Antifungal Agents

Question 1

Polyene Antibiotics

Answer 1

•Polyene antibiotics were the first antifungals developed and have a complex structure consisting of a cyclic ester with multiple conjugated double bonds. The drug inserts into the cell membrane and binds ergosterol, resulting in pores that lead to electrolyte leakage and subsequent cell death. Although they have activity against a broad range of fungi, they are also associated with significant toxicity because of their affinity for cholesterol, an animal cell membrane component.

Question 2

Amphitocerin B

Answer 2

• The only polyene that can be given systemically is amphotericin B.
• Amphotericin B has a very broad spectrum of activity against many fungal species and, despite its significant toxicity, tends to be the drug chosen for severe or recalcitrant fungal infections. Organisms susceptible include most yeasts, including Candida albicans and Cryptococcus neoformans, most Aspergillus species, and all the dimorphic fungi

Question 3

Amphitocerin B - Not Susceptible

Answer 3

•Candida lusitaniae and C. guilliermondii,Pseudallescheria boydii, Fusarium spp., Aspergillus terreus, and perhaps fungi belonging to the Zygomyces class.

Question 4

Amphitocerin B Adverse Effects

Answer 4

•Amphotericin B is a highly toxic agent. Adverse events can be divided into two groups.

• The first are those that are infusion-related. These include fevers, chills, inflammation of the veins (phlebitis), and cardiac arrhythmias. The drug should always be infused through a central venous catheter to decrease the risk of phlebitis.
• The second group of adverse events involve longer-term toxicities associated with renal abnormalities. These include potassium and magnesium wasting, renal tubular acidosis, decline in renal function, and anemia, the latter related to a decrease in renal erythropoietin production.

Question 5

Nystatin

Answer 5

•Nystatin is the only other polyene antifungal currently in use and has a similar spectrum of activity as amphotericin B. However, it is available only in topical preparations. These include a “swish and swallow” liquid, a skin cream, or in vaginal creams or suppositories.

Question 6

Azole Antifungals

Answer 6

•Azole antifungals were first developed in the 1970’s. They can be structurally distinguished by the number of nitrogens in the azole ring. Those with two (imidazoles) are no longer commonly used. Those with three (triazoles) represent the major azole antifungals in current use.

Question 7

Ketoconazole

Answer 7

•Ketoconazole, an imidazole that was commonly used in the past and is now inexpensive, is now used less frequently because of its lack of broad antifungal activity and relatively high rate of drug interactions

Question 8

Triazoles

Answer 8

•The triazoles, particularly fluconazole and itraconazole, and to a lesser extent, the newer agents posaconazole and voriconazole, have largely supplanted ketoconazole. Isavuconazole is a new triazole antifungal that was recently approved for use in patients with aspergillosis or mucormycosis. It is administered as a prodrug, isavuconazonium sulfate, where the triazole is conjugated to an ammonia moiety. The triazoles have increased activity against many Candida spp, Cryptococcus and against most of the dimorphic fungal pathogens. Itraconazole and the more recently released triazoles posaconazole, voriconazole, and isavuconazole also have activity against Aspergillus spp. However, with increasing use of azoles, resistance has been described, particularly in Candida spp. Although multifactorial, a calcium-dependent efflux pump is most the most common mechanism of resistance.

Question 9

Problem with Azoles

Answer 9

•One major problem with azole antifungals is their interaction with the cytochrome P450 (CYP) system. Azole antifungals are both metabolized by and inhibit these enzymes, especially CYP3A4, CYP2C19, and CYP2C9. This leads to many bidirectional interactions with other drugs. For example, there are drugs that increase the activity of CYP3A4. This will lead to an increase in metabolism of azole antifungals and a decrease in efficacy. Two commonly use drugs that are associated with this effect are rifampin and phenytoin. Since azole antifungals block the activity of CYP3A4, drugs that depend on this enzyme for metabolism may reach higher systemic levels than anticipated. Two commonly used drugs that are affected by this are warfarin and simvastatin. Combining an azole antifungal with either may lead to severe toxicity. In the case of warfarin, this could manifest as a marked increase in warfarin’s anticoagulant effect and life-threatening bleeding. For simvastatin, and to a lesser extent for other statins, toxic levels may lead to muscle breakdown and renal failure, a condition called rhabdomyolysis. In addition, grapefruit and grapefruit juices are potent inhibitors of intestinal CYP3A4. While this may increase the absorption of some drugs, it has the opposite effect on itraconazole because it results in an increase in the metabolism of itraconazole in the gut lumen, leading to decreased systemic absorption of active drug. For this reason, persons on itraconazole should not eat grapefruits or drink grapefruit juice. This effect does not appear to occur with other azole antifungals.

