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Antifungal Agents

Fungi are eukaryotes, and they share many of the structural and metabolic characteristics of human cells. As a result, designing agents that affect fungi without harming human cells has proved difficult. One major difference between the two cell types is the primary sterol building block used to form the plasma membrane. The fungal plasma membrane consists of ergosterols; the major sterol component of the human plasma membrane is cholesterol. This difference has been exploited in the development of two classes of drugs. The polyenes act by binding to ergosterol and disrupting the fungal membrane. These agents are fungicidal. The azoles inhibit ergosterol synthesis, and lowered ergosterol levels results in fungal membrane breakdown. These agents are usually fungistatic.

Antifungal Agents

The Major Difference Between Mammalian And Fungal Cells

Like mammals, fungi are eukaryotes. Drug therapy takes advantage of fact that fungi use ergosterols rather than cholesterol as the major building block of their plasma membrane.

Agents for Treatment of Systemic Fungal Infections

Amphotericin В

Chemical Structure, Mechanism of Action, and Spectrum of Activity

Amphotericin В is a long, cyclic polyene compound that forms a large rod-like structure. Multiple molecules bind to ergosterol in the fungal membrane, forming pores that result in leakage of intracellular potassium and in fungal cell death. This fungicidal action is rapid and does not require active growth.

About the Mechanism of Action and Spectrum of Amphotericin В

  1. Polyene compound forms rod-like structures that bind to ergosterol in the fungal membrane, forming pores that result in a leak of intracellular potassium.
  2. Rapidly cidal; does not require active growth.
Antifungal Agents

Toxicity

Nephrotoxicity is the major complication associated with the conventional deoxycholate form of amphotericin B. This agent causes vasoconstriction of renal arterioles, resulting in a reduction in glomerular filtration rate. Vasoconstriction also impairs proximal and distal tubular reabsorption, causing potassium, magnesium, and bicarbonate wasting. These effects are reversible.

However, permanent loss of nephrons and permanent damage to tubular basement membranes are also observed and correlate with the total dose administered. Renal dysfunction is observed in virtually all patients receiving this drug, and serum creatinine levels of 2 to 3 mg/dL are to be expected. Hydration with normal saline before infusion reduces nephrotoxicity.

Fever is commonly associated with administration of amphotericin B, and fever can be associated with chills and tachypnea, particularly if the drug is infused too rapidly. This agent should be infused slowly [2 to 3 hours for the deoxycholate form (amphotericin В deoxycholate) and under 2 hours for the lipid preparations]. Fever and chills usually diminish with each subsequent dose. However, if those reactions persist, the patient can be premedicated with acetaminophen or 25 to 50 mg hydrocortisone can be added to the solution. This febrile reaction does not represent an allergic reaction and should not be misinterpreted as anaphylaxis. A 1 mg test dose preceding administration of the full dose has not proved to be helpful, and use of a test dose delays achievement of therapeutic antifungal serum and tissue levels. Because of a high incidence of phlebitis, amphotericin В should be administered through a centrally placed intravenous line.

Pharmacokinetics

At physiologic pH, amphotericin В deoxycholate is insoluble in water. It is stored as a powder that is dispersed as colloidal suspension in a 5% dextrose solution. Following intravenous infusion, amphotericin В is bound to lipoproteins in the serum and then leaves the circulation. The drug is stored in the liver and other organs and subsequently released into the circulation. Lipid-associated amphotericin В is ingested by macrophages, resulting in high intracellular levels in that cell type. This drug shows poor penetration of the blood-brain barrier and brain. Therapeutic levels are detectable in inflamed pleural fluid, peritoneum, and joint fluid. Amphotericin В is degraded slowly, and degradation is not affected by hepatic or renal dysfunction. Serum concentrations of the drug are detectable 7 weeks after therapy is discontinued.

Antifungal Agents

Spectrum of Activity

Amphotericin В is effective against most fungal infections and remains the most effective agent for systemic fungal infections. Clinical resistance to amphotericin В has been demonstrated among Candida lusitaniae, Fusarium species, and Pseudalles-cheria boydii. C. lusitaniae initially is susceptible to amphotericin B, but develops resistance during treatment. The alterations in sterol structure required for amphotericin В resistance often reduce tissue invasiveness, such strains being capable of growing only on mucosal surfaces or in the urine. Efficacy of Various Amphotericin В Preparations — Lipid-associated preparations of amphotericin В are preferred because of their lower nephrotoxicity. However, these preparations are very expensive and in most clinical trials have comparable efficacy to amphotericin-B deoxycholate.

