Anti Fungal Therapies

Introduction

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.

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.

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".

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.

Mechanism of Action

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.

Types of Antifungal Therapies

Prophylactic and preemptive therapy

Empiric therapy

Specific therapy

Clinical trial design for antifungalcompounds

Prophylactic and preemptive therapy

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.

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).

EMPIRIC THERAPY

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.

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.

SPECIFIC THERAPY

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.

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.

CLINICAL TRIAL DESIGN FORANTIFUNGAL COMPOUNDS

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 unwillingness of many investigators to perform double-blinded clinical trials

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).

What are the targets for antifungal therapy?

Cell membraneFungi use principally ergosterol instead of cholesterol

Cell WallUnlike mammalian cells, fungi have a cell wall

DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.

Cell Membrane Active Antifungals

Cell membrane • Polyene antibiotics - Amphotericin B, lipid

formulations - Nystatin (topical)

• Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals)

Effect of azoles on C. albicans

Before exposure After exposure

Azoles

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.

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.

Examples Of Diseases which cure by Antifungal Therapies

Paracoccidioidomycosis

Penicillium marneffei infection

SporotrichosisUnusual fungal

infections

Coccidioidomycosis

ParacoccidioidomycosisTreatment:1. Long-term treatment required2. Assess response to treatment regularly, as relapses

are common3. 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 effective5. Oral or parenteral fluconazole 200–400 mg per day for

6 months, if itraconazole or ketoconazole not absorbed6. 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

Penicillium marneffei infection

Type of disease: MildTreatment:1. Itraconazole 200–400 mg per day or ketoconazole 400

mg per day SevereTreatment: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

Sporotrichosis

Type of Disease: PulmonaryTreatment: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

CNSTreatment:1. Refractory to antifungal therapy

OsteoarticularTreatment:1. Itraconazole 400 mg per day for 12 months

or longer: shorter courses lead to relapse2. Fluconazole 400–800 mg per day is less

effective; use where there is itraconazole intolerance

DisseminatedTreatment:1. Amphotericin B 1 mg/kg per day, continue

until total dose of 1–2 g administered2. For less acute disease, itraconazole 400 mg

per day For AIDS patients, lifelong itraconazole to prevent relapse

Unusual fungal infections

Type of disease: Fusariosis (Fusarium species)Treatment:1. Correct neutropenia2. 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)

Pseudallescheriosis (Pseudallescheria boydii, Scedosporium apiospermum)

Treatment:1. Surgical removal if possible2. 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

PhaeohyphomycosisTreatment:1. Skin and subcutaneous tissue disease2. Occasional dissemination: surgical excision3. Itraconazole (oral solution) 400 mg per day

Trichosporonosis(Trichosporon species)Treatment: 1. Correct neutropenia2. Amphotericin B 1.0–1.5 mg/kg per day Paecilomyces lilacinusTreatment:1. Itraconazole 200 mg per day 3 months. Malassezia (Pityrosporum) septicemiTreatment:1. Remove intravascular catheter2. Fluconazole 1 g i.v. per day if fungemia

exists

Coccidioidomycosis

Type of disease: Primary pulmonary No dissemination risk Treatment:1. Observe, or fluconazole 400 mg per day for

3–6 months. Dissemination riskTreatment:1. Amphotericin B 0.5–0.7 mg/kg per day,

followed by fluconazole 400 mg for 6 months

Pulmonary cavity(uncomplicated) or fibronodular disease

Treatment:1. Surgical resection or closure2. 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 threateningTreatment: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

slowly progressive or stableTreatment:1. Fluconazole 400–800 mg/kg per day, or

itraconazole 200 mg b.d. MeningitisTreatment:1. Fluconazole 600–1200 mg per day2. Itraconazole 400–600 mg per day3. Amphotericin B directly into CSF together

with systemic therapy followed by oral fluconazole 600–1200 mg/kg/day