Anti fungal therapies

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how to cure or treat fungal infection, all treatments are described in this presentation.

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Anti fungal therapies

  1. 1.  Fungal Infection: Any inflammatory condition caused by a fungus. Most fungal infections are superficial and mild, though persistent and difficult to eradicate. Some, particularly in older, debilitated, or immunosuppressed or immunodeficient people, may become systemic and life threatening. Some kinds of fungal infections are aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and histoplasmosis.
  2. 2.  Anti Fungal Agent:  Definition An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host.  Polyene Antifungal Drugs Amphotericin, nystatin, and pimaricin interact with sterols in the cell membrane (ergosterol in fungi, cholesterol in humans) to form channels through which small molecules leak from the inside of the fungal cell to the outside.  Azole Antifungal Drugs Fluconazole, itraconazole, and ketoconazole inhibit cytochrome P450- dependent enzymes (particularly C14-demethylase) involved in the biosynthesis of ergosterol, which is required for fungal cell membrane structure and function.  Allylamine and Morpholine Antifungal Drugs Allylamines (naftifine, terbinafine) inhibit ergosterol biosynthesis at the level of squalene epoxidase. The morpholine drug, amorolfine, inhibits the same pathway at a later step.
  3. 3.  Antimetabolite Antifungal Drugs 5-Fluorocytosine acts as an inhibitor of both DNA and RNA synthesis via the intracytoplasmic conversion of 5-fluorocytosine to 5-fluorouracil.  Therapy: Therapy literally means curing, healing and is the attempted remediation of a health problem usually following a diagnosis. In the medical field, it is synonymous with the word "treatment". Among psychologists, the term may refer specifically to psychotherapy or "speech therapy".
  4. 4.  Anti Fungal Therapies: An antifungal medication is a pharmaceutical fungicide used to treat and prevent mycoses such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over-the- counter. Non-surgical therapies were limited to the use of large doses of potassium iodide, weak acids such as phenol, dyes such as methyl violets or other noxious agents including bromine, potassium permanganate, and oil of turpentine with olive oil.
  5. 5. Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism with fewer adverse effects to the host. Unlike bacteria, both fungi and humans are eukaryotes. Thus, fungal and human cells are similar at the biological level. This makes it more difficult to discover drugs that target fungi without affecting human cells. As a consequence, many antifungal drugs cause side-effects. Some of these side- effects can be life-threatening if the drugs are not used properly. Antifungal agents (such as ketoconazole) are often found in antidandruff shampoos. The antifungal drugs inhibit the yeast Malassezia globosa, which encourages seborrhoeic dermatitis and tinea versicolor.
  6. 6. Prophylactic and preemptive therapy Empiric therapy Specific therapy Clinical trial design for antifungal compounds
  7. 7. The terms prophylaxis, targeted prophylaxis, and preemptive are often used interchangeably in conjunction with antifungal therapy. Prophylaxis generally refers to the broad use of antifungal therapy in a heterogeneous group of patients who are at variable risk of developing superficial or invasive fungal infection. By definition, prophylactic antifungal therapy is administered to patients who are considered to be at risk for fungal infection, but who have no symptoms of infection at the time that the antifungal agent is initiated. Prophylaxis may be systemic (e.g. oral or parenteral fluconazole) or topical (e.g. oral nystatin). Virtually any population can be given prophylactic antifungal therapy, but it is typically administered to high-risk patient populations including selected medical and surgical intensive care unit (ICU) patients.
  8. 8. Preemptive antifungal therapy is administered to persons who are not only at risk but also have markers of early infection, for example, colonization with a fungal pathogen. The group that has been best described in conjunction with preemptive therapy is the liver transplant population who meet criteria for very high risk of invasive fungal infection including prolonged intraoperative time, preexisting renal failure, early colonization with Candida spp., retransplant for early graft failure, and choledochojejunostomy anastomosis (Collins et al.1994).
  9. 9. Empiric antifungal therapy refers to the use of these agents among patients with findings and/or symptoms of suspected invasive fungal disease. The use of empiric antifungal therapy has been studied most extensively in persistently febrile and neutropenic patients (Walsh et al. 1999, 2002; Wingard et al. 2000). The primary goal of empiric antifungal therapy in this setting is to prevent breakthrough fungal infections and to treat baseline infections due to molds and other important fungi in this uniquely susceptible host. However, all neutropenic patients are not alike, and the risk of invasive fungal infection is directly related to the underlying condition(s) and the duration and depth of neutropenia.
