Download Antifungal Agents

CHAPTER 43
Antifungal Agents and Resistance
Compared with antibacterial agents, relatively few antimicrobials are available for
treatment of fungal infections. Many substances with antifungal activity have proved
either to be unstable, to be toxic to humans, or to have undesirable pharmacologic
characteristics, such as poor diffusion into tissues. Of the agents in current clinical use
the newer azole compounds have the broadest spectrum with significantly lower toxicity
than earlier antifungal agents. An even newer class of cell wall active agents offers hope
for the selective toxicity that β-lactams provide for antibacterial therapy.
Antifungal Agents
I. CYTOPLASMIC MEMBRANE
A. Polyenes
1. The polyenes nystatin and amphotericin B are lipophilic and bind to ergosterol the
dominant sterol in the cytoplasmic membrane of fungal cells
2. Ergosterol binding forms membrane channels
3. Active against most fungi
4. Insoluble compounds must be infused in suspension
5. Therapy must be titrated against toxicity
B. Azoles
1. Antifungal azoles for systemic administration are ketoconazole, fluconazole,
itraconazole and voriconazole
2. Clotrimazole and miconazole are limited to topical use
3. Inhibit enzyme crucial for synthesis of membrane ergosterol
4. Less toxic than amphotericin B
5. Itraconazole, voriconazole prime systemic agents
C. Allylamines
1. Group of synthetic compounds that act by inhibition of an enzyme (squalene
epoxidase) important in the early stages of ergosterol synthesis
2. Include an oral agent, terbinafine, and a topical agent, naftifine
3. Used in the treatment of dermatophyte (ringworm) infections.
II. NUCLEIC ACID SYNTHESIS
A. Flucytosine
1. 5-Flucytosine (5FC) is an analog of cytosine and a potent inhibitor of RNA and
DNA synthesis
2. Enzymatically modified form makes defective RNA
3. Metabolites interfere with DNA synthesis
4. Active against yeasts but not molds
5. Resistance develops during therapy if used alone
III. CELL WALL SYNTHESIS
A. Echinocandins
1. Caspofungin has good activity against Candida and Aspergillus and a wide range
of other fungi
2. Inhibit glucan synthease an enzyme crucial for cell wall glucan synthesis
3. Current use is Candida, Aspergillus
4. Newest echinocandins, micafungin and anidulafungin have the same mode of
action and similar spectrum.
B. Nikkomycins
1. Nikkomycins inhibit chitin synthetase which polymerizes the N-acetylglucosamine subunits which make up chitin
2. Inhibit chitin synthesis
3. Agent in development, nikkomycin Z, has activity against dimorphic fungi like
Coccidioides immits and Bastomyces dermatitidis but not against yeast or
Aspergillus
OTHER ANTIFUNGAL AGENTS
1.
2.
3.
4.
5.
Griseofulvin is active only against the agents of superficial mycoses
Microtubule disruption interferes with cell division
Active against dermatophytes
Potassium iodide is effective only for cutaneous Sporothrix schenckii
Tolnaftate a derivative of naphthiomate has activity against
Resistance to Antifungal Agents
I. Definition of Resistance
1. Concepts are similar to bacterial resistance (Chapter 23)
2. Laboratory methods are more variable
II. Mechanisms of Resistance
1. The same resistance mechanisms seen in bacteria except enzymatic inactivation of
antifungals by fungi is unknown
2. The powerful means for gene transfer like conjugation and transposition are also
absent
A. Polyene Resistance
1. Decrease in membrane ergosterol decreases susceptibility
B. Flucytosine Resistance
1. Flucytosine requires a permease for entry into the cell and then multiple enzymes
to modify it to the active metabolites
2. Mutation of any of these enzymes confers resistance
C. Azole Resistance
1. Azole extruded by efflux pump
2. Enzyme target altered
3. Demethylase up-regulated or bypassed
D. Echinocandin Resistance
Mutations in subunits of the glucan synthetase target have been correlated with increased
resistance