Viral and Fungal Diseases and Treatments PDF

Infection & Infectious Diseases-2: Fungal & Viral Infections N112 Pathopharmacology Samuel Merritt University Fungal Infection  Etiology: Fungus Thick rigid cell walls Some are part of normal flora Yeast VS Mold  Systemic Fungal Infe...

Infection & Infectious Diseases-2: Fungal & Viral Infections N112 Pathopharmacology Samuel Merritt University Fungal Infection  Etiology: Fungus Thick rigid cell walls Some are part of normal flora Yeast VS Mold  Systemic Fungal Infection Pathogenesis Immunocompromised host Environmental fungal spores/normal flora over-grow/invade host defenses Systemic Fungal infection  Fungal Clinical Manifestations Superficial Localized inflammation Itching Subcutaneous Localized or more wide spread inflammation Ulcers and abscesses Systemic Pain/discomfort Malaise Possible fever ↑ neutrophils in early infection  Treatment Implications Antifungals Difficult to deliver Topical Systemic-stress/damage liver Antifungal Agents  Systemic Mycoses Treatment can be difficult Infections often resist treatment Treatment may require prolonged therapy with drugs that frequently prove toxic 8  Major Groups of Antifungal Agents Drugs for systemic mycoses/infections Drugs for superficial mycoses/infections Note: A few drugs are used for both. 9  Drugs for Systemic Mycoses Opportunistic Immunocompromised host Candidiasis, aspergillosis, cryptococcosis, mucormycosis Non-opportunistic: Farmers’ Lung Disease Can occur in any host Sporotrichosis, blastomycosis, histoplasmosis, coccidioidomycosis 10  Four Classes of Antifungal Drugs 1. Polyene 2. Azoles 3. Echinocandins 4. Pyrimidine analogs 11  Amphotericin B Broad-spectrum antifungal agent (also used against some protozoa) Highly toxic Infusion reaction and renal damage occur in many patients Must be given IV; no oral administration Uses Drug of choice for most systemic mycoses Before amphotericin B, systemic fungal infections were usually fatal 12  Amphotericin B Mechanism of action Binds to ergosterol (much more than cholesterol) in fungal cell membrane Bacterial cell membranes lack sterols Fungi damaged more than human cells Increases permeability Cell leaks intracellular cations (especially potassium) Fungistatic or fungicidal 13  Amphotericin B Adverse effects Infusion reactions Nephrotoxicity Hypokalemia Results from damage to kidneys Potassium supplements may be needed Monitor serum levels Bone marrow suppression 14  Amphotericin B Infusion reaction Fever, chills, rigors, nausea, and headache Caused by release of proinflammatory cytokines Symptoms begin 1 to 3 hours after start of infusion and last for about 1 hour Less intense with lipid-based amphotericin B formulations 15  Amphotericin B Infusion reaction (Cont.) Mild reactions: Pretreatment options Diphenhydramine + acetaminophen Aspirin can help but may increase renal damage IV meperidine or dantrolene can be given if rigors occur Hydrocortisone can be given with caution Amphotericin infusion produces a high incidence of phlebitis; this can be minimized by changing peripheral venous sites often, administering amphotericin through a large central vein, and pretreatment with heparin 16  Azoles Broad-spectrum antifungal drugs Alternative to amphotericin B for most systemic mycoses Lower toxicity Can be given orally Disadvantage Inhibit P450 drug-metabolizing enzymes and can increase levels of many other drugs 17  Itraconazole [Sporanox] Azole group of antifungal agents Lower toxicity level Use Systemic mycoses (alternative to amphotericin B) Mechanisms of action Inhibits the synthesis of ergosterol Inhibits fungal cytochrome P450 – dependent enzymes 18  Itraconazole [Sporanox] Side effects (well tolerated in usual doses) Cardiosuppression Transient decrease in ventricular ejection fraction Liver damage Watch for signs of liver dysfunction Can inhibit drug-metabolizing enzymes GI effects Nausea, vomiting, diarrhea, rash, abdominal pain 19  Fluconazole [Diflucan] Azole group of antifungal agents Fungistatic Same mechanism of action as itraconazole Good PO absorption IV and PO dosage the same 20  Fluconazole [Diflucan] Adverse effects Nausea Headache Vomiting Abdominal pain Diarrhea 21  Ketoconazole Azole group of antifungal agents Mechanism of action Inhibits ergosterol Use: Alternative to amphotericin B for systemic mycoses Less toxic and only somewhat less effective Slower effects More useful in suppressing chronic infections than in treating severe, acute infections 22  Ketoconazole Adverse effects (generally well tolerated) GI (can be reduced if given with food) Hepatotoxicity Rare but potentially fatal hepatic necrosis Effect on sex hormones Can inhibit steroid synthesis in humans Other adverse effects Rash, itching, dizziness, fever, chills, constipation, diarrhea, photophobia, and headache 23  Superficial and Subcutaneous Mycoses Mycoses caused by two groups of organisms Candida species Usually in mucous membranes and moist skin Chronic infections may involve scalp, skin, and nails