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Chapter 44: Antifungal Agents and Resistance

OVERVIEW

Overview

Compared with antibacterial agents, relatively few antimicrobials are available for treatment of fungal infections. Many substances with antifungal activity have proved to be unstable, to be toxic to humans, or to have undesirable pharmacologic characteristics, such as poor diffusion into tissues. Newer antifungal agents target fungal-specific cellular features and demonstrate lower toxicity than older drug classes.

Many antifungals are too toxic for use

Many fungal infections are self-limiting and require no chemotherapy. Superficial mycoses are often treated, but topical therapy can be used, thus limiting toxicity to the host. Invasive or systemic fungal infections that are not controlled by the host’s immune system require the prolonged use of antifungals. Given that most of the patients with these infections also have underlying immunosuppression, invasive mycosis can be among the most difficult of all infectious diseases to treat successfully. The characteristics of currently used antifungal agents are discussed next and summarized in Table 44–1. They are discussed in the text that follows in relation to their target of action, as illustrated in Figure 44–1.

TABLE 44–1abcdFeatures of Antifungal Agents
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TABLE 44–1 Features of Antifungal Agents
AGENT ACTION RESISTANCE ROUTE CLINICAL USE
Polyenes
Nystatin Cell membrane pores Sterol modification Topical Most fungi
Amphotericin B Cell membrane pores Sterol modification Intravenous Aspergillus, Candida, Cryptococcus, Histoplasma, Sporothrix, Coccidioides
Azoles
Fluconazole Ergosterol synthesis (demethylase) Efflux, demethylase alteration, bypass, overproductiona Oral, intravenous Candida, Cryptococcus, Histoplasmac, Coccidioidesc
Itraconazole Ergosterol synthesis (demethylase) Efflux, demethylase alteration, bypass, overproductiona Oral, intravenous Aspergillus, Sporothrix, Candida, Blastomyces, Histoplasma, Coccidioides
Voriconazole Ergosterol synthesis (demethylase)   Oral, intravenous Candida, Aspergillus, some saprophytic molds
Posaconazole Ergosterol synthesis (demethylase)   Oral, intravenous Candida, Aspergillus (prophylaxis), Zygomycetes
Isavuconazole Ergosterol synthesis (demethylase)   Oral, intravenous Candida, Aspergillus (prophylaxis), Zygomycetes
Clotrimazole Ergosterol synthesis (demethylase)   Topical Candida, dermatophytes
Ketoconazole Ergosterol synthesis (demethylase)   Topical Candida, dermatophytes
Miconazole Ergosterol synthesis (demethylase)   Topical Candida, dermatophytes
Allylamines
Terbinafine Ergosterol synthesis (squalene epoxidase) ?Efflux Oral, topical Dermatophytes
Flucytosine (5-FC)
  DNA synthesis, RNA transcription Permease or modifying enzymesb mutation Oral Candida and Cryptococcusd
Echinocandins
Caspofungin Glucan synthesis (β-glucan synthase) Altered synthase Intravenous Candida, Aspergillus
Micafungin Glucan synthesis (β-glucan synthase) Altered synthase Intravenous Candida, Aspergillus
Anidulafungin Glucan synthesis (β-glucan synthase) Altered synthase Intravenous Candida, Aspergillus
Nikkomycins Chitin synthesis (chitin synthase)     Developmental
Griseofulvin Microtubule disruption Unknown Oral Dermatophytes
Potassium iodide Unknown Unknown Oral Sporothrix schenckii

5FC, 5-Flucytosine.

a

Most work is with fluconazole and Candida; other azoles are to be assumed to be similar.

b

Cytosine deaminase and uracil phosphoribosyltransferase (the enzymes that modify 5-FC to active forms).

c

Itraconazole generally preferred.

d

Only in combination with amphotericin B owing to developing resistance

FIGURE 44–1.

Sites of action of antifungal agents. This figure demonstrates the cellular targets of the major antifungal agents: (1) ...

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