Chemotherapy of Fungal Diseases

CHEMOTHERAPY OF FUNGAL DISEASES
TABLE OF CONTENTS
Fungal infections Introduction Causes Infection Fungi Types of fungal infections Superficial Sub-Cutaneous Systemic Antifungal drugs Classification Polyenes Heterocyclic benzofurans Imidazoles Triazoles Antimetabolites
SHADAN COLLEGE OF PHARMACY DEPT. OF PHARMACOLOGY
Echinocandins Allylamines Others
Fungal infections
Introduction Fungal infections are also called as mycoses. Fungi that cause a disease usually exist as commensals in the environment. Mycosis is gone before we notice and was not a serious threat before 1950. But now more sinister infections which are iatrogenic have come into existence. A variety of environmental and physiological conditions can contribute to the development of fungal diseases. Fungal infection may be contageous. Inhalation of fungal spores or localized colonization of the skin may initiate persistent infections; therefore, mycoses often start in the lungs or on the skin Causes of fungal infection People are at risk of fungal infections when they are taking strong Broad spectrum antibiotics for a long period of time because these antibiotics not only kill harmful bacteria, but also healthy bacteria that are not pathogenic and prevent the entry of other organisms. This alters the
SHADAN COLLEGE OF PHARMACY
DEPT. OF PHARMACOLOGY
balance of microorganisms in the mouth, vagina, intestines and other places in the body, and results in an overgrowth of fungus. Individuals with weakened immune systems are also at risk of developing fungal infections. People with HIV/AIDS, people under steroid treatments (using corticosteroids), and people taking chemotherapy (anticancer drugs) are at higher risk. Other reasons for fungal infections include immunosuppressant drugs, dentures, indwelling catheters and implants. People with diabetes also tend to develop fungal infections. Very young and very old people, also, are groups at risk
What is an Infection? An infection is the colonization in a host organism by parasite species. Infecting parasites seek to use the host's resources for its various functions, like reproduction, often resulting in disease. There is actually a war taking place when there is infection and it is between the host organisms
and the foreign invading organisms. When the host organisms lose the battle, infection happens. Infections are usually considered to be caused by microscopic organisms or micro parasites like viruses, prions, bacteria, and viroids, though larger organisms like macro parasites and fungi can also infect. Nosocomial infections, which are also referred to as hospital-acquired infections, are a common cause of complications in people who have been hospitalized.
What is a fungus? Fungus is the main decomposer of organic matter and has fundamental roles in nutrient cycling and exchange. They have long been used as a direct source of food, (mushrooms and truffles), in fermentation of various food products, such as wine, beer, and soy sauce. Fungi can cause serious diseases in humans, several of which may be fatal if untreated. Mycology is the branch of biology concerned with the systematic study of fungi. It is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts, molds and mushrooms. As other eukaryotes, fungal cells contain membrane-bound nuclei with chromosomes that contain DNA, organelles such as
mitochondria, sterol containing membranes (the sterol moiety in fungus is ergosterol where as in mammalians it is cholesterol), and ribosomes of the 80S type.
Fungi, as they lack chloroplasts, cannot synthesize food and hence are heterotrophic organisms, requiring preformed organic compounds as energy sources. Around 100,000 species of fungi have been formally described by taxonomists. Fungi may be broadly divided into three main groups. They are
Moulds grow in the form of multicellular filaments called
hyphae. They reproduce by spores, which may produce mycotoxins leading to illness. Spores are the infecting stages.
Yeasts
they usually ferment sugars. they grow by budding, The nucleus of the parent cell splits into a daughter nucleus and migrates into the daughter cell. The bud continues to grow until it separates from the parent cell, forming a new cell. They cause systemic and topical infections.
Dimorphic
fungi they are named so as they are capable of changing growth pattern. At room temperature, it grows as a mold. At body temperature, it grows as a yeast They can be considered as primary pathogens as they cause systemic mycosis.
Fungi may be endemic which is pathogenic in all exposed patients (e.g. histoplasma capsulatum, coccidioides immitis). They may be opportunists (e.g. Candida, aspergillus), which cause infections in patients with immune deficiencies who would otherwise not be infected. They are less virulent in normal individuals They may cause illness via mycotoxins One mold species may produce many different mycotoxins and/or the same mycotoxin as another species. They may cause allergic
reaction after inhalation of spores
Types of fungal infections

Fungal infections can be broadly classified in to following types Superficial subcutaneous systemic Superficial mycoses These diseases are restricted to the keratinized layers of the skin, hair, and nails. They may extend deeper into the epidermis, and may cause invasive hair and nail diseases. Host immune responses may be evoked, resulting in pathologic changes expressed in the deeper layers of the skin. The organisms that cause these diseases are called
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dermatophytes. The resulting diseases are often called ringworm (even though there is no worm involved) or tinea; others include Microsporum, Trichophyton, and Epidermophyton fungi.
