Antifungal Drugs PDF

Pharmacology 3 Antifungal Drugs Dr. Lina Tamimi  Increase of fungal infection?! Advances in surgery Cancer treatment Treatment of patients with solid organ and bone marrow transplantation The HIV epidemic Increasing use of broad-spectrum antimicrobial...

Pharmacology 3 Antifungal Drugs Dr. Lina Tamimi  Increase of fungal infection?! Advances in surgery Cancer treatment Treatment of patients with solid organ and bone marrow transplantation The HIV epidemic Increasing use of broad-spectrum antimicrobial therapy in critically ill patients. These changes have resulted in increased numbers of patients at risk for fungal infections.  Classification of Antifungals 1. Systemic drugs (oral or parenteral) for systemic infections. 2. Oral systemic drugs for mucocutaneous infections (mucosal surfaces, skin, and nails) 3. Topical drugs for mucocutaneous infections. Targets of antifungal drugs 1. Systemic drugs  1.1. Amphotericin B Was the only effective antifungal drug available for systemic use. Highly effective in many serious infections, it is also quite toxic. The new agents in these classes offer more targeted, less toxic therapy than older agents such as amphotericin B for patients with serious systemic fungal infections.  Amphotericin B is a naturally occurring polyene antifungal produced by Streptomyces nodosus. In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of several life-threatening mycoses. MOA Amphotericin B binds to ergosterol in the plasma membranes of sensitive fungal cells it forms pores (channels) that require hydrophobic interactions between the lipophilic segment of the polyene antifungal and the sterol. The pores disrupt membrane function allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. Copyright © 2015 Wolters Kluwer All Rights Reserved  Against/spectrum: Amphotericin B is either fungicidal or fungistatic, depending on: the organism the concentration of the drug. It is effective against a wide range of fungi, including: Candida albicans Histoplasma capsulatum Cryptococcus neoformans Coccidioides immitis Blastomyces dermatitidis strains of Aspergillus. It is also used in the treatment of the protozoal infection leishmaniasis. Copyright © 2015 Wolters Kluwer All Rights Reserved  Resistance: Infrequent, but may associated with decreased ergosterol content of the fungal membrane. Organisms that are usually resistant to amphotericin B include : organisms that cause chromoblastomycosis Aspergillus terreus Candida lusitaniae Scedosporium spp some Fusarium spp Copyright © 2015 Wolters Kluwer All Rights Reserved  Pharmacokinetics: Amphotericin B is administered by slow, IV infusion Amphotericin B is insoluble in water and must be co-formulated with either: sodium deoxycholate (conventional) or variety of artificial lipids to form liposomes. The liposomal preparations have the primary advantage of reduced: renal toxicity infusion toxicity However, due to high cost, liposomal preparations are reserved mainly as salvage therapy for patients who cannot tolerate conventional amphotericin B.  Distribution Amphotericin B is extensively bound to plasma proteins and is distributed throughout the body. Inflammation favours penetration into various body fluids, but little of the drug is found in the CSF, vitreous humor, or amniotic fluid. However, amphotericin B does cross the placenta. Elimination Low levels of the drug and its metabolites appear in the urine over a long period of time some are also eliminated via the bile. Dosage adjustment  NO Dosage adjustment in patients with hepatic dysfunction  but when conventional amphotericin B causes renal dysfunction, the total daily dose is decreased by 50%. Routes of administration Orally, Bladder irrigation, Intrathecal Mostly IV: Injection of 0.6 mg/kg/d of amphotericin B results in average blood levels of 0.3–1 mcg/mL Poorly absorbed from GIT Oral amphotericin B is thus effective only on fungi within the lumen of the tract and cannot be used for treatment of systemic disease.  Adverse effects: Amphotericin B has a narrow Therapeutic Index. The total adult daily dose of the conventional formulation should not exceed 1.5 mg/kg/d whereas lipid formulations have been given safely in doses up to 10 mg/kg/d. 1. Immediate toxicity: fever and chills, muscle spasms, vomiting, headache phlebitis : These occur most commonly 1 to 3 hours after starting the IV admin. Could be prevented by: Premedication with a : corticosteroid , heparin or an antipyretic 2. Cumulative Toxicity: Renal impairment: Patients may exhibit a reversible↓ in GF rate and renal tubular function. ↑ Serum creatinine ↓Cr. Clearance K+ and Mg+2 are lost Azotemia is exacerbated by other nephrotoxic drugs, such as: aminoglycosides, cyclosporine, pentamidine, and vancomycin To decrease its severity: adequate hydration To minimize nephrotoxicity: normal saline (sodium loading) infusions lipid-based amphotericin B products can be used. 3. Hypotension: A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation. Care must be exercised in patients taking digoxin and other drugs that can cause potassium fluctuations. 