untitled

so the main thrust of research has been to develop for-
mulations that minimize these effects, such as chronic
renal toxicity. There are now several lipid formulations
of amphotericin B, either approved for human use or
in stages of development. For example, the commer-
cial formulation named AmBisome consists of small
(<100 nm diameter) liposomes consisting of a single
layer of phospholipids that incorporate amphotericin
B. Single dose intravenous toxicity tests on mice
showed that AmBisome had an LD 50 value (the dose
resulting in 50% mortality) of more that 175 mg/kg,
compared with an LD 50 of 2–3 mg/kg for a standard
colloidal formulation of amphotericin B mixed with
sodium deoxycholate. Amphotericin in the new for-
mulations has the potential to control several systemic
fungal pathogens, including Candida, Cryptococcus,
Aspergillus, Blastomyces, Coccidioides, and Histoplasma.
Further details of drug delivery systems for antifungal
agents can be found in Adler-Moore & Proffitt (2004).

Azole drugs

The azole drugs are ergosterol biosynthesis inhibitors
similar to those used for plant disease control, but with
structures designed for the treatment of systemic
mycoses of humans. They act by blocking sterol
demethylation at the C-14 position, during the path-
way from lanosterol to ergosterol (see Fig. 7.15).
Depending on whether these drugs have two or three
nitrogens in the five-membered heterocyclic ring, they
are termed imidazoles or triazoles.

Ketoconazole(an imidazole; Fig. 17.14) was the

first of these drugs to be developed for treatment of

humans. It has strong activity against Candidaand

Cryptococcus neoformans, and also can be used against

other systemic pathogens such as Blastomyces dermati-

tidisand Coccidioides immitis, but it has little activity

against Aspergillus. However, ketoconazole has several

adverse side effects, and it has been largely replaced by

the more recent and less toxic triazole drugs such as

fluconazole(Fig. 17.14) and itraconazole(Fig. 17.14).

Although ketoconazole is still available, it is used

mainly as a second-line drug for infections that do not

respond to the triazoles.

Fluconazole is mainly used against Candidaand

Cryptococcusspecies, and is available as both oral and

intravenous formulations. It also has limited activity

against Histoplasmaand Blastomyces, but almost no

activity against other human pathogens. It is a widely

used front-line drug against many Candida albicans

infections, but is not effective against some of the

less common Candidaspp. such as C. kruseiand C.

glabrata.

Itraconazole is available in oral or intravenous

forms and is active against many fungi including

yeasts, dimorphic fungi, and mycelial fungi. Its spec-

trum includes Candidaspp., Cryptococcus, Aspergillus,

Histoplasma, Blastomyces, Coccidioides, and dermato-

phytes. However, resistance to itraconazole has been

reported among many fungi, and this sometimes leads

to cross-resistance to drugs with a similar mode of

action. Three new triazoles with different spectra of

activity have recently been developed. In one case,

352 CHAPTER 17

Ketoconazole

Fluconazole

Itraconazole

CI

N

O

N

O

N C

CI

CH 3

CH 2

CH 2

O

F

F OH

N

N

N

N

N

CH 3

CH 2

CH 2 O

CH 2

CHCH 2 CH 3

CH 3

O

Cl OH

H

N

O O

N N

N

N

N

N

N

N

Fig. 17.14Imidazole and triazole drugs.