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Examples: Beard - tinea barbae, Body - tinea corporis, feet -tinea pedis (also called athlete's foot), Groin area - tinea cruris (also called jock itch), Scalp - tinea capitis
Tinea (Ring worm) They occur as several patches of ringworm on the skin at once. The fungus thrives in warm, moist areas. They are contagious, and can be passed through direct contact, or contact with items such as shoes, stockings, and shower or pool surfaces. The most common symptom is cracked, flaking, peeling skin between the toes or side of the foot. Other symptoms can include: Red and itchy skin, Burning or stinging pain, Blisters that ooze or get crusty. If the fungus spreads to your nails, they can become discolored, thick, and even crumble Ringworm can affect the skin on your: Beard - tinea barbae, Body - tinea corporis, feet -tinea pedis (also called athlete's foot), Groin area - tinea cruris (also called jock itch), Scalp tinea capitis
Athlete's foot (Tinea pedis); Athlete's foot may last for a short or long time and may come back after treatment. It occurs when a certain fungus (Tinea versicolor) grows on your skin in your feet. In
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addition to the toes, it may also occur on the heels, palms, and between the fingers.
Dermatomycosis It is one of the most frequent dermal lesions in which, not only the skin but also dermal appendices like hair and nails are affected. Mycosis of smooth skin is represented by single or multiple sots with light or more manifested desquamation. It can be accompanied by itching. Their friability and thickening is specific at infection of skin and nails. They are caused by Microsporum, Trichophyton, and Epidermophyton fungi.
Subcutaneous mycoses Subcutaneous mycoses involve the dermis, subcutaneous tissues, muscle, and fascia. These infections are chronic and
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can be initiated by piercing trauma to the skin, which allows the fungi to enter. These infections are difficult to treat and may require surgical interventions such as debridement. E.g. mycetoma, chromoblastomycosis, sporotrichosis
Mycetoma
Mycetoma is a chronic subcutaneous infection caused by actinomycetes fungi. This infection results in a granulomatous inflammatory response in the deep dermis and subcutaneous tissue, which can extend to the underlying bone. Mycetoma is characterized by the formation of grains containing aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses. The body parts affected most commonly in persons with mycetoma include the foot or lower leg, with infection of the dorsal aspect of the forefoot being typical. The hand is the next most common location. Lesions on the chest and back are frequently caused by Nocardia species, whereas lesions on the head and neck are usually caused by Streptomyces somaliensis.
Chromoblastomycosis
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Chromoblastomycosis is a chronic fungal infection of the skin and the subcutaneous tissue caused due to inoculation of dematiaceous fungi usually Fonsecaea pedrosoi, Phialophora verrucosa, Cladosporium carrionii, or Fonsecaea compacta, through the skin. The causative organism enters through sites of local trauma (e.g., cut on the hand, foot splinter, local trauma related to carrying soil-contaminated material). A neutral response initially occurs, which may be followed by a granulomatous reaction. Spread occurs through skin facial planes and can involve the bone. Hematogenous or lymphatic spread is uncommon Chromoblastomycosis spreads very slowly; it is rarely fatal and usually has a good prognosis, but it can be very difficult to cure. The infection builds at the site over a period of years, and a small red papule (skin elevation) appears. The lesion is usually not painful and there are few, if any symptoms. Usually, the infection slowly spreads to the surrounding tissue while still remaining localized to the area around the original wound. However, sometimes the fungi may spread through the blood vessels or lymph vessels, producing metastatic lesions at distant sites. Another possibility is secondary infection with bacteria. This may lead to lymph stasis (obstruction of the lymph vessels) and elephantiasis. The nodules may become ulcerated, or multiple nodules may grow and coalesce, affecting a large area of a limb
Sporotrichosis
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Sporotrichosis is a long-term (chronic) skin infection due to the fungus Sporothrix schenckii, which is found in vegetation. Infection commonly occurs when the skin is broken while handling plant materials such as rosebushes, briars, or mulch-rich dirt. Widespread (disseminated) sporotrichosis can develop in people with compromised immune systems when they inhale dust filled with spores. Symptoms include a small, painless, red lump that develops at the site of infection and eventually turns into an ulcer. The lump may develop up to 3 months after an injury. Sores are often on the hands and forearm, because these areas are common injury sites. The fungus follows lymphatic channels in the body. Small ulcers appear in lines on the skin as the infection goes up an arm or leg. These sores do not heal unless they are treated and may remain for years. The nodules may drain small amounts of pus from time to time. Body-wide (systemic) sporotrichosis can cause lung and breathing problems, bone infection, arthritis, and infection of the nervous system. Systemic mycoses Systemic mycoses due to primary pathogens originate primarily in the lungs and may spread to many organ systems. Organisms that cause systemic mycoses are inherently virulent. E.g. histoplasmosis, coccidioidomycosis, blastomycosis