4. Anemia: due to reduced erythropoietin production by damaged renal tubular cells 5. Seizures and a chemical arachnoiditis (spine) with serious neurologic sequelae ……………………………. After intrathecal therapy with amphotericin  1.2. FLUCYTOSINE Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Pyrimidine Analog related to the chemotherapeutic agent 5- fluorouracil (5-FU). Antifungal Drugs MOA  Synergy effect Synergy with amphotericin B has been demonstrated in vitro and in vivo. It may be related to enhanced penetration of the flucytosine through amphotericin-damaged fungal cell membranes. Care of dose adjustment with amphotericin B (nephrotoxic) In vitro synergy with azole drugs has also been seen, although the mechanism is unclear. Against/spectrum: The spectrum of activity of flucytosine is restricted to: 1. C neoformans 2. some Candida sp 3. dematiaceous molds that cause chromoblastomycosis. Flucytosine is not used as a single agent but combination therapy with: Amphotericin B for cryptococcal meningitis Itraconazole for chromoblastomycosis. Resistance: Resistance is thought to be mediated through: --- Altered metabolism of flucytosine --- It develops rapidly in the course of flucytosine monotherapy Pharmacokinetics only in an oral formulation: well absorbed (> 90%), with serum concentrations peaking 1–2 hours The oral dosage is 100–150 mg/kg/d in patients with normal renal function. It is poorly protein-bound ……….. penetrates well into all body fluid compartments, including the CSF half-life of 3–4 hours  adverse effects The adverse effects of flucytosine result from: metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. 1. Bone marrow toxicity with anemia, leukopenia and thrombocytopenia are the most common adverse effects 2. Derangement of liver enzymes occurring less frequently. 3. toxic enterocolitis can occur.  Toxic Levels rise rapidly with renal impairment and can lead to toxicity. Renal toxicity is more likely to occur in: AIDS patients renal insufficiency patients  1.3. Azoles  Azole antifungals are made up of two different classes of drugs: 1. Imidazoles 2. Triazoles.  Similar mechanisms of action and spectra of activity  Significant difference in pharmacokinetics and therapeutic uses  In general:  Imidazoles are given topically for cutaneous infections  Triazoles are given systemically for the treatment or prophylaxis of cutaneous and systemic fungal infections.  Imidazoles exhibit a lesser degree of selectivity than the Triazoles, which justify their higher incidence of drug interactions and adverse effects Agents  Mechanism of action reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes.  Against/spectrum : spectrum of action of azole medications is broad Azoles are generally considered fungistatic: against Candida species Against: Candida C neoformans endemic mycoses (Blastomycosis , coccidioidomycosis, histoplasmosis)  the dermatophytes; also known as tinea, are the most common fungal infections of the skin, hair, and nails pulmonary fungal diseases itraconazole and voriconazole are active against Aspergillus infections. voriconazole is fungicidal against Aspergillus Azoles are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii. Side effects : Relatively nontoxic. The most common adverse reaction is relatively minor gastrointestinal upset. All azoles have been reported to cause abnormalities in liver enzymes and, very rarely, clinical hepatitis. ketoconazole Inhibits cytochrome P450 isoforms by interferes with the synthesis of adrenal and gonadal steroids and may lead to gynecomastia, menstrual irregularities, and infertility. Azole use should be avoided during pregnancy  Drug interaction All azole drugs are prone to drug interactions because they affect the mammalian cytochrome P450 system of enzymes to some extent. Ketoconazole may increase the plasma levels of many other drugs, including cyclosporine, oral hypoglycemics, phenytoin, and warfarin.  