Antifungal Agents

Chapter 50 Antifungal Agents






















Abbreviations
ABLC Amphotericin B lipid complex
AIDS Acquired immunodeficiency syndrome
CSF Cerebrospinal fluid
GI Gastrointestinal
IV Intravenous


Therapeutic Overview


Fungal infections (mycoses) are less frequent than bacterial or viral infections but may be prevalent in some locations that favor growth of specific pathogenic strains. However, serious infections have become increasingly common in the hospital setting. A person must almost always have a predisposing condition that disables one or more host defense mechanisms for a fungal infection to develop. Fungal infections are facilitated by a loss of mechanical barriers (burns, major surgery, and intravascular catheters), the presence of immunodeficiency conditions (malignancies and their treatments, organ transplantation and antirejection therapy, acquired immunodeficiency syndrome [AIDS]), or metabolic derangements (diabetes mellitus), and suppression of competing microorganisms (excessive








































Therapeutic Overview
Cutaneous and Subcutaneous Mycoses
Treat with dermatological preparations, occasionally systemic agents
Epidermophyton species
Microspora species
Sporothrix species
Trichophyton species
Systemic Mycoses
Difficult to treat; available drugs often cause deleterious side effects; often need long-term therapy
Aspergillus species
Candida species
Blastomyces dermatitidis
Cryptococcus neoformans
Coccidioides immitis
Fusarium species
Histoplasma capsulatum
Paracoccidioides brasiliensis
Mucormycosis

broad-spectrum antibacterial agent use). Many fungal infections are superficial and primarily annoying. Others are systemic and can be life-threatening, particularly in patients with compromised defenses, such as those receiving immunosuppressive drugs. The toxicity of many antifungal drugs limits their use, and unfortunately there are few agents useful in treating systemic fungal infections.


Fungi are more complex than bacteria or viruses. They have different ribosomes and cell wall components and possess a discrete nuclear membrane. The major classes of fungal infections and examples of prevalent species that are often causative organisms are summarized in the Therapeutic Overview Box.



Mechanisms of Action


The principal antifungal drugs are the polyenes, azoles, allylamines, echinocandins, and others including flucytosine and griseofulvin. The sites of action of these agents are shown in Figure 50-1.









Polyenes


The polyene (i.e., multiple double bonds) drugs are macrocyclic lactones that contain a hydrophilic hydroxylated portion and a hydrophobic conjugated double bond portion. The structure of amphotericin B, the most widely used polyene antifungal drug, is shown in Figure 50-2.



Polyenes act by binding to sterols in the cell membrane and forming channels, allowing K+ and Mg++ to leak out. The polyenes become integrated into the membrane to form a ring with a pore in the center approximately 0.8 nm in diameter. K+ leaks out through these pores, followed by Mg++, and with the loss of K+, cellular metabolism becomes deranged (Fig. 50-3). It is thought that derangement of the membrane alters activity of membrane enzymes. The principal sterol in fungal membranes, ergosterol, has a higher affinity for polyenes than does cholesterol, the principal sterol of mammalian cell membranes. Therefore the polyenes show greater activity against fungal cells than mammalian cells, and fungi that lack ergosterol are not susceptible to amphotericin B.



Amphotericin B lipid complex (ABLC) and liposomal amphotericin were among the first amphotericin-lipid formulations to receive approval for use in the United States. ABLC is an amphotericin B-nonliposomal formulation that complexes with two phospholipids. Liposomal amphotericin incorporates the drug into small unilamellar lipid vesicles. It is postulated that by incorporating amphotericin B into these lipid moieties, active drug can be selectively transferred to ergosterol containing fungal membranes without interfering with the cholesterol-containing human membrane, thereby resulting in decreased toxicity.






Others





Pharmacokinetics


Pharmacokinetic parameters for the antifungal drugs are summarized in Table 50-1.








Polyenes


Amphotericin B is insoluble in water, has a large lipophilic domain in its structure, and is not absorbed from the gastrointestinal (GI) tract. It is administered orally only to treat fungal infections of the GI tract, which sometimes develop after depletion of bacterial microflora after administration of broad-spectrum antibacterial drugs. For parenteral use, amphotericin B is combined with the detergent deoxycholate to form a colloidal suspension.


Amphotericin B enters pleural, peritoneal, and synovial fluids, where it reaches a concentration approximately half that in serum. It crosses the placenta and is found in cord blood and amniotic fluid and also enters the aqueous but not the vitreous humor of the eye. Cerebrospinal fluid (CSF) concentrations reach one third to one half those in serum. Most amphotericin B in the body probably is bound to cholesterol-containing membranes in tissues.


The principal pathway for amphotericin B elimination is not known. Some is excreted by the biliary route, and only 3% is eliminated in urine. Renal dysfunction does not affect plasma concentrations, and amphotericin B is not removed by hemodialysis.


The pharmacokinetics of ABLC and liposomal amphotericin and their relation to clinical efficacy are less clear. ABLC is taken up rapidly by the reticuloendothelial system and achieves high concentrations in the lung, liver, and spleen. As a result, the elimination phase is much longer than with amphotericin B. Liposomal amphotericin, at similar recommended doses, achieves higher serum levels and improved penetration of the central nervous system, as well as more-rapid plasma clearance than amphotericin B or ABLC.



Azoles


Ketoconazole can be administered orally, and its absorption is favored in an acidic pH. Therefore coadministration of antacids, H2 receptor antagonists, or proton pump inhibitors reduces absorption. The effects of food on absorption of this agent have been inconsistent, and plasma concentrations vary widely among patients receiving the same dose.


Ketoconazole is distributed in saliva, skin, bone, and pleural, peritoneal, synovial, and aqueous humor fluids. It penetrates very poorly into the CSF (~5% of plasma concentration). The plasma concentration declines biexponentially, with a distribution half-life of approximately 2 hours followed by an elimination half-life of 8 hours.


Ketoconazole is extensively metabolized by hydroxylation and oxidative N-dealkylation. It does not induce its own metabolism, as clotrimazole does. However, rifampin induces the release of microsomal enzymes that increase ketoconazole oxidation. Only 2% to 4% of a dose is excreted in urine unchanged, and renal insufficiency does not affect plasma concentrations or half-life, although half-life is prolonged in patients with hepatic insufficiency. Ketoconazole inhibits hepatic P450 enzymes and thus is known to cause many drug-drug interactions.


Miconazole is now primarily used topically and rarely by the intravenous (IV) route. It is minimally water soluble and not adequately absorbed from the GI tract. Its half-life is only 30 minutes, and it is metabolized by O-dealkylation and oxidative N-dealkylation but does not induce its own metabolism. Only 1% is excreted in the urine unchanged. Penetration into the CSF and sputum is poor, but penetration into joint fluid is good.

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Jun 18, 2016 | Posted by in PHARMACY | Comments Off on Antifungal Agents

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