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Blastomycosis
It is a rare infection that may develop when people breathe in (inhale) a fungus called Blastomyces dermatitidis, which is found in wood and soil, particularly where there is rotting vegetation. The fungus enters the body through the lungs, infecting them. The fungus then spreads (disseminates) to other areas of the body. The infection may affect the skin, bones and joints, and other areas. Blastomycosis is rare. Lung infection may not cause any symptoms. Symptoms may be seen if the infection spreads. Symptoms may include: bone pain, chest pain, cough (may produce brown or bloody mucus), fatigue, fever, general discomfort, uneasiness, or ill feeling (malaise),joint pain, muscle pain, night sweats, rash, shortness of breath, sweating, unintentional weight loss
Coccidioidomycosis
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Coccidioidomycosis is infection with the spores of the fungus Coccidioides immitis. Infection spreads by breathing in fungal particles from soil. The infection starts in the lungs. There are three forms of coccidioidomycosis: acute, chronic, or disseminated. Acute is almost always mild, with few or no symptoms, and goes away without treatment. The incubation period -- the time between breathing in the spores and becoming sick -is 7 to 21 days. Chronic can develop 20 or more years after initial infection. Infections (lung abscesses) can form and rupture, releasing pus (emphysema) between the lungs and ribs (pleural space). Disseminated coccidioidomycosis is a widespread form of the disease. Infection spreads to other parts of the body, including the skin, brain, bones, and heart. Meningitis occurs in up to half of all people with disseminated coccidioidomycosis.Travelling to an area where the fungus is commonly seen raises the risk for this infection. Most people with this infection never have symptoms. Others may have cold- or flu-like symptoms or symptoms of pneumonia. If symptoms occur, they typically start 5 to 21 days after being exposed to the fungus. They include change in mental status, chest pain (can vary from mild to severe) cough, possibly producing blood, fever, headache, joint pain, loss of appetite, muscle aches, neck stiffness, etc.
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Histoplasmosis Histoplasmosis is an infection due to the Histoplasma capsulatum fungus. The infection enters the body through the lungs. Histoplasma fungus grows as a mold in the soil, and infection results from breathing in airborne particles. Soil contaminated with bird or bat droppings may have a higher concentration of histoplasma. There may be a short period of active infection, or it can become chronic and spread throughout the body. Histoplasmosis may have no symptoms. Most people who do develop symptoms will have a flu-like syndrome and lung (pulmonary) complaints related to pneumonia or other lung involvement. Those with chronic lung disease (such as emphysema and bronchiectasis) are at higher risk of a more severe infection. People with histoplasmosis may develop inflammation (irritation and swelling) in response to the initial infection. This can affect the skin, bones or joints, or the lining of the heart (pericardium). These symptoms are not due to fungal infection of those body parts, but to the inflammation. In a small number of patients, histoplasmosis may become widespread (disseminated), and involve the blood, meninges (outer covering of the brain), adrenal glands, and other organs. Symptoms depend on the type of infection. Acute symptomatic pulmonary histoplasmosis: fever, chills, cough, chest pain, etc.Chronic pulmonary histoplasmosis: Chest pain, cough, possibly coughing up blood, fever, shortness of breath, sweating,Disseminated histoplasmosis:
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Fevers, headache, neck stiffness, mouth sores, skin lesions, etc.
Systemic mycoses due to opportunistic pathogens are infections of patients with immune deficiencies who would otherwise not be infected. Examples of opportunistic mycoses include Candidiasis, Cryptococcosis and Aspergillosis.
Candidiasis Candidiasis or thrush is a fungal infection of any of the Candida species (all yeasts), of which Candida albicans is the most common. Also commonly referred to as a yeast
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infection, Candidiasis is also technically known as candidosis, moniliasis, and oidiomycosis. Candidiasis encompasses infections that range from superficial, such as oral thrush and vaginitis, to systemic and potentially life-threatening diseases. Candida infections of the latter category are also referred to as candidemia. Superficial infections of skin and mucosal membranes by Candida causing local inflammation and discomfort are common in many human populations. Candidiasis is usually a very localized infection of the skin or mucosal membranes, including the oral cavity (thrush), the pharynx or oesophagus, the gastrointestinal tract, the urinary bladder, or the genitalia (vagina, penis).Candidiasis is a very common cause of or vaginitis. Candida infections can affect the oesophagus with the potential of becoming systemic, causing a much more serious condition, a fungemia called candidemia. In children it is normally seen around the mouth as white patches.
