Dr Rabia Arshad

 Enlist the classification of antifungal drugs

 Enlist the primary uses for different antifungal
drugs
 State the effects and side effects of these drugs
 Diseases by Fungi are called mycoses
 Often chronic in nature
 Causes cutaneous , subcutaneous and systemic
diseases
 Rigid cellwall made up of chitin
 Chitin is a polymer of N acetyl glucosamine
 Cell membrane consists of ergosterol
 4 th common cause of septicemia
 Immunocompromised patients
 Systemic antifungal drugs for systemic
infections – Amphotericin B, Flucytosine,
Azoles, Echinocandins
 Systemic antifungal drugs for mucocutaneous
infections – Griseofulvin, Terbinafine
 Topical antifungal therapy – Nystatin, Topical
Azoles, Topical Alkylamines
 Amphotericin B
 Polyene macrolide
 Poorly absorbed from GIT
 Oral amphotericin B, effective on fungi within
the lumen of the tract and canbe used for Rx of
systemic disease
 Amphotericin B binds to ergosterol and alters
the permeability of the cell by forming
amphotericin B-associated pores in the cell
membrane
 Slow IV infusion
 Insoluble in water may require addition of Na
deoxycholate
 Artificial lipids that forms liposomes
 ergosterol

ergosterol with
pore

+ a polyene
 when amphotericin B ergosterol binding is
impaired, either by decreasing memb conc of
ergosterol
 by modifying sterol target mol to reduce its
affinity for the drug
a) infusion-related toxicity – fever, chills, muscle
spasms, vomiting, headache, hypotension
b) Anaemia with zidovudine
c) Slower toxicity – renal damage, abnormalities
of liver function, anemia. with intrathecal
therapy, seizures and arachnoiditis
d) Na loading and liposomes
e) Antipyretic and steroides
 Broadest spectrum of action
 Active against yeasts, including Candida
albicans, Cryptococcus neoformans, orgs
causing endemic mycosis, including
Histoplasma capsulatum, Blastomyces
dermatitidis, Coccidioides immitis and
pathogenic molds, such as Aspergillus
fumigatus and mucor
 leishmaniasis
 DOC for nearly all life-threatening mycotic infs
 Used as induction regimen for serious fungal
infs then replaced by one of the newer azole
drugs for ch therapy or prevention of relapse.
Local adm for mycotic corneal ulcers and
keratitis, fungal arthritis, candiduria responds
to bladder irrigation with the drug
 Pyrimidine analog related to 5-FU
 Flucytosine is taken up by fungal cells via the
enzyme cytosine permease
 Converted intracellularly first to 5-FU then to
5-fluorodeoxyuridine monophosphate (F-
dUMP) and fluorouridine triphosphate (FUTP),
which inhibit DNA and RNA synthesis
respectively
5-flucytosine permease
5-flucytosine
(outside)
(inside)
Cytosine
deaminase

5dUMP 5-fluorouracil
(inhibits
thymidylate
synthase) Phosphoribosyl
transferase
RNA 5-FUMP
 Bone marrow toxicity with anemia, leukopenia,
thrombocytopenia
 derangement of liver enzs occurring less
frequently
 Toxic enterocolitis
 Sp of activity restricted to Cryptococcus
neoformans, some candida species, and
dermatiaceous molds that cause
chromoblastomycosis
 Combined with amphotericin B for
cryptococcal meningitis or with itraconazole
for chromoblastomycosis
 Imidazoles & Triazoles
 Imidazoles – ketoconazole, miconazole,
clotrimazole
 Triazoles – itraconazole, fluconazole,
voriconazole
 Antifungal activity results from reduction of
ergosterol synthesis by inhibition of fungal
cytochrome P450 enzymes
 Acetyl CoA

Squalene
Allylamine
Squalene
monooxygenase drugs
Squalene-2,3 oxide

Lanosterol

14-a-demethylase Azoles
(ergosterol)
 Sp quite broad ranging from many candida
species, Cryptococcus neoformans, endemic
mycoses (blastomycosis, coccidioidomycosis,
histoplasmosis), the dermatophytes and in case
of itraconazole and voriconazole, even
aspergillus infs
 Also useful in Rx of intrinsically amphotericin-
resistant orgs such as Pseudallescheria boydii
 Given orally
 Inhibits human gonadal and steroidal synthesis
 Inhibits cyp 450
 No coverage to aspergillosis
 Needs gastric acid for its dissolution
 No CSF entery
 Side effects are frank hepatitis , GIT symptoms,
and endocrine effects
 Drug interactions
 Available in oral and I/V formulations
 Interacts with hepatic microsomal enzymes,
though to a lesser degree than ketoconazole
 Reduced bioavailability of itraconazole when
taken with rifamycins
 Azole are choice for Rx of diseases due to
dimorphic fungi histoplasma, blastomyces,
sporothrix
 Has activity against aspergillus species
 Used extensively in Rx of dermatophytoses and
onychomycosis
 Good CSF penetration
 Unlike ketoconazole and itraconazole, oral
bioavailability is high
 Drug interactions also less common
 Available in oral & I/V formulations
 Azole of choice in Rx and secondary
prophylaxis of cryptococcal miningitis
 I/V fluconazole equivalent to amphotericin B
in Rx of candidemia in ICU pts with normal
white blood cell counts
 Activity against dimprphic fungi limited to
coccidioidal dis, and in particular for
meningitis.
 No activity against aspergillus or other
filamentous fungi
 Newest triazole
 Available in oral & I/V formulations
 Metabolism predominantly hepatic, propensity
for inhibition of P450 low
 Toxicities – rash, elevated hepatic enzymes,
transient visual disturbances (common, 30%
pts, include blurring and changes in color
vision or brightness
 Similar to itraconazole in its sp of action,
having excellent activity against candida
species (including fluconazole-resistant species
and the dimorphic fungi
 less toxic than amphotericin B, more effective
in Rx of invasive aspergillosis
 Newest class of antifungal drugs
 Caspofungin , micafungins,anidulafungin
 Available only in I/V form
 Acts at the level of the fungal cell wall by
inhibiting the synthesis of beta(1-3) glucan,
resulting in disruption of fungal cell wall and
cell death
 Well tolerated, minor GI side effects and
flushing, elevated liver enzymes when
combined with cyclosporine
 Used only for pts with invasive aspergillosis
who have failed to respond to amphotericin B
 Active also against candida species in
mucocutaneous candidiasis and candidal
bloodstream infs
 Insoluble fungistatic drug
 Only use is in systemic Rx of dermatophytosis
 MOA at cellular level unclear, deposited in
newly forming skin where it binds to keratin,
protecting skin from new infection
 Action to prevent inf of new skin structures,
must be adm for 2-6 weeks for skin and hair
infs to allow replacement of inf keratin by
resistant structures
 Nail infs require therapy for months to allow
regrowth of new protected nail and is often
followed by relapse
 A/Es – allergic syndrome like serum sickness,
hepatitis, intermittant porphyria , drug
interactions with warfarin and phenobarbital
as enhances p450
 Largely replaced by newer antifungal drugs
such as itraconazole and terbinafine
 Not with alcohol
 Oral formulation
 Used in Rx of dermatophytoses, esp
onychomycosis
 Like griseofulvin, keratophilic but it is
fungicidal
 Like azole drugs, interferes with ergosterol
biosynthesis, but rather than interacting with
P450 system, it inhibits fungal enz squalene
epoxidase leading to acc of toxic sterol
squalene
 Achieves a cure rate of up to 90% for
onychomