Antifungal drugs Polyenes Antimetabolites and Azoles uses

what is a short definition  

Fungi rule their own kingdom. There are thousands
of species of these saprophytic and parasitic
organisms, but, as with bacteria, only a small minority
are pathogens. Most pathogenic fungi are
opportunistic and require a compromised host or
disrupted barrier in order to cause infection in
humans. In a way, the increase of systemic fungal
infections can be seen as a medical advance, because
improvements in transplantation,. highlights some of the medically
important fungi. Yeasts are solitary forms of fungi
that reproduce by budding. When they are left to
grow in colonies, they have a moist, shiny appearance.
Molds are multicellular fungi that consist of
many branching hyphae and can reproduce either
by translocation of existing hyphae to a new area,
or through spore formation and spread.

Common Clinical Fungi

Yeasts        

Candida ,Cryptococcus                  

Dimorphic 

Histoplasma   Blastomyces Coccidioides Paracoccidioides        

Fungi Moulds 

Aspergillus Fusarium Scedosporium Zygomycetes

some common antifungal drugs

Antifungal pharmacotherapy has several problems
that often make fungal infections more difficult to treat than bacterial infections. One is that
fungal disease often presents no differently than
bacterial disease, but the pathogens can be more
difficult to isolate on culture. This makes the
prompt initiation of empiric therapy important
when invasive fungal infections are suspected. Prophylaxis
is also used in highly susceptible populations
to prevent fungal infections from developing.

Polyenes

amphotericin B,
nystatin (topical)
For many years, amphotericin B deoxycholate was
the standard of care for many systemic fungal infections,
for both its broad antifungal spectrum and a
lack of available alternatives. Polyenes work by binding
to ergosterol in the cell membrane of fungi, disrupting
its function. Amphotericin B is notable for its
toxicities, principally nephrotoxicity and infusionrelated
reactions. To attenuate these toxicities, three
lipid forms were developed: amphotericin B colloidal
dispersion (ABCD), amphotericin B lipid complex,
and liposomal amphotericin B (LAmB).
Amphotericin B formulations have seen considerably
less use since the introduction of the echinocandins
and broad-spectrum azoles, but they
still have utility. Activity against yeasts and many
moulds, proven efficacy in understudied disease
states, and a long history of use help maintain their
place in the antifungal armamentarium.

Spectrum

Good: most species of Candida and Aspergillus,
Cryptococcus neoformans, dimorphic fungi,
many moulds

Moderate: Zygomycetes

Poor: Candida lusitaniae, Aspergillus terreus

Adverse Effects on body

Nephrotoxicity and infusion-related reactions are
the most common adverse effects.
Dosing Issues
The multiple formulations of amphotericin B can
lead to confusion over their dosing. Amphotericin B
deoxycholate is generally dosed between 0.5 and
1.5 mg/kg/day, where the lipid formulations are
dosed at 3–6 mg/kg/day.

uses of Polyenes

Amphotericin B formulations remain the drugs of
choice for cryptococcal meningitis and serious forms
of some other fungal infections, such as dimorphic
fungi and some mould infections. Because of their
broad spectrum, they are also a reasonable choice if
fungal infection is suspected but the infecting organism
is not known, as in febrile neutropenia.
Their use in candidiasis and aspergillosis has declined
with the availability of newer, safer agents

Antimetabolites

Agent: flucytosine (5-FC)
Flucytosine has a mechanism of action that is distinct
from that of other antifungals in that it has an
antimetabolite that interferes with DNA synthesis.
Flucytosine was originally investigated as an oncology
drug, but it was found to be significantly
more active against fungi than against human cancer
cells. The primary role of flucytosine is in combination
therapy with amphotericin B formulations
for cryptococcal disease. Because of its toxicity and
relative lack of efficacy, it is rarely used for other
infections.

Spectrum

Good: in combination with amphotericin B: Cryptococcus
neoformans, most species of Candida

Moderate: monotherapy: Cryptococcus neoformans,

most species of Candida

Poor: moulds, Candida krusei

uses of Antimetabolites
As stated above, most flucytosine use is in combination
with an amphotericin B formulation for treatment
of cryptococcal meningitis. This combination
may also be used to treat other forms of cryptococcal
infection and, uncommonly, to treat Candida infection.
It may be an acceptable option for the
clearance of candiduria in patients who cannot receive
fluconazole because of allergy or resistance

Azoles

■ Introduction to Azoles
Agents: ketoconazole, fluconazole, itraconazole,
voriconazole, posaconazole, multiple
topical formulations
The azoles are a broad class of antifungal agents
whose drug development has recently been expanding.
They work by inhibiting fungal cytochrome
P450, decreasing ergosterol production. One might
expect that this mechanism of action would lead to
issues with drug interactions, and this is indeed a
significant problem with these drugs.
Azoles have become mainstays of antifungal
pharmacotherapy. As they have been developed,
agents of variable antifungal spectrums and toxicity
profiles have been introduced. These differences
are fundamental and are among the most important
characteristics to know if you use them clinically.
Because they are so different, we will discuss
the commonly used systemic agents individually

Fluconazole

The introduction of fluconazole in 1990 was a breakthrough
in antifungal pharmacotherapy. Fluconazole
is highly bioavailable, available in both oral and
IV formulations, and highly active against many
species of Candida. Before this, clinicians were faced
with the toxicity and inconvenience of amphotericin
B for serious forms of candidiasis. Fluconazole has a
low incidence of serious adverse reactions, and converting
from IV to oral therapy is simple. Though a
shift toward non-albicans species of Candida has affected
the use of fluconazole, it remains an important,
frequently utilized agent.

Spectrum

Good: Candida albicans, Candida tropicalis, Candida

parapsilosis, Candida lusitaniae, Cryptococcus
neoformans, Coccidioides immitis

Moderate: Candida glabrata (can be susceptible

dose-dependent, or resistant)
Poor: moulds, many dimorphic fungi, Candida
krusei

Dosing Issues

Fluconazole doses for systemic fungal infections have
been escalated, particularly for the treatment of Candida
glabrata.

used for

Fluconazole remains a drug of choice for many susceptible
fungal infections, including invasive and
noninvasive candidiasis and cryptococcal disease
Itraconazole
Itraconazole is a broader-spectrum azole than fluconazole
that could probably have a bigger place in
antifungal pharmacotherapy today if it were not for
pharmacokinetic issues that have hampered its
greater use. It has activity against Aspergillus
and other mould species and was once commonly
used as a step-down therapy in aspergillosis, but
this use has declined since voriconazole became
available.

Spectrum

Good: Candida albicans, Candida tropicalis, Candida

parapsilosis, Candida lusitaniae, Cryptococcus
neoformans, Aspergillus species, many
dimorphic fungi

Moderate: Candida glabrata and Candida krusei

(can be susceptible dose-dependent, or resistant)

Poor: Zygomycetes, many other moulds

used for

Itraconazole remains a drug of choice for some dimorphic
fungal infections, like histoplasmosis. It
once had a larger role in the management and prophylaxis
of aspergillosis and other mould infections,
but it has been largely replaced by voriconazole.