Symptoms of Candidiasis may vary depending on the area affected. Infection of the vagina or vulva may cause severe itching, burning, soreness, irritation, and a whitish or
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whitish-gray cottage cheese-like discharge, often with a curd-like appearance. Symptoms of infection of the male genitalia include red patchy sores near the head of the penis or on the foreskin, severe itching, or a burning sensation. Candidiasis of the penis can also have a white discharge, although uncommon.
Cryptococcosis Cryptococcosis, or cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species; Cryptococcus neoformans and Cryptococcus gattii. Cryptococcosis is believed to be acquired by inhalation of the infectious propagule from the environment. The infection is due to the basidiospore created through sexual or asexual reproduction. Cryptococcosis is a defining opportunistic infection for AIDS. In humans, C. neoformans causes three types of infections: Wound or Cutaneous Cryptococcosis, Pulmonary Cryptococcosis and Cryptococcal meningitis. Symptoms include fever, fatigue, chest pain, dry cough, swelling of abdomen, headache, blurred vision and confusion
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Pulmonary Aspergillosis The spectrum of pulmonary disease ranges from noninvasive disease, such as with colonization of the organism or the presence of a fungus ball (aspergilloma), or an allergic response responsible for the syndrome of allergic bronchopulmonary aspergillosis (ABPA), to semi-invasive or invasive infections such as chronic necrotizing pneumonia and invasive pulmonary aspergillosis. Aspergillus species enter the host most commonly through the lungs by the inhalation of conidia. The conidia resting in alveoli begin to enlarge and germinate. Hyphal transformation with vascular Invasion and dissemination of infection are potential sequela.
Various types of Aspergillus species are: A. fumigatus, A. flavus, A. Niger, A. terreus. Although infection with Aspergillus has been reported involving virtually all organ sites, the upper airways, lungs, and surrounding structures are those most frequently involved. It is additionally
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important to recognize the spectrum of disease attributed to aspergillosis Clinical presentation of IPA includes pleuritic chest pain, dyspnoea, haemoptysis, dry cough, and fever. A careful history should be taken in those at risk for IPA given their frequent inability to mount an immunologic response and thus lack of a febrile response. The symptoms of haemoptysis and pleuritic chest pain serve as a reminder to the angioinvasive nature of aspergillosis.
Rhinocerebral mucormycosis Rhinocerebral mucormycosis is an opportunistic but fulminant fungal infection, Caused by Rhizopus species, order Mucorales. The fungus directly invades blood vessels. It propagates by Arterial thrombosis causing ischemic necrosis of the surrounding tissue. The disease begins in the nasal cavity and then spreads to adjacent areas like parnasal sinuses, orbit and brain to produce life threatening, Orbito- cerebral manifestations. The Rhinoorbitocerebral mucormycosis is known to exist in two forms, the wellknown acute form and the less well-recognized chronic form. Acute Rhinocerebral mucormycosis is an opportunistic but fulminant fungal infection. Chronic or indolent variety of Mucormycosis is a slowly progressive disease characterized by granulomatous chronic infection that extends beyond the sinus walls.
Anti-fungal drugs
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Polyenes benzofuran Azoles ketokonazole lotrimazole miconazole fluconazole oriconazole traconazole osaconazole antimetabolites echinocandins
amphotericin nystatin griseofulvin Imidazoles c
triazoles v i p flucytosine capsofungin micafungin

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ngin allylamines
anidulafu naftifine terbinafine butanafine tolnaftate, pradimin,
others amorolfine, nikkomycins, etc.
Anti-fungal drugs
An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host. These are the drugs that are used to treat mycoses. Different classes of drugs are included in this that target various sites in the fungal cell such as the plasma membrane, sterol biosynthesis, DNA biosynthesis, and glucan biosynthesis. Fungal membranes and sterol biosynthetic enzymes are different enough from ours that
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these agents can kill fungi but not us. Fungi make -glucan, so drugs that target -glucan biosynthesis have low sideeffects. Until two to three decades ago, only a few drugs were available for the treatment of fungal infections. The status of antifungal therapy changed dramatically in the late 1960s with the introduction of newer broader spectrum agents that acted by disruption of the fungal cell membrane.
Some of the more recently developed broad-spectrum antifungal drugs include the triazoles terconazole, itraconazole, and fluconazole and the dimethylmorpholine amorolfine. Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membranes integrity.
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Allylamines inhibit ergosterol synthesis. -3-glucan synthase inhibitor block the production of the (1,3)-glucan protein damaging the cell wall. Every component of the cell wall and membrane can be targeted. Drugs not available in the market such as Nikkomycin and Polyoxin target chitin synthase. Mannoproteins (help in adhesion to the surface on entry) are another potential target. Other antifungals such as flucytosine inhibit DNA/RNA synthesis and griseofulvin inhibits fungal cell mitosis preventing cell proliferation and function.