Dermatophytic infections (for example, ringworm) Usually confined to skin, hair, and nails Tinea pedis (ringworm of the foot, or “athlete’s foot”), tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin, or “jock itch”), and tinea capitis (ringworm of the scalp) 24  Superficial and Subcutaneous Mycoses Oral candidiasis (thrush) Vulvovaginal candidiasis 75% of women experience at least once Risk factors Pregnancy, diabetes, debilitation, HIV, oral contraceptives, systemic glucocorticoids, anticancer agents, and systemic antibiotics Onychomycosis 25  Superficial Mycoses Dermatophytic infections (e.g., ringworm) Tinea pedis (feet) Tinea capitis (scalp) Drugs 26  Tinea corporis (body) Image result for tinea cruris Tinea cruris (groin)  Tinea capitis (scalp)  Onychomycosis (Fungal Infection of the Nails) Oral therapy Itraconazole (Sporanox) Topical therapy Ciclopirox (Penlac Nail Lacquer) Laser therapy 30  Subcutaneous Candidiasis Oral candidiasis Topical: nystatin, clotrimazole, miconazole, and amphotericin B Immunocompromised patients may need oral therapy with fluconazole or ketoconazole 31  Nystatin [Mycostatin] Polyene antibiotic Used only for candidiasis Drug of choice for intestinal candidiasis Also used for candidal infections in skin, mouth, esophagus, and vagina Can be administered orally or topically 32 Viral Infection  Etiology: Viral Small Composed of Capsid DNA or RNA Possibly protective envelope Examples: HIV, coronavirus, adenovirus  DNA Viral Infection Pathogenesis Host enzymes Penetrate Produce viral convert DNA initial defenses proteins to mRNA Release of new Budding or Viruses viral bodies in lyses of cell assembled the host  Role of Immunization Confer immunity to the host by direct exposure to the pathogen Decrease number of susceptible hosts in the population CDC recommendations Vary by age Change over time Antiviral Agents I: Drugs for Non-HIV Viral Infections  Antiviral Therapy Our ability to treat viral infections remains limited Viruses use biochemical machinery of host cells to reproduce Difficult to suppress viral replication without doing significant harm to the host Antivirals suppress biochemical processes unique to viral reproduction 38  Acyclovir [Zovirax] Active only against members of the herpesvirus family Agent of first choice for herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection Herpes simplex genitalis Mucocutaneous herpes simplex infections VZV infections 39  Acyclovir [Zovirax] Herpesvirus develops resistance to acyclovir Decreased thymidine production Alteration in thymidine kinase Alteration of viral DNA polymerase 40  Acyclovir [Zovirax]: Adverse Effects Intravenous therapy Phlebitis Reversible nephrotoxicity Neurotoxicity Oral therapy Gastrointestinal Vertigo Topical therapy Stinging sensations 41  Cytomegalovirus Infection Cytomegalovirus (CMV): Member of the herpesvirus group Transmitted by direct contact with body fluids 50% to 80% of Americans age 40 years or older harbor the virus Can remain dormant for life Immunosuppressed patients at high risk for reactivation of dormant virus 42  Ganciclovir [Cytovene, Vitrasert, Zirgan] Synthetic antiviral agent Uses Herpes simplex viruses, including CMV Prevention and treatment of CMV infection in immunocompromised patients, including transplant patients, those with HIV infection, and those receiving immunosuppressive drugs Serious side effects Granulocytopenia Thrombocytopenia 43  Ganciclovir [Cytovene, Vitrasert, Zirgan] Adverse effects Granulocytopenia Thrombocytopenia Reproductive toxicity Nausea, fever, rash, anemia, liver dysfunction, confusion, and other central nervous system (CNS) symptoms 44  Influenza Virus Droplet precaution S/S Vaccine Tamiflu (Oseltamivir) ✓Neuraminidase inhibitors ✓Start in the first 48 hrs HIV/AIDS  HIV Transmission Blood transmission Needle transmission Infected blood product Sexual contact Unprotected with infected partner Perinatal In utero During delivery Breast milk HIV: Pathogenesis & Treatment Implications GP120 bind to Reverse CD4 receptor transcriptase Healthy host Virus core RNA to T helper cell/ injected in cytoplasm DNA macrophage DNA polymerase Combines w CCR5/CXCR4 Gp 41 implants in cell membrane Refold/ Fuses to 2nd DNA change host cell strand shape HIV: Pathogenesis & Treatment Implications Protease Infected Double cell Creates stranded DNA prolifer- new virion ates Integrase New viruses HIV provirus enter Enters spliced into circulation to nucleus host’s DNA infect more cells  HIV/AIDS Pathogenesis Acute HIV Infection Chronic HIV AIDS (Stage 1) Infection (Stage 2) (Stage 3) Seroconversion Clinical latency CD4 < 200 Rapid virus and/or an production opportunistic infection  HIV/AIDS Clinical manifestations Flu-like Asymptomatic Cancers symptoms Mild, generalized Opportunistic infections Hairy leukoplakia symptoms Chronic skin rashes Chronic Cough/ SOB lymphadenopathy Painful swallowing Persistent diarrhea Fever Stage 2 Stage 1 Stage 3 Vision loss Weight loss Extreme fatigue N/V Severe headaches  Opportunistic