Table. Systemic Antifungal Agents: Half-Life, Dosing, Renal Dosing, and Cost

Antifungal (trade name) Half-life (h) Dose Dose for reduced creatinine clearance (mL/min)
Amphotericin В deoxycholate (Fungizone) 15d 0.3-1.0 mg/kg IV q24h (infuse over 4-6 h) No change required
Amphotericin В lipid preparations (Abelcet,Amphotec, AmBisome) 7d 3-5 mg/kg IV q24h No change required
Fluconazole (Diflucan) 20-50 100-200 mgPO q12-24h 200-400 mg IV q24h 10-50: Half the dose < 10:One quarter to half the dose
Ketoconazole (Nizoral) 1-4 200-400 mgPOq12-24h No change required
Itraconazole (Sporanox) 20-60 100-200 mgPOq12-24h 200mglVq12hX4, then 200 mg q24h <30:Contraindicated
Posaconazole (Noxafil) 35 200mgPOq6h,or 400mgPOq12h No change required
Voriconazole (Vfend) Nonlinear kinetics 200mgPOq12h 6mg/kglVq12hX2, then 4mg/kgq12h <50:IVnot recommended; switch to oral
Anidulafungin (Eraxis) 10-15 200 mg IV, then 100mgq24h No change required
Caspofungin (Cancidas) 9-11 70 mg IV, then 50 mg q24h No change required
Micafungin (Mycamine) 14-17 150mglVq24h No change required
Flucytosine (Ancobon) 3-6 25-33 mg/kg PO q6h 10-50:25 mg/kg q12-24h 25mg/kgq24h(<10)

About the Toxicity of Amphotericin В

  1. Nephrotoxicity is observed with virtually all patients receiving amphotericin В deoxycholate; reduced by hydration using normal saline. Reversible in most cases. Permanent damage with prolonged therapy.
  2. Fever is common with all preparations. Slow infusion (2 to 3 hours with amphotericin В deoxycholate, less than 2 hours with liposomal preparations) reduces severity. Premedication with corticosteroids or acetaminophen, or both, often reduce fever.
  3. Phlebitis is common, requiring administration by central intravenous line.

Liposomal amphotericin В was shown to be superior to amphotericin В deoxycholate for the treatment of pulmonary histoplasmosis. The lipid-associated preparations are recommended in patients with significant preexisting renal dysfunction or in patients who develop progressive renal failure (serum creatinine above 2.5 mg/dl) while being treated amphotericin В deoxycholate. Clinicians also need to be aware of the observation that amphotericin В deoxycholate-related renal dysfunction (50% increase in baseline creatinine to a minimum of 2 mg/ml) is associated with a 6.6-fold increased risk of death.

About Amphotericin Spectrum of Activity and Preparations

  1. Preferred antifungal agent for severe systemic fungal infections.
  2. Effective against most fungi except Candida lusitaniae, Fusarium, and Pseudallescheria boydii.
  3. Lipid-associated preparations reduce nephrotoxicity, but similar incidence of fever, with efficacy comparable to conventional amphotericin В deoxycholate.
  4. Higher doses of lipid-associated preparations required: 3 to 5 mg/kg daily as compared with 0.3 to 1.4 mg/kg for amphotericin В deoxycholate.
  5. Very high cost. Recommended for patients with significant pre-existing renal dysfunction or those who develop progressive renal dysfunction on amphotericin В deoxycholate (serum creatinine >2.5 mg/dL).

Azoles

Chemical Structure and Mechanism of Action

The azoles are chemically synthesized agents that come in two classes. The first to be synthesized were the imidazoles (miconazole and ketoconazole). Those compounds are now seldom used for systemic infections, being primarily reserved for topical treatment of superficial fungal infections. The second class, the triazoles, are preferred for systemic fungal infection; they are well absorbed orally and have excellent toxicity profiles. All azoles inhibit a cytochrome P450-dependent demethylation system that results in decreased production of ergosterol and accumulation of intermediate sterols. The loss of ergosterol results in altered fungal membrane permeability, disturbed activity of membrane surface enzymes, and retention of metabolites. These agents have broad antifungal activity, but they demonstrate fungistatic rather than fungicidal activity. Itraconazole can antagonize amphotericin В activity by reducing its binding target, ergosterol.