Polyenes
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Polyene antimycotics are typically obtained from some species of Streptomyces bacteria. The polyenes bind to sterols in the fungal cell membrane i.e. ergosterol and promote leakiness which may contribute to fungal cell death. Amphotericin B, nystatin, and natamycin are examples of polyene antimycotics.
Amphotericin
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections. It was extracted from Streptomyces nodosus, a filamentous bacterium. Mechanism: Amphotericin B associates with ergosterol, the main component of fungal cell membranes, forming a transmembrane channel that leads to monovalent ion (K+, Na+, H+ and Cl) leakage, which is the primary effect leading to fungal cell death.
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Pharmacokinetics: It is poorly absorbed orally, hence given by iv route for systemic infections. It can be given orally for localized git infections. It can be applied topically. Metabolism not known. It is highly protienbound and is excreted by kidney slowly through months Side effects: Because mammalian and fungal membranes are similar in structure and composition, hence may cause cellular toxicity. Side effects include high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. Nephrotoxicity is a frequently reported side effect, electrolyte imbalances (e.g. hypokalemia and hypomagnesemia) may also result. Increased liver enzymes and hepatotoxicity are common. In the circulatory system,
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several forms of anemia and other blood dyscrasias (leukopenia, thrombopenia), serious cardiac arrhythmias (including ventricular fibrillation), and even frank cardiac failure have been reported. Skin reactions, including serious forms, are also possible Interactions with drugs: Flucytosine: Toxicity of flucytosine is increased and allows a lower dose of amphotericin B. Diuretics or cisplatin: Increased renal toxicity and increased risk of hypokalemia. Corticosteroids: Increased risk of hypokalemia Cytostatic drugs: Increased risk of kidney damage, hypotension and bronchospasms. Other nephrotoxic drugs : Increased risk of serious renal damage, monitor kidney function closely. Foscarnet, ganciclovir, tenofovir, adefovir: Risk of hematological and renal side effects of amphotericin B are increased. transfusion of leukocytes : Risk of pulmonal (lung) damage occurs. Space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function.
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Nystatin
Nystatin is a polyene antifungal drug to which many molds and yeast infections are sensitive, including Candida. nystatin is of bacterial origin. It was isolated from Streptomyces noursei. nystatin may be safely given orally as well as applied topically due to its minimal absorption through mucocutaneous membranes such as the gut and the skin. Mechanism: Like amphotericin B and natamycin, nystatin binds to ergosterol, a major component of the fungal cell membrane. When present in sufficient concentrations, it forms pores in the membrane that lead to K+ leakage and death of the fungus. Pharmacokinetics: Gastrointestinal absorption of nystatin is insignificant. Most orally administered nystatin is passed unchanged in the stool. In patients with renal insufficiency receiving oral therapy with conventional dosage forms, significant plasma concentrations of nystatin may occasionally occur. Cutaneous, vaginal, mucosal and esophageal Candida
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infections usually respond well to treatment with nystatin. Cryptococcus is also sensitive to nystatin.
Benzofuran Griseofulvin
It is derived from the mold Penicillium griseofulvum. Griseofulvin is administered orally. It is used both in animals and in humans, to treat fungal infections of the skin commonly known as ringworm and nails.
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Mechanism:
The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis. It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. It is only when hair or skin is replaced by the keratin-griseofulvin complex that the drug reaches its site of action. Griseofulvin will then enter the dermatophyte through energy dependent transport processes and bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.
Pharmacokinetics: Griseofulvin is given orally in divided doses to attain maximum level in the blood. It is mainly excreted through
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faeces. Because of its very low water solublity absorption from G.I.T is irregular. Absorption is increased by taking it with fat and by microfining the drug particles. Griseofulvin gets deposited in keratin forming cells of skin, hair and nails. It is specially concentrated and retained in tinea infected cells. Side effects: Known side effects of griseofulvin include: Can reduce the effectiveness of oral contraceptives as it is a cytochrome p450 enzyme inducer, Confusion, Considered unsafe for those with porphyria, Diarrhea, Dizziness, Fatigue, Headache, Hives, Impairment of performance of routine activities, Impairment of liver enzymatic activity, Inability to fall or stay asleep, Itching, Loss of taste sensation, Nausea, Oral thrush (yeast infection of the mouth), Possibly a teratogen inducing mutations, Sensitivity to alcohol, with a disulfiram/antabuse-like reaction, Sensitivity to prolonged sun exposure, Skin rashes, Swelling, Tingling in the hands or feet, Upper abdominal pain. Azoles Azole antifungal agents have added greatly to the therapeutic options for treatment of systemic fungal infections. The azoles that are available for systemic use can be classified into two groups: the triazoles (fluconazole, itraconazole, voriconazole, posaconazole) and the imidazoles (ketoconazole).