Pharmacokinetics: Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Inducers of drug metabolizing enzymes (eg, rifampin) decrease the bioavailability of itraconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form. The drugs are distributed to most body tissues, but with the exception of fluconazole drug levels achieved in the CNS are very low.  1.3.1. Fluconazole Fluconazole was the first member of the triazole class of antifungal agents. It is the least active of all triazoles its spectrum limited to yeasts and some dimorphic fungi. Better gastrointestinal tolerance  Against/spectrum: Fluconazole is a drug of choice in: 1. esophageal and oropharyngeal candidiasis and for most infections caused by Coccidioides. 2. A single oral dose usually eradicates vaginal candidiasis. 3. drug of choice for treatment and secondary prophylaxis against cryptococcal meningitis 4. alternative drug of choice (with amphotericin B) in treatment of active disease due to Cryptococcus neoformans. The drug is also equivalent to amphotericin B in candidemia.  1.3.2. Itraconazole Itraconazole is a synthetic triazole broad antifungal spectrum compared to fluconazole. Itraconazole is the drug of choice for the treatment of blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis. It is rarely used for treatment of infections due to Candida and Aspergillus species ………………… because of the availability of newer and more effective agents. Itraconazole is also used extensively in the treatment of dermatophytoses, especially onychomycosis. 1.3.3. Voriconazole wider spectrum than itraconazole. It is a co-drug of choice for treatment of invasive aspergillosis; greater efficacy than amphotericin B. an alternative drug in candidemia with activity against some fluconazole-resistant organisms in AIDS patients has been used in the treatment of candida esophagitis and stomatitis. adverse effects similar to those of the other azoles high trough concentrations are associated with visual and auditory hallucinations and an increased incidence of hepatotoxicity.  Voriconazole is not only a substrate but also an inhibitor of CYP2C19, 2C9, and 3A4 isoenzymes. Inhibitors and inducers of these enzymes may impact levels of voriconazole, leading to toxicity or clinical failure. In addition, drugs that are substrates of these enzymes are impacted by voriconazole Due to significant interactions, use of voriconazole is contraindicated with many drugs (for example, rifampin, rifabutin, carbamazepine, and the herb St. John’s wort). 1.3.4. KETOCONAZOLE Ketoconazole was the first oral azole introduced into clinical use. greater propensity to inhibit mammalian cytochrome P450 it is less selective for fungal P450 than are the newer azoles. Systemic ketoconazole has fallen out of clinical use Topical use  1.3.5. Posaconazole New: Is a new triazole, the broadest spectrum tablets and Iv infusion only in a liquid oral formulation dosage of 800 mg/d, divided into two or three doses. Absorption is improved when taken with meals high in fat. rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented.  Posaconazole is the broadest spectrum member of the azole family activity against most species of Candida and Aspergillus. It is the only azole with significant activity against the agents of mucormycosis (black fungus). It is currently licensed for salvage therapy in invasive aspergillosis  prophylaxis of fungal infections during induction chemotherapy for leukemia, and for allogeneic bone marrow transplant patients with graft-versus-host disease. It is the only azole with activity against Rhizopus, one of the agents of mucormycosis 1.3.6. ISAVUCONAZOLE prodrug of the newest triazole, isavuconazole highly bioavailable oral capsules and an intravenous formulation antifungal spectrum similar to that of posaconazole invasive aspergillosis and invasive mucormycosis. Coadministration with strong: 3A4 inhibitors (eg, ritonavir) or 3A4 inducers (eg, rifampin) is not recommended. 1.3.7. OTESECONAZOLE tetrazole antifungal antifungal spectrum Candida species, including fluconazole-resistant Strains recurrent vulvovaginal candidiasis lower affinity for human CYP enzymes than triazole antifungals, leading to reduced potential for toxicity and associated adverse effects  1.4. Echinocandins MOA Fungicidal first systemic selective antifungal that destroys fungal cell wall Echinocandins act at the level of the fungal cell wall by: inhibiting the synthesis of β(1–3)-glucan. disruption of the fungal cell wall and cell death. best tolerated and safest class  Semisynthetic Echinocandins derivatives:  Caspofungin  micafungin  anidulafungin are available for IV administration once daily. The dose of Caspofungin does not need to be adjusted in renal impairment, but adjustment is warranted with moderate hepatic dysfunction. All three agents are well tolerated the most common adverse effects being fever, rash, nausea, and phlebitis at the infusion site. They can also cause a histamine-like reaction (flushing) when infused too rapidly.  