections.
• a broad-spectrum antifungal agent also used against some protozoa
• Highly toxic, infusion reactions and renal damage occur in many patients.
• Needs to be administered IV due to no oral administration.
• The drug of choice for most systemic mycoses.
• Before amphotericin B, systemic fungal infections were usually fatal.

Amphotericin B: Mechanism of Action

• Binds to ergosterol, much more than cholesterol, in the fungal cell membrane.
• Bacterial cell membranes lack sterols compared to fungi, which are damaged more than human cells.
• Increases permeability, cells leak intracellular cations, especially potassium, that they use for function, Fungistatic or fungicidal
• cell wall becomes permeable, causing leakage of fungal contents.

Amphotericin B: Adverse Effects

• Infusion reactions: nausea/fever, chills, headache, and rigors.
• Causes nephrotoxicity.
• Hypokalemia toxic kidney is unable to retain potassium
• May cause bone marrow suppression, reducing WBC/RBC/platelet production.

Amphotericin B Infusion Reaction

• Fever, chills, rigors, nausea, and headache are related to cytokine release.
• Symptoms usually begin 1-3 hours after the start of infusion and last about an hour.
• Less intense with lipid-based amphotericin B formulations.

Amphotericin B Infusion Reaction Continued.

• Mild reactions: Pretreatment options include diphenhydramine + acetaminophen, aspirin, IV meperidine or dantrolene, and/or hydrocortisone, as giving normal saline before infusion may prevent dehydration.
• Amphotericin infusion causes a high incidence of phlebitis; minimized by changing peripheral venous sites often, administering through a large central vein, and pretreatment with heparin has a toxic effect if administered slowly IV over 4-6 hours

Azoles

• Broad-spectrum antifungal drugs, as well as an alternative to amphotericin B for most systemic mycoses
• Azoles have lower toxicity than amphotericin B and can be given orally; however, they have hepatotoxic disadvantages that inhibit P450 drug-metabolizing enzymes and can increase the levels of many other drugs.
• Slow process, taking weeks to work, may cause GI side effects, P450 inhibition, and/or hepatotoxicity

Itraconazole [Sporanox]

• This one is an azole group of antifungal agent with a lower toxicity level.
• treats systemic mycoses and is an alternative to amphotericin B.
• It inhibits the synthesis of ergosterol, similar to polyenes, as well as inhibits fungal cytochrome P450 – dependent enzymes.

Itraconazole [Sporanox]: Side Effects

• Well tolerated in usual doses.
• Can cause transient decrease in ventricular ejection fraction and/or liver damage, can inhibit drug-metabolizing enzymes, and cause GI effects like nausea/vomiting/diarrhea/rash/abdominal pain.

Fluconazole [Diflucan]

• an azole group of antifungal agent that is fungistatic.
• It has the same mechanism of action as itraconazole and has good PO absorption.
• IV and PO dosages of fluconazole is the same.
• Adverse effects includes nausea, headache, vomiting, abdominal pain, and diarrhea.

Ketoconazole

• an Azole antifungal agent that inhibits ergosterol.
• Use: Alternative to amphotericin B for systemic mycoses, less toxic and only somewhat less effective, slower effects.
• Is more useful in suppressing chronic infections than in treating severe, acute infections.

Ketoconazole: Adverse Effects

• Ketoconazole is generally well tolerated.
• GI-related adverse effects can be reduced if given with food.
• Can cause hepatotoxicity, rare but potentially fatal hepatic necrosis, and/or has an effect on sex hormones.
• Can inhibit steroid synthesis in humans and causes rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache.

Superficial and Subcutaneous Mycoses

• Mycoses caused by dermatophytic.
• Usually caused by yeast infections
• Includes Candida species usually in mucous membranes and moist skin, chronic infections may involve scalp, skin, and nails.
• Also, dermatophytic infections, ringworm, can be confined to skin, hair, nails.
• Can involve tinea pedis, tinea corporis, tinea cruris, and tinea capitis.

Superficial and Subcutaneous Mycoses

• Both usually has mucous membrane affected
• Includes Oral candidiasis (thrush): oral cavity infections.
• Vulvovaginal candidiasis affects 75% of women at least once, with risk factors include pregnancy, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibiotics.
• Onychomycosis

Superficial Mycoses

• Dermatophytic infections, ringworm involves Tinea pedis, and Tinea capitis.

Onychomycosis

• Onychomycosis does not spread to the skin and is difficult to treat so not much blood circulation, therefore is also a fungal infection of the nails.
• Is less common in women, is has visk of high factor of moisture
• Laser therapy is less problematic, with no insurance coverage.
• Topical therapy, Penlac Nail Lacquer is less effective.
• Usually takes 6-12 months of oral therapy, using itraconazole.

Subcutaneous Candidiasis

• Oral candidiasis includes "thrush", and is often due to common stressors - immunocompromised or recovering from an infection.
• Topical treatments include nystatin, clotrimazole, miconazole, and common polyenes.
• Immunocompromised patients may need oral therapy with fluconazole or ketoconazole.

Nystatin [Mycostatin]

• A polyene antibiotic used only for candidiasis. _ Nystatin is NOT systemic and works locally, also has less side effects
• The drug of choice for intestinal does not absorb in GI.
• The drug is also used for candidal infections in skin, mouth, esophagus, and vagina, and is therefore administered orally or topically.

Etiology: Viral

• Viruses are small, comprised of a capsid to carry genes of the pathogens.
• Have DNA or RNA but not both, possibly with a protective envelope.
• Examples: HIV, coronavirus, adenovirus, stomach flu

DNA Viral Infection Pathogenesis

• Enters mirror cellular pathogen.
• The virus uses penetration of initial defenses, loses capsids and injects DNA/RNA inside converts host enzymes to mRNA with the use of translation to produce viral proteins, resulting in a budding or lysis of the cell and will start with a release of new viral bodies in the host

Role of Immunization

• No vaccine for HIV vine
• Confer immunity to the host via direct exposure and decrease the number of susceptible hosts in the population using polio, influenza, COVID
• CDC recommendations varies by age and over time.

Antiviral Therapy

• Difficult to suppress viral replication without doing significant harm to the host.
• The goal is to antiviral suppress biochemical processes that are unique to viral reproduction.
• Viruses use biochemical machinery of host cells to reproduce.
• The ability to treat viral infections is limited.

Acyclovir [Zovirax[

• Acyclovir is a herpes and varicella medication.
• It is active only against members of the herpesvirus and varicella family and is is first choice for herpes simplex virus and varicella-zoster virus.
• For HSV1- oral
• For HSV2 - genital
• VZV-shingles

Acyclovir [Zovirax]

• It damages of the viruses to block DNA polymerase, by making cells to look like thiamine cells
• The Thymidine kinase adds p to acyclovir and gets incorporated in viral DNA Herpesvirus develops resistance to acyclovir.
• Thymidine is a kinase that adds a phosphate group to thymidine, and blocks DNA from replicating.
• Decreases thiamine production, alteration occurs in altered DNA.

Acyclovir [Zovirax]

• Includes adverse effects; intravenous therapy, oral therapy, topical therapy.
• For intravenous thearpy, phlebitis reversible, nephrotoxicity and neurotosocity can be found.
• Oral thereapy can be found, that the Gastrointestinal, vertigo.
• For Topical Therapy you can see stinging sensations

Cytomegalovirus infection

• Cytomegalovirus, CMV, cannot be treated with acyclovir.
• Is a herpes member of the herpes virrus group and may only trasmitted throug body contact in direct contact with fluids.
• Is dormant until the for age 40.
• The 50% to 80 % of the americans is likely risk of reactivation or more in order which 40 age from adults, has high risk of of reacion due to immunosuppression, and is there dormant life

Ganciclovir

• Family of ciclovir that is a synthetic antiviral agent to treat preventions.
• Can also be used used for for CMV infections in transplant those with receiving Herpes receiving simplx, viruses, including, those which are HIV infections.
• The drug and its agents can cause serious side effects, thrombocytopina and granuloytopenia, causing bone marrow suppression and decrease wbcs.

Ganciclovir [Cytovene, Vitrasert, Zirgan]

• Absorve those skin agents may cause, and that may also affect those reiceves who administers to adults.
• Affect Adverse with symptoms with reproductive toxicity from central system with other CNS
• And has also been know the have Granulocyopenia and Thromboctoenia.

Influenza Virus

• Includes communible virus where live vaccines are provided for those with dropets for percatious.
• It may be that for the that through airaway, from more symptatic that those with comon cold.
• It should be noted that wear a mask and surgical hand hygeine.
• Antiviral drug calll Tamiflu is used, and that may reduce s/s those which are pregnant.
• They reduce that risk for pregnant covered

Tamlifu-ndres viral load and heeps unw studh in nfected cells

• It's not super effective may also pregnant nwren are often immunocompromised to this medication helps decrease rish
• Airbone need: and N95 which are different trains it can every year

HIV Transmission

• Those with HIV infection are at risk of transission
• Through needle transmission and infected through with blood products.
• Unprotheded, also with sexual to to perinatals
• . It causes transmission the increases if paicent on mawaire they are infected.
• • Transmission the patient to meds

HIV: Pathogenesis & Treatment

• The when gaset the and cd4.
• The orange color from the infection _ In a cells virus helper _ To that and to

HIV: Pathogenesis & Treatment Implications

• Orange
• The virus interfers by making new viruses by spliced into its DNA that also is integtase

Pathogenesis of HIV and AIDS

• The acute phase involves seroconversion and can have rapid and increase viruses to plasms . This may lead to seroconversion from plasma and body

• That the clican of infection is lower and The leads the pathogens through the patient

AIDS Clinical Manifestations

• Stage 1 can be the taken after or to overstime and
• Which as cd4 of In can have can be lead to be to over- the the active by stopping

Opportunistic Infections

• Can sprad from mall interstions to , pnacompersion states to those those of

• And seen tumberculsis Avium

• Dissemated over the body causes

HIV treatment implication

• With the the may and after of
• But may help or and of
• Is needed that antiretroviral treatments be given , and needs for supportive care. This help througj of infections

Drugs for HIV Infection and Related

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Study notes covering the etiology and pathogenesis of fungal infections. It highlights the characteristics of fungi, including their cell walls and forms such as yeast and mold. Pathogenesis in immunocompromised hosts and clinical manifestations of fungal infections are discussed.