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General
mechanism:
The fungistatic effect correlated with inhibition of ergosterol synthesis and elevated lanosterol/ergosterol ratios in the organisms. The fungicidal effect involved rapid membrane damage and was unrelated to the imidazole-induced block in ergosterol synthesis. Imidazoles Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazoles are a class of heterocycles with similar ring structure, but varying substituents. When grown aerobically they were fungistatic at low concentrations and fungicidal at high concentrations. When grown anaerobically the fungistatic effect was not seen, but killing still occurred at high concentrations. Ketoconazole
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Ketoconazole is a synthetic antifungal drug. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet Mechanism:It interferes with the fungal synthesis of ergosterol. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14-alpha-demethylase (P45014DM). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Pharmacokinetics: Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption when taken orally. Lower doses of fluconazole and itraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes. Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole have largely replaced ketoconazole for internal use. Clotrimazole Clotrimazole is an antifungal medication commonly used in the treatment of fungal infections, such as vaginal yeast infections, oral thrush, and ringworm athlete's foot and jock itch. Mechanism: Clotrimazole alters the permeability of the fungal cell wall and inhibits the activity of enzymes within the cell. This leads eventually to the cell's death. It does not appreciably spread through the user's body but remains at the point of application. Potential for drug interactions with clotrimazole oral exists, as it is a potent, specific inhibitor of cytochrome P450 oxidase and may alter the metabolism of other drugs.
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Side effects include skin rash, hives, blistering, burning, itching, peeling, redness, stinging, swelling, or other sign of skin irritation.
Miconazole
Miconazole is an imidazole antifungal agent commonly applied topically to the skin or to mucus membranes. It works by inhibiting the synthesis of ergosterol. It can also be used against certain species of Leishmania protozoa which are a type of unicellular parasite that also contain ergosterol in their cell membranes. In addition to its antifungal and antiparasitic actions, it also has some limited antibacterial properties. Miconazole is also used in Ektachrome film developing.
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Unlike nystatin, some miconazole is absorbed by the intestinal tract when used orally which may lead to drug interactions. Of note may be interactions with anticoagulants, phenytoin, terbinafine, some newer atypical antipsychotics, ciclosporin and some statins used to treat hypercholesterolemia. Triazoles Triazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a fivemembered ring of two carbon atoms and three nitrogen atoms. Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. Mechanism: fluconazole inhibits the fungal cytochrome P450 enzyme 14-demethylase. Mammalian demethylase activity is much less sensitive to fluconazole than fungal
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demethylase. This inhibition prevents the conversion of lanosterol to ergosterol. Fluconazole is primarily fungistatic; however, it may be fungicidal against certain organisms in a dose-dependent manner, specifically Cryptococcus. Adverse drug reactions associated with fluconazole therapy include Common: rash, headache, dizziness, nausea, vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes Infrequent: anorexia, fatigue, constipation. Rare: oliguria, hypokalaemia, paraesthesia, seizures, alopecia, StevensJohnson syndrome, thrombocytopenia, other blood dyscrasias, serious hepatotoxicity including hepatic failure, anaphylactic/anaphylactoid reactions. Very rare: prolonged QT interval, torsades de pointes. FDA is now saying that treatment with chronic, high doses (400800mg/day) of Diflucan (fluconazole) during the first trimester of pregnancy may be associated with a rare and distinct set of birth defects in infants.
Voriconazole
Voriconazole is a triazole antifungal medication that is generally used to treat serious, invasive fungal infections. These are generally seen in patients who are immunocompromised, and include invasive candidiasis,
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invasive aspergillosis, and certain emerging fungal infections. Being metabolized by hepatic cytochrome P450, voriconazole interacts with some drugs. Administration is contraindicated with some drugs (such as sirolimus, rifampin, rifabutin, and ergot alkaloids) and dose adjustments and/or monitoring when coadministered with others (including cyclosporine, tacrolimus, omeprazole, and phenytoin). Voriconazole may be safely administered with cimetidine, ranitidine, indinavir, macrolide antibiotics, mycophenolate, and prednisolone. The most common side effects associated with voriconazole include transient visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. Unlike most adverse effects, which are similar to other azole antifungal agents, visual disturbances (such as blurred vision or increased sensitivity to light) are unique to voriconazole. Voriconazole is phototoxic. It has been associated with an increased risk of squamous-cell carcinoma of the skin. They generally occur approximately one-half hour after administration, and last approximately 30 minutes. In some patients they may go away after continued use. Studies have shown that there is no damage to the eye or long-term effect on vision. However, patients taking voriconazole should be advised against driving at night or other potentially hazardous tasks. Liver function tests should be evaluated at the start of and during the course of therapy.
