DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Antifungal Agents
John E. Bennett
There are 200,000 known species of fungi, and estimates
of the total size of Kingdom Fungi range to well
over a million. Residents of the kingdom are quite
diverse and include yeasts, molds, mushrooms, smuts,
the pathogens Aspergillus fumigatus and Candida albicans,
and the source of penicillin, Penicillium chrysogenum.
Fortunately, only ~400 fungi cause disease in
animals, and even fewer cause significant human disease.
However, fungal infections are becoming more
common: Patients with AIDS and patients whose
immune systems are compromised by drug therapy are
especially susceptible to mycotic infections. Fungi are
eukaryotes with unique cell walls containing glucans
and chitin, and their eradication requires different
strategies than those for treatment of bacterial infections.
Available agents have effects on the synthesis of
membrane and cell-wall components, on membrane
permeability, on the synthesis of nucleic acids, and on
microtubule/mitotic spindle function (Figure 57–1).
Antifungal agents described in this chapter are discussed
under two major headings, systemic and topical,
although this distinction is somewhat arbitrary. The imidazole,
triazole, and polyene antifungal agents may be
used either systemically or topically, and many superficial
mycoses can be treated either systemically or topically.
Although Pneumocystis jirovecii, responsible for
life-threatening pneumonia in immunocompromised
patients, is a fungus and not a protozoan, its treatment is
discussed elsewhere because the drugs used are primarily
antibacterial or antiprotozoal rather than antifungal.
Major pharmaceutical companies have closed their antifungal
development programs, although a few small firms continue to sponsor
research in this field. Thus, the near future in this area is likely
to be limited to expansion of experience with existing compounds
(Table 57–1). The most recent systemic antifungals to reach clinical
development, posaconazole (NOXAFIL) and isavuconazole (in phase
III trials in the U.S.), are both triazoles.
SYSTEMIC ANTIFUNGAL AGENTS:
SYSTEMIC DRUGS FOR DEEPLY
INVASIVE FUNGAL INFECTIONS
Amphotericin B
Chemistry. Amphotericin B is one of a family of some 200 polyene
macrolide compounds with antifungal activity. Those studied to date
share the characteristics of four to seven conjugated double bonds,
an internal cyclic ester, poor aqueous solubility, substantial toxicity
on parenteral administration, and a common mechanism of antifungal
action. Amphotericin B (see following structure) is a heptaene
macrolide containing seven conjugated double bonds in the trans
position and 3-amino-3,6-dideoxymannose (mycosamine) connected
to the main ring by a glycosidic bond. The amphoteric behavior for
which the drug is named derives from the presence of a carboxyl
group on the main ring and a primary amino group on mycosamine;
these groups confer aqueous solubility at extremes of pH. X-ray
crystallography has shown the molecule to be rigid and rod-shaped,
with the hydrophilic hydroxyl groups of the macrolide ring forming
an opposing face to the lipophilic polyenic portion.