Toxicity

Ketoconazole not only interferes with fungal sterol metabolism, but at higher doses it also interferes with testosterone and cortisone production. Gynecomastia and loss of libido are commonly observed. Severe hepatitis can develop during treatment with this agent. As a result of its many toxicities, ketoconazole is rarely prescribed today. The triazoles (fluconazole, itraconazole, posaconazole, voriconazole) demonstrate minimal toxicity. Side effects include headache, gastrointestinal intolerance, and asymptomatic increases in serum transaminase levels. Voriconazole infusion can be associated with transient loss of light perception. This symptom resolves with subsequent doses. Visual hallucinations less commonly occur.

About the Mechanism of Action of the Azoles

  1. Inhibit cytochrome P450-dependent demethylation, resulting in decreased ergosterol production and altered fungal membrane permeability.
  2. Azoles are usually fungistatic.
  3. Itraconazole can antagonize amphotericin В activity by reducing its binding target.

Pharmacokinetics

Fluconazole is well absorbed orally, and serum levels after ingestion of the oral preparation are comparable to those with intravenous administration. Penetration into tissues and body fluids, including the cerebrospinal fluid, is excellent. Itraconazole is more variable in its oral absorption and requires stomach acidity for adequate absorption. Capsule absorption is enhanced by food and reduced by agents that reduce stomach acidity. Itraconazole penetrates most tissues, but does not cross the blood-brain barrier and enters ocular fluids only minimally.

Posaconazole oral absorption is enhanced by food, particularly high-fat meals or liquid nutritional supplements. Voriconazole is well absorbed orally, demonstrating 96% bioavailability and also can be given intravenously. All of the azoles are metabolized by the liver via the cytochrome P450 system, and as a consequence, drug-drug interactions are common with these agents. Rifampin, rifabutin, long-acting barbiturates, carba-mazepine, and cisapride usually lower azole levels. The azoles slow the metabolism of Coumadin, warfarin, phenytoin, tacrolimus, cyclosporine, certain antihista-mines, benzodiazepines, calcium channel blockers, sulfonylureas, prednisolone, digoxin, statins, and anti-HIV protease inhibitors.

The doses of these agents usually need to be lowered in the presence of azoles. Drug-drug interactions have proven to be the most problematic with voriconazole. Voriconazole is metabolized primarily by the P450 enzyme CYP2C19, and that enzyme has variable activity depending on the patient's genetic background.

About Azole Toxicity

  1. Ketoconazole interferes with testosterone and cortisone production, resulting in gynecomastia and loss of libido. Hepatitis can be severe, and the drug should be discontinued when symptoms of hepatitis develop. Liver function tests should be performed.
  2. Rare side effects of fluconazole, itraconazole, posaconazole, and voriconazole include headache, gastrointestinal intolerance, asymptomatic elevation of serum transaminases.
  3. Intravenous infusion of voriconazole can be associated with transient loss of light perception.
  4. Drug-drug interactions with other agents metabolized by the cytochrome P450 system are common, particularly with voriconazole and ketoconazole.

About the Spectrum of Activity and Indications for Fluconazole

  1. No activity against Aspergillus. Active against Candida albican, but natural resistance in С glabrata and С krusei is common. Active against Cryptococcus neoformans.
  2. With prolonged treatment, drug resistance can develop in Candida species.
  3. Treatment of choice for oral candidiasis and Candida vulvovaginitis.
  4. Can be used for uncomplicated С albicans fungemia in the non-immunocompromised patient.
  5. Can be used to complete therapy of cryptococ-cal meningitis in HIV patients after an initial course of amphotericin B.
  6. Prophylaxis reduces Candida infections in neu-tropenic patients.

The role of prophylaxis in other settings remains controversial because of the risk of selecting for resistant strains. As a consequence, serum levels can vary by up to a factor of 4 in individuals with rapid as opposed to slow metabolism. In the United States, the co-administration of rifabutin and voriconazole is contraindicated because rifabutin levels may increase by a factor of 3, while voriconazole levels drop below therapeutic levels. Rifampin, carbamazepines, and long-acting barbiturates can also markedly reduce voriconazole levels, and these drugs should probably be discontinued when voriconazole is being administered.