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Itraconazole
Itraconazole is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously. The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications. Itraconazole is a relatively well-tolerated drug (although not as well tolerated as fluconazole or voriconazole) and the range of adverse effects it produces is similar to the other azole antifungals. Elevated alanine aminotransferase levels, "Small but real risk" of developing congestive heart failure, Liver failure, sometimes fatal. The cyclodextrin that is used to make the syrup preparation can cause diarrhea. Side-effects that may indicate a greater problem include: nausea, vomiting, abdominal pain, fatigue, loss of appetite, yellow skin (jaundice), yellow eyes, itching, dark urine, pale stool Posaconazole
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Posaconazole works by disrupting the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems such as ATPase and enzymes of the electron transport system and thus inhibiting growth of the fungi. It does this by blocking the synthesis of ergosterol by inhibiting of the enzyme lanosterol 14-demethylase and accumulation of methylated sterol precursors. Posaconazole is significantly more potent at inhibiting 14-alpha demethylase than itraconazole. Side effects: allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. pale skin, easy bruising or bleeding, unusual weakness,fever, chills, cough, body aches, flu symptoms; slow, fast, or pounding heartbeats;feeling light-headed, fainting; numbness or tingly feeling around your mouth, fast or slow heart rate, muscle... Antimetabolite Flucytosine Flucytosine, or 5-fluorocytosine, a fluorinated pyrimidine analogue, is a synthetic antimycotic drug. It is structurally related to the cytostatic fluorouracil and to floxuridine. It is available in oral and in some countries also in injectable form. Two major mechanisms of action have been elucidated: One is that the drug is intrafungally converted into the cytostatic fluorouracil that undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis and disturbs the building of certain essential proteins.
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The other mechanism is the conversion into 5fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis. Antiproliferative actions on bone marrow and GI tissue: Due to the drug's preference to affect rapidly proliferating tissues, bone marrow depression (anemia, leukopenia, pancytopenia, or even rarely agranulocytosis) may occur. Aplastic anemia has also been seen. Bone marrow toxicity can be irreversible and may cause death, particular in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitis. Liver function: Elevations of liver enzymes and
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bilirubin, hepatic dysfunction, jaundice and, in one patient, liver necrosis have all been seen. Renal function: Increased BUN and serum creatinine have been noted. Crystalluria (formation of crystals and excretion in the urine) and acute renal failure have also been seen. Adverse central nervous system effects are frequent and include confusion, hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo and sedation. Skin reactions: Rash, pruritus, and photosensitivity have all been noticed. Toxic epidermal necrolysis (Lyell's syndrome) may also be encountered and may be life-threatening. Anaphylaxis: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed. Allylamines Allylamine is an organic compound with the formula C3H5NH2. This colorless liquid is the simplest stable unsaturated amine. Naftifine Naftifine is an allylamine antifungal drug for the topical treatment of tinea pedis, tinea cruris, and tinea corporis (fungal infections). Its precise mechanism of action is unknown, but may involve selectively blocking sterol biosynthesis via inhibition of the squalene 2,3-epoxidase enzyme. The half-life is approximate 23 days. The metabolites are excreted in the urine and feces.
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[TERB-terbinafine;FLU-fluconazole;ITRAitraconazole;VOR-voriconazole] Terbinafine Terbinafine hydrochloride is a synthetic allylamine antifungal. It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty tissues. Terbinafine hydrochloride is a white fine crystalline powder that is freely
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soluble in methanol and dichloromethane, soluble in ethanol, and slightly soluble in water. Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that is part of the fungal cell membrane synthesis pathway. Because terbinafine prevents conversion of squalene to lanosterol, ergosterol cannot be synthesized. This is thought to change cell membrane permeability, causing fungal cell lysis. Many side effects and adverse drug reactions have been reported with terbinafine possibly due to its extensive biodistribution and the often extended durations involved in anti-fungal treatment. Gastrointestinal Problems Diarrhea, constipation, nausea, sickness, fullness, abdominal pain, indigestion, dyspepsia, gastritis, cholestasis, flatulence, altered stool colour,abdominal muscular pain. Central Nervous System / Neurological Problems Headaches, dizziness, vertigo, lightheadedness, decreased concentration levels, paraesthesia (pins and needles) Hepatic Problems Raised liver enzymes, liver inflammation (hepatitis), liver damage, liver failure Immune System Problems Decreased white blood cell counts including pancytopenia, leukopenia, lymphopenia, thrombocytopenia, agranulocytosis, and neutropenia. Autoimmune reactions such as lupus erythematosus Psychological Problems Depression, anxiety, insomnia, increased / unusual dream activity, malaise. Sensory Problems Complete loss of taste (ageusia), decreased taste (hypogeusia) and distorted taste (dysgeusia) often involving a metallic taste sensation and dry mouth. Visual disturbances including blurred vision, green vision and double vision. Skin Problems Rash, hives. (urticaria), skin irritation, itching (pruritis), jaundice , Stevens-Johnson syndrome. Other Fatigue, increased heart rate
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(tachycardia), hair loss, decreased red blood cell count (anemia), muscle pain (myalgia), joint pain (arthralagia). Butenafine Butenafine hydrochloride is an odorless white crystalline powder that is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water. Like the allylamine antifungals, butenafine works by inhibiting the synthesis of ergosterol by inhibiting squalene epoxidase, Lacking ergosterol, the cell membranes increase in permeability, allowing their contents to leak out. Butenafine is indicated for the topical treatment of tinea (pityriasis) versicolor due to M. furfur, as well as athletes foot (Tinea pedis), ringworm (Tinea corporis) and jock itch (Tinea cruris) due to E. floccosum, T. mentagrophytes, T. rubrum, and T. tonsurans. It has superior fungicidal activity against this group of fungi when compared to that of terbinafine, naftifine, clotrimazole, and tolnaftate. It also displays superior activity against Candida albicans when compared against terbinafine and naftifine. Butenafine demonstrates low minimum inhibitory concentrations against cryptococcus and aspergillus. Butenafine is typically available as a 1% topical cream. Echinocandins: The fungal cell wall is an attractive target. Echinocandins inhibit B1,3-glucan synthase. Fungi have cell walls but mammals do not. Moreover, the enzyme is active outside the cell, so the drug does not need to enter.