Against/spectrum: majorly: candidiasis, especially in critically ill and neutropenic patients less commonly in salvage regimens for invasive aspergillosis. empiric antifungal therapy in patients with febrile neutropenia. The major advantages of echinocandins relative to other antifungal agents are: 1. their fungicidal activity against Candida spp, including fluconazole-resistant C. glabrata and C. Krusei 2. combined with their relatively low potential for renal or hepatic toxicity or serious drug-drug interactions 1.4.1. Caspofungin Concomitant administration of Caspofungin with certain CYP450 enzyme inducers (for example, rifampin) may require an increase in the daily dose. invasive aspergillosis prophylaxis of candidal infections Caspofungin should not be co-administered with cyclosporine due to a high incidence of elevated hepatic transaminases with concurrent use. 1.4.2.Micafungin 1.4.3. anidulafungin Micafungin and Anidulafungin do not need to be adjusted in renal impairment or mild to moderate hepatic dysfunction. Severe hepatic dysfunction: Anidulafungin can be administered Micafungin has not been studied in this condition. Anidulafungin are not substrates for CYP450 enzymes and do not have any associated drug interactions. Micafungin has been shown to increase levels of nifedipine, cyclosporine, and sirolimus 1.4.5. Triterpenoids: ibrexafungerp newly developed class of antifungal agents. The first and only antifungal in this class is ibrexafungerp. MOA This agent demonstrates Concentration dependent fungicidal activity, Similar to echinocandins Spectrum Candida species including azole-resistant isolates. Aspergillus species. metabolism occurs via hydroxylation by CYP3A4, followed by glucuronidation and sulfation of a hydroxylated inactive metabolite. The metabolites are primarily excreted via feces with 51% excreted as unchanged drug. 2. ORAL SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS  2.1. GRISEOFULVIN Griseofulvin is a very insoluble fungistatic drug derived from a species of penicillium. Its only use is in the systemic treatment of dermatophytosis It is administered at a dosage of 1 g/d. Absorption is improved when it is given with fatty foods  MOA at the cellular level is unclear Binds to keratin in newly forming skin, protecting the skin from new infection to prevent infection of these new skin structures Administration of Griseofulvin must be administered for 2–6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse Adverse effects and contraindications Allergic syndrome much like serum sickness, hepatitis Hepatotoxicity contraindication in hepatic failure It has a drug interaction with warfarin by decreasing its serum concentration  2.2. TERBINAFINE A synthetic allylamine that is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses, especially onychomycosis  Administration One tablet given daily for 12 weeks achieves a cure rate of up to 90% for onychomycosis more effective than griseofulvin or itraconazole. Adverse effects Rare consisting primarily of gastrointestinal upset and headache. not seem to affect the P450 system 3. TOPICAL ANTIFUNGAL THERAPY  3.1. NYSTATIN MOA -Like amphotericin B Nystatin is a polyene macrolide much like amphotericin B. It is too toxic for parenteral administration and is only used topically. It is not absorbed to a significant degree from skin, mucous membranes, or the gastrointestinal tract nystatin has little toxicity oral use is often limited by the unpleasant taste  creams, ointments, suppositories and other forms for application to skin and mucous membranes. Nystatin is active against most Candida sp and is most commonly used for suppression of local candidal infections. common indications include: 1. oropharyngeal thrush 2. vaginal candidiasis 3. intertriginous candidal infections( where two skin areas may touch or rub together).  3.2. Azoles Most used :Clotrimazole and Miconazole Both are available OTC often used for vulvovaginal candidiasis Oral clotrimazole troches are available for treatment of oral thrush and are a pleasant-tasting alternative to nystatin  Topical and shampoo forms of ketoconazole are also available and useful in the treatment of: seborrheic dermatitis tinea capitis pityriasis versicolor  3.3. TOPICAL ALLYLAMINES Terbinafine and naftifine are allylamines available as topical creams. Both are effective for treatment of : 1. tinea cruris ( fungal infection that affects the skin of your genitals, inner thighs and buttock and) 2. tinea corporis (also known as ringworm, is a superficial fungal infection (dermatophytosis) of the arms and legs) 3. Tinea pedis or athlete’s foot (infection of the soles of the feet and the interdigital (spaces).