Question 10

Azole Resisitance

Answer 10

•Azole antifungal resistance is of two types. Intrinsic resistance is predictable by knowing the particular fungal species. For example, all Candida krusei are resistant to fluconazole while Aspergillus spp. are all resistant to imidazole azole antifungals such as ketoconazole. Acquired resistance occurs after repeated exposures to the drug. Multiple mechanisms have been identified with the two most common being a calcium-dependent efflux pump and alteration or overexpression of 14-α demethylase.

Question 11

Yeast (Cryptococcus, Candida Albicans)

Answer 11

Fluconazole

Question 12

Dimoprhic (Histo, Blasto, Cocci)

Answer 12

Itraconazole

Question 13

Mold (Aspergillus)

Answer 13

posaconazole, voriconazole, and isavuconazole

Question 14

Mold (Mucorales)

Answer 14

Posaconazole and isavuconazole

Question 15

Echinocanidins

Answer 15

•These are synthetically derived cyclic lipopeptides with the original molecule derived from Aspergillus. Their large size precludes oral absorption and all must be given intravenously. They are degraded in the liver with inactive metabolites excreted in the urine. They have a relatively long half-life of 8 to 13 hours. They act by inhibiting the synthesis of β-1,3-glucan by blocking the interaction between UDP-glucose and the glucan synthase subunit, Rho.

Question 16

Echinocandins Activity

Answer 16

•The echinocandins have a very specific spectrum of antifungal activity. They are very active against Candida and Aspergillus spp. and perhaps Pneumocystis, but have no documented activity against the dimorphic fungi, Cryptococcus, Zygomycetes, Fusarium or dermatophytes.

Question 17

Echinocandins Types

Answer 17

•There are currently three currently available echinocandins, caspofungin, micafungin, and anidulofungin. They all appear to be similar in antifungal activity, toxicity and pharmacodynamics. Currently, micafungin is preferred based on cost.

Question 18

Terbinafine

Answer 18

•This is the only allylamine antifungal available in the United States. It inhibits squalene epoxidase, an early ergosterol precursor. While mostly used for dermatophyte infection, terbinafine has activity against a variety of other fungi and definitely has a role in the treatment of sporotrichosis and scedosporiosis. It is only available as an oral 250 mg tablet or as a topical agent. It is highly lipophilic and concentrates in keratinized tissue, with skin and hair levels tenfold higher than in serum and with therapeutic levels found in these tissues up to 12 weeks after therapy discontinuation. This property accounts for its usefulness for dermatophyte infections. It is extensively metabolized in the liver to inactive compounds with 80-85% of these excreted in the urine. One of its most common uses is the treatment of onychomycosis, or nail bed fungal infection. A dose of 250 mg orally daily for three to six months has a cure rate of between 82 to 92%.

Question 19

Flucystosine

Answer 19

•Originally synthesized in 1957, flucytosine was recognized as an antifungal in 1963. It acts by both inhibiting thymidine kinase and by binding to mRNA and resulting in mis-sense proteins. When used alone, fungal resistance rapidly emerges. It is only active against the yeasts Candida and Cryptococcus. Flucytosine is only available as a tablet and is well absorbed with a half-life of about 4 hours. It is excreted unchanged in the urine. As an antimebolite, it causes significant gastrointestinal, hepatic and bone marrow toxicity, which are exacerbated by renal insufficiency. Currently, its only major use is in combination with amphotericin B for the treatment of cryptococcosis. In this case, it is used in a dose of 25 mg/kg of body weight fourtimes each day orally. Close monitoring for bone marrow toxicity is mandatory

Question 20

Griseofulvin

Answer 20

•This drug is an old oral antifungal derived from Penicillium griseofulvum. It inhibits fungal mitosis by binding to tubulin and is rapidly fungicidal. While it is active against most dermatophytes, it has no activity against Candida spp. or any deep mycoses. It is supplied in a 500 mg tablet in a microcrystalline formulation that improves its absorption, which is also improved with a fatty meal. It is infrequently used today but is occasionally emp

Question 21

Nikkomycin Z

Answer 21

•Not yet approved for use, nikkomycin Z inhibits chitin synthase by acting as an analog of UPDN-acetylglucosamine. There is curren