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Caspofungin
is an antifungal drug. It shows activity against infections with Aspergillus and Candida, and works by inhibiting the enzyme (1,3)-D-Glucan synthase and thereby disturbing the integrity of the fungal cell wall. Caspofungin is administered intravenously. Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side effects. Gastrointestinal system: nausea, vomiting, abdominal pain, and diarrhea Central nervous system: headacheWhole body: fever, phlebitis or thrombophlebitis, complications at the intravenous cannulation site (e.g. induration), unspecified pain, flu-like syndrome, myalgia, chills, and paresthesiaRespiratory: dyspneaRenal: increased plasma creatinineHematological: anemiaElectrolytes: hypokalemiaLiver: increased liver enzymes (asymptomatic)Hypersensitivity: rash, facial edema, pruritusOther: tachycardiaCyclosporine: see under Hepatic effects Tacrolimus: potential pharmacokinetic interactions Other systemic antimycotic agents: with amphotericin B, itraconazole and mycophenolate, no interactions have been seen Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethason)
Micafungin
Micafungin (trade name Mycamine) is an echinocandin antifungal drug developed by Astellas Pharma. It inhibits the
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production of beta-1,3-glucan, an essential component of fungal cell walls. Micafungin is administered intravenously. Known hypersensitivity to micafungin or any other ingredient contained in the formulation is a contraindication for its use.
Anidulafungin
There is preliminary evidence it has a similar safety profile to caspofungin. It has proven efficacy against oesophageal candidiasis, but its main use will probably be in invasive Candida infection; it will probably also have application in treating invasive Aspergillus infection. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (13)-D-glucan synthase, which is an important component of the fungal cell wall. Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment. Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1,3)-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells and therefore is an attractive target for antifungal activity
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Others Amorolfine
Amorolfine is a morpholine antifungal drug that inhibits D14 reductase and D7-D8 isomerase, which depletes ergosterol and causes ignosterol to accumulate in the fungal cytoplasmic cell membranes. It is probably the most effective topical solution for the treatment of toe nail infections, although 'systemic treatments are more effective. Amorolfine 5% nail lacquer in once-weekly or twice-weekly applications. Tolnaftate
Tolnaftate is a synthetic over-the-counter anti-fungal agent. It may come as a cream, powder, spray, or liquid aerosol, and is used to treat jock itch, athlete's foot and ringworm. Tolnaftate is a thiocarbamate. Although the exact mechanism of action is not entirely known, it is believed to inhibit the squalene epoxidase, an important enzyme in the
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biosynthetic pathway of ergosterol in a similar way to allylamines. nikkomycins
The nikkomycins work by competitive inhibition of chitin synthase, the fungal enzyme that forms chitin, a component of the fungal cell wall. Nikkomycin Z has in vitro and in vivo activity against Histoplasma capsulatum and Blastomyces dermatitidis. However, in vitro, its MIC to Histoplasma sp varies considerably, and its utility in this setting requires further study. In vitro evidence also exists for activity of Nikkomycin Z against Coccidioides immitis. The drug has little to no activity against yeasts such as C. albicans, C. tropicalis, and Cryptococcus neoformans. It is also inactive against A. fumigatus. Further study is necessary to determine if nikkomycin Z will have clinical utility.

Chemotherapy of Fungal Diseases

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CHEMOTHERAPY OF FUNGAL DISEASES