Spectrum of Activity and Treatment Recommendations

Fluconazole has no activity against Aspergillus species, and some strains of Candida, including С glabrata and С krusei, demonstrate natural resistance. Because of increased production of demethylase and increased drug efflux, any Candida species can develop resistance. Fluconazole is recommended for the treatment of oropharyngeal and vulvovaginal candidiasis. Intravenous fluconazole has proved therapeutically equivalent to amphotericin В in uncomplicated candidemia in the non-immunocompromised host. However, for the immunocompromised (including neutropenia) host, and for seriously ill patients with deep tissue Candida infection, amphotericin В or caspofungin should  be  used.  Fluconazole  is  also  effective  for completing the treatment of cryptococcal meningitis in patients with AIDS.

About the Spectrum of Activity and Indications for Itraconazole

  1. Improved activity against histoplasmosis, coc-cidiomycosis, blastomycosis,and sporotrichosis.
  2. Used in less severe cases of histoplasmosis and coccidiomycosis.
  3. Used to prevent relapse of disseminated histoplasmosis in patients with AIDS.
  4. Absorption of the drug is erratic.

After initial therapy with amphotericin B, with or without flucytosine, for 2 weeks, fluconazole (400 mg daily) treatment for 2 months, followed by daily fluconazole maintenance therapy (200 mg daily), is recommended. The role of fluconazole in patients with non-AIDS-related cryptococcal infection has not been defined. The use of fluconazole for prevention of fungal infections has been explored in neutropenic allogeneic bone marrow transplant patients and was found to reduce mortality and the incidence of invasive Candida infections, but no effect on the incidence of Aspergillus infections was observed.

Fluconazole prophylaxis of leukemia patients also reduced the incidence of invasive Candida infections, but had no effect on mortality. Fluconazole is frequently used in the surgical intensive care unit in the hopes of preventing candidemia in patients. To date, such prophylaxis has not been proved to significantly reduce Candida infections, and this practice increases the prevalence of fluconazole-resistant fungi, including C. krusei and С glabrata. Because of the risk of selecting for resistant fungi, fluconazole prophylaxis is not recommended in patients infected with HIV.

About the Spectrum of Activity of Voriconazole and Posaconazole

  1. Voriconazole is preferred for Aspergillus and active against Candida albicans.
  2. Posaconazole has activity against Aspergillus and Zygomyces (broadest-spectrum azole).

Itraconazole

As compared with fluconazole, itraconazole has demonstrated improved activity against histoplasmosis, coccidiomycosis, blastomycosis, and sporotrichosis. Itraconazole can be used for acute and chronic vaginal candidiasis and HIV-associated oral and esophageal candidiasis, and for consolidation and maintenance therapy for cryptococcal meningitis in patients with AIDS. Itraconazole is the preferred agent for the treatment of lymphocutaneous sporotrichosis and of non-meningeal, non-life-threatening histoplasmosis, blastomycosis, and coccidiomycosis. For disseminated histoplasmosis and coccidiomycosis, amphotericin В remains the treatment of choice. Itraconazole is recommended as primary prophylaxis and for the prevention of relapse of histoplasmosis in patients with AIDS.

Voriconazole and Posaconazole

As compared with amphotericin В deoxycholate, voriconazole demonstrates increased activity against Aspergillus and has proven to be superior for the treatment of invasive aspergillosis. Voriconazole is also approved for the treatment of Fusarium and Scedosporium. Clinical trials exploring the efficacy of voriconazole for invasive candidiasis are currently under way. The newest azole, posaconazole, has the broadest spectrum in the class. In addition to being effective against Aspergillus, this agent has activity against many of the Zygomycetes. Posaconazole is currently approved as salvage therapy for mucormycosis.

Caspofungin/Anidulafungin/Micafungin

Chemical Structure and Mechanism of Action

The echinocandins are all derived from echinocandin В, a semisynthetic lipopeptide that blocks synthesis of β-(l,3)-D-glucan. That polysaccharide is a critical component of the cell wall in many pathogenic fungi.

About the Echinocandins

  1. Block synthesis of a cell wall polysaccharide vital to many pathogenic fungi.
  2. Active against Aspergillus and Candida, including isolates resistant to other antifungal agents. Not active against Cryptococcus.
  3. Toxicities tend to be mild.
  4. Recommended for the treatment of invasive Aspergillus in patients who have failed on, or cannot tolerate,amphotericin В and for oral and esophageal candidiasis refractory to azoles and amphotericin B.

Toxicity

The echinocandins have proven to be very safe, provoking only the occasional fever, rash, or flushing of the face during infusion. Serum levels are increased by co-administration of cyclosporin. Agents that may reduce serum levels including efavirenz, nelfinavir, Dilantin, Tegretol, rifampin, and dexamethasone. The echinocandins can reduce serum levels of tacrolimus.

Pharmacokinetics

The echinocandins are not absorbed by the gastrointestinal tract and must be administered intravenously. They are metabolized by the liver.

Spectrum of Activity and Treatment Indications

The echinocandins are active against Aspergillus and Candida, including isolates that are resistant to other antifungal agents. They are less effective against С parapsilosis in vitro, and are not active against Cryptococcus. They are approved for the treatment of invasive aspergillosis in patients who fail on, or are unable to tolerate, amphotericin В or itraconazole. Caspofungin can also be used to treat oral candidiasis that is refractory to azole or amphotericin В therapy.

Flucytosine

Chemical Structure and Mechanism of Action

Flucytosine, or 5-fluorocytosine (5-FC), is a fluorine analog of cytosine. After a multi-step conversion requiring deamination and phosphorylation, the resulting product, 5-fluo-rouracil (5-FU) acts as an inhibitor of thymidylate syn-thetase, impairing Deoxyribonucleic acid and RNA synthesis. In humans, 5-FC is not toxic because of a lack of the deaminase required for conversion to 5-FU.

Toxicity

The major toxicity of flucytosine is bone marrow suppression leading to neutropenia, anemia, and thrombocytopenia. This side effect is dose-related and usually occurs when serum levels exceed 125 µg/mL. Patients with diminished bone marrow reserve such as those with AIDS and those receiving cancer chemotherapy are more likely to suffer this complication. Commonly, 5-FC is administered in combination with amphotericin B. As discussed earlier in this chapter, amphotericin В impairs renal function, and reductions in renal function reduce the clearance of 5-FC. In patients with renal dysfunction, monitoring of peak (2 hours after oral administration) and trough levels (just before the next dose) is recommended. Doses should be adjusted to maintain serum levels between 20 and 100 µg/mL.

About Flucytosine

  1. Impairs fungal Deoxyribonucleic acid and RNA synthesis; fun-gistatic.
  2. Cleared by the kidneys; penetrates all tissues and fluids, including the cerebrospinal fluid.
  3. High levels cause bone marrow suppression. In patients with renal failure, doses should be adjusted, and serum levels should be monitored.
  4. Never use as monotherapy.

In cryptococcal meningitis, the combination of amphotericin В and flucytosine sterilize the cerebrospinal fluid faster than does amphotericin В alone. In animal studies, combination therapy is beneficial for Candida infections, but efficacy has not be proven in humans.

Pharmacokinetics

Flucytosine is well absorbed orally. Because it is a small molecule, 5-FC penetrates tissues well and crosses the blood-brain barrier. Therapeutic levels can be achieved in the cerebrospinal fluid, aqueous humor, joint fluid, and respiratory secretions. The kidneys clear 5-FC.

Spectrum of Activity and Treatment Recommendations

Most strains of С albicans and Cryptococcus neoformans are sensitive to 5-FC. Native resistance varies geographically. About 15% of С albicans stains and 3% to 5% of Cryptococcus neoformans demonstrate resistance. The effect of 5-FC is usually fungistatic, and it should never be used alone, because resistance rapidly develops with monotherapy. The combination of 5-FC and amphotericin В demonstrates additive or synergis-tic activity in cryptococcal infections. In cryptococcal meningitis, amphotericin В and 5-FC sterilize the cerebrospinal fluid faster than amphotericin В alone. In vitro and animal testing also suggest that combination therapy for Candida may be of benefit; however, efficacy has not been proven in patients.

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