  10. 10.  Induction therapy for acute myelogenous leukemia is associated with a very high rate of invasive fungal infection and associated high mortality, especially due to invasive mold infections. Myeloablative therapy for most solid tumors usually leads to shorter periods of neutropenia and far less risk of invasive fungal infection. The appropriate use of empiric antifungal therapy in the setting of persistent fever and neutropenia requires that the patient have persistent fever despite a reasonable course (usually 96 hours or more) of broad-spectrum antibacterial therapy, and that there is no other obvious explanation for the clinical deterioration of the patient. It remains one of the most poorly understood and understudied areas in the discipline of antimicrobial therapy.
  11. 11. Specific therapy refers to therapy directed at a specific pathogen which has been detected by culture, histopathology, and serology, or in the absence of laboratory evidence, then clinical/radiographic evidence strongly suggestive of invasive fungal disease. These include such findings as hepatosplenic bull’s eye lesions suggesting chronic disseminated candidiasis, the halo or air crescent sign on chest suggesting invasive aspergillosis, and disseminated cutaneous lesions consistent with invasive candidiasis. Specific therapy is often based on presumptive evidence of infection, but it is nonetheless targeted towards the organisms most likely responsible for the clinical picture.
  12. 12.  The treatment of central nervous system (CNS) cryptococcosis has become more uniform because of data generated fro therapeutic trials among patients with and without the acquired immunodeficiency syndrome (AIDS) who have CNS cryptococcosis (Saag et al. 2000). By contrast, very few large clinical trials have been done among patients with less common invasive mycoses such as aspergillosis,histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis. Thus, the ‘gold standard’ of treatment for these mycoses is often based upon data generated from smaller comparative studies without significant power to discern differences in therapeutic outcome.
  13. 13.  The design and implementation of the clinical trials involving antimycotic agents has been a challenge to clinicians since the availability of amphotericin B in 1958. The key challenges to the clinical investigator include: Slow patient accrual because of restrictive eligibility criteria for uncommon diseases Establishment of meaningful clinical end points The absence of validated surrogate markers of success or failure (e.g. serological studies) The unwillingness of many investigators to perform double-blinded clinical trials The need for large numbers of study centers to facilitate completion of these trials in a reasonable timeframe (Rex et al. 2001).
  14. 14. A recently published candidemia treatment trial enrolled only about 10 percent of all patients with candidemia at study sites (Pappas et al. 2003; Rex et al. 2003). Most of these potentially eligible patients were excluded due to prior antifungal therapy, abnormal laboratory values, age, comorbid conditions, and other considerations. Patient accrual into studies for therapy of invasive aspergillosis has been even more challenging. In a recent open-label trial comparing voriconazole to amphotericin B and other licensed antifungal therapy for the primary treatment of invasive aspergillosis, it required more than 5 years and almost 100 centers to enroll almost 300 eligible patients, again reflecting the effect of restrictive inclusion criteria and the difficulty in establishing a firm diagnosis of an uncommon disorder on patient accrual (Herbrecht et al. 2002).
  15. 15. Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.
  16. 16. Cell membrane • Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) • Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)
  17. 17. Effect of azoles on C. albicans Before exposure After exposure
  18. 18.  The azoles are a very large group of synthetic agents, which includes drugs used in bacterial and parasitic as well as fungal infections. The majority are used as a topical treatment. The drugs listed here are the few which are suitable for systemic administration. The azoles are widely used because of their broad therapeutic window, wide spectrum of activity, and low toxicity.  Members of the azole group have either an imidazole or triazole ring with N carbon substitution.  Imidazole ring: five-membered ring structure containing two nitrogen atoms.  Triazole ring: five-membered ring structure containing three nitrogen atoms.  While ketoconazole was more widely used before the development of newer, less toxic, and more effective triazole compounds, fluconazole and itraconazole, its use has now been limited. Unfortunately, azoles are generally fungistatic (especially in Candida) and resistance to fluconazole is emerging in several fungal pathogens.
  19. 19.  The azoles inhibit the fungal P450 enzymes responsible for the synthesis of ergosterol, the main sterol in the fungal cell membrane. The azoles act through an unhindered nitrogen, which binds to the iron atom of the heme, preventing the activation of oxygen which is necessary for the demethylation of lanosterol. In addition to the unhindered nitrogen, a second nitrogen in the azoles is thought to interact directly with the apoprotein of lanosterol demethylase. It is thought that the position of this second nitrogen in relation to the apoprotein may determine the specificity of different azole drugs for the enzyme.  The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of membrane-associated enzymes. The overall effect is an inhibition of replication (ie. the azoles are fungistatic drugs). A further repercussion is the inhibition of transformation of candidal yeast cells into hyphae-the invasive and pathogenic form of the parasite.  Since no drug acts with complete specificity, it is not surprising that the azoles also have some effect on the closely related mammalian p450 enzymes. These are a large family of haem proteins. Hepatic p450 enzymes are involved in the detoxification of drugs whereas extrahepatic enzymes play an important part in several synthetic pathways including steroid biosynthesis in the adrenal gland.
  20. 20. Paracoccidioi domycosis Penicillium marneffei infection Sporotrichosis Unusual fungal infections Coccidioidomycosis
  21. 21. Treatment: 1. Long-term treatment required 2. Assess response to treatment regularly, as relapses are common 3. Oral itraconazole 100 mg per day for 6 months is preferred treatment. 4. Ketoconazole 200–400 mg per day for up to 12 months almost as effective 5. Oral or parenteral fluconazole 200–400 mg per day for 6 months, if itraconazole or ketoconazole not absorbed 6. Amphotericin B 1.0 mg/kg per day for 4–8 weeks, followed by sulfadiazine 500–1000 mg at 4 h intervals for 6–12 months; children, 60–100 mg/kg per day in divided doses
  22. 22. Type of disease:  Mild Treatment: 1. Itraconazole 200–400 mg per day or ketoconazole 400 mg per day  Severe Treatment: 1. Amphotericin B 1 mg/kg per day for 2 weeks, then itraconazole 200–400 mg per day or ketoconazole 400 mg per day for a further 6 weeks provided improvement is seen with amphotericin B Long-term maintenance for patients with AIDS, itraconazole 200 mg per day – relapse common if treatment discontinued
  23. 23. Type of Disease:  Pulmonary Treatment: 1. Difficult to treat, relapse common Clinical outcome improved by lobectomy and concomitant amphotericin B 1 mg/kg per day, substituted by itraconazole 400 mg per day upon improvement 2. For less severe disease, itraconazole 400 mg per day from outsetDissemination risk  CNS Treatment: 1. Refractory to antifungal therapy
  24. 24.  Osteoarticular Treatment: 1. Itraconazole 400 mg per day for 12 months or longer: shorter courses lead to relapse 2. Fluconazole 400–800 mg per day is less effective; use where there is itraconazole intolerance  Disseminated Treatment: 1. Amphotericin B 1 mg/kg per day, continue until total dose of 1–2 g administered 2. For less acute disease, itraconazole 400 mg per day For AIDS patients, lifelong itraconazole to prevent relapse
  25. 25. Type of disease:  Fusariosis (Fusarium species) Treatment: 1. Correct neutropenia 2. Amphotericin B 1.0–1.5 mg/kg per day, or liposomal amphotericin B 5 mg/kg per day 3. Flucytosine 25 mg/kg every 6 h for non- responders(reversal of neutropenia necessary for recovery)
  26. 26.  Pseudallescheriosis (Pseudallescheria boydii, Scedosporium apiospermum) Treatment: 1. Surgical removal if possible 2. Miconazole 600 mg every 6 h i.v. usually best initial reatment for seriously ill patients (amphotericin B not effective) 3. Itraconazole 400 mg per day for other patients  Phaeohyphomycosis Treatment: 1. Skin and subcutaneous tissue disease 2. Occasional dissemination: surgical excision 3. Itraconazole (oral solution) 400 mg per day
  27. 27.  Trichosporonosis(Trichosporon species) Treatment: 1. Correct neutropenia 2. Amphotericin B 1.0–1.5 mg/kg per day  Paecilomyces lilacinus Treatment: 1. Itraconazole 200 mg per day 3 months.  Malassezia (Pityrosporum) septicemi Treatment: 1. Remove intravascular catheter 2. Fluconazole 1 g i.v. per day if fungemia exists
  28. 28. Type of disease:  Primary pulmonary  No dissemination risk Treatment: 1. Observe, or fluconazole 400 mg per day for 3–6 months.  Dissemination risk Treatment: 1. Amphotericin B 0.5–0.7 mg/kg per day, followed by fluconazole 400 mg for 6 months
  29. 29.  Pulmonary cavity(uncomplicated) or fibronodular disease Treatment: 1. Surgical resection or closure 2. Fluconazole 400 mg per day or itraconazole 200 mg b.d. for at least 12 months. If no response, amphotericin B 0.5–0.7 mg/kg/d  Progressive pulmonary or disseminated (nonmeningeal)  immediately life threatening Treatment: 1. Amphotericin B 1.0–1.5 mg/kg per day, to achieve a total dose of 2500–3000 mg; switch to fluconazole when disease is under control
  30. 30.  slowly progressive or stable Treatment: 1. Fluconazole 400–800 mg/kg per day, or itraconazole 200 mg b.d.  Meningitis Treatment: 1. Fluconazole 600–1200 mg per day 2. Itraconazole 400–600 mg per day 3. Amphotericin B directly into CSF together with systemic therapy followed by oral fluconazole 600–1200 mg/kg/day

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