Infections Cryptosporidium—diarrhea Candida albicans—thrush PNA Cytomegalovirus (CMV) TB pneumocystis carinii (PCP) Mycobacterium avium complex (MAC)—disseminated over the body Kaposi Sarcoma—cancers of skin and GI tract  HIV/AIDS Treatment implications Antiretroviral treatment Supportive care Treatment of opportunistic infections Antiviral Agents II: Drugs for HIV Infection and Related Opportunistic Infections  Drugs for HIV Infection and Related Opportunistic Infections Human immunodeficiency virus is a retrovirus (HIV-1 and HIV-2) HIV has RNA as genetic material Uses reverse transcriptase to convert RNA into DNA and integrase to insert its DNA into ours Target cells: CD4 T cells (helper lymphocytes) Transmission via blood and body fluids Virus is present in all body fluids 55  Human Immunodeficiency Virus Promotes immunodeficiency by killing CD4 T lymphocytes Transmission of HIV Clinical progression Difference between HIV and AIDS Global epidemic Standard antiretroviral therapy (ART) Reduced AIDS deaths by 72% Highly active antiretroviral therapy (HAART) 56  Classification of Antiretroviral Drugs Five types of antiretroviral drugs Inhibit enzymes required for HIV Reverse transcriptase inhibitors Integrase strand transfer inhibitors Protease inhibitors Block viral entry into cells Fusion inhibitors CCR5 antagonists 57  Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine [Retrovir] Inhibits HIV replication by suppressing synthesis of viral DNA Adverse effects Hematologic toxicity Lactic acidosis with hepatomegaly Myopathy Gastrointestinal effects Central nervous system (CNS) reactions Others Drug interactions 58  Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Differ from NRTIs in structure and mechanism of action NNRTIs bind to active center of reverse transcriptase and cause direct inhibition Active as they are administered 59  Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz [Sustiva] Nevirapine [Viramune] Delavirdine [Rescriptor] Etravirine [Intelence] Rilpivirine [Edurant] 60  NNRTIs Efavirenz [Sustiva] Preferred agent for treating HIV Only NNRTI recommended for first-line therapy of HIV infection Drug interactions Adverse effects Transient adverse CNS effects in 50% of patients Rash Teratogenicity 61  Protease Inhibitors Among the most effective antiretroviral drugs Nine are available Used in combination with NRTIs; can reduce viral load to an undetectable level Resistance 62  Protease Inhibitors Adverse effects Hyperglycemia/diabetes Fat redistribution Hyperlipidemia Reduced bone density Increased bleeding in people with hemophilia Reduced bone mineral density Elevation of serum transaminase Drug interactions 63  Protease Inhibitors Lopinavir/ritonavir (Kaletra) Ritonavir Indinavir Saquinavir Nelfinavir 64  HIV Integrase Strand Transfer Inhibitors Raltegravir [Isentress] Indicated for combined use with other antiretroviral agents to treat adults infected with HIV-1 Adverse side effects Insomnia, headache, and rare hypersensitivity reactions FDA pregnancy risk: Category C 65  Enfuvirtide [Fuzeon] HIV fusion inhibitor Widely known as T-20 First and only HIV fusion inhibitor Blocks entry of HIV into CD4 T cells Twice-daily subQ dosing Adverse effects Injection-site reactions, pneumonia, and hypersensitivity reactions 66  Maraviroc [Selzentry] CCR5 antagonist Indicated for combined use with other antiretroviral drugs to treat patients age 16 years or older who are infected with CCR5-tropic HIV-1 strains Adverse effects Drug interactions 67  Combination HIV Medication abacavir/dolutegravir/lamivudine (Triumeq) dolutegravir/rilpivirine (Juluca) elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (Stribild) elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya) efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla)  Principal Laboratory Tests Used to Guide Therapy CD4 T-cell counts: Principal indicator of how much immunocompetence remains Plasma HIV RNA (viral load) assays: Ongoing treatment of HIV infection is guided primarily by monitoring viral load, which is determined by measuring HIV RNA in plasma 69  HIV Drug Resistance In most cases, resistance emerges over the course of treatment as a result of nonadherence to the prescribed regimen Rarely, resistance results from primary infection with a drug-resistant HIV variant Resistance tests can be used to guide drug selection, especially when changing a regimen that has failed 70  HIV Treatment in Pregnancy Same principles that guide antiretroviral therapy in nonpregnant adults Mother-to-child transmission HIV Risk for transmission can be greatly reduced by ART, which minimizes maternal viral load The same general principles apply to children 71  HIV Treatment Treatment of young patients Treatment of older patients Preventing HIV infection with drugs Pre- and postexposure prophylaxis Preventing perinatal HIV transmission Prophylaxis and treatment of opportunistic infections 72  HIV Vaccines Obstacles to vaccine development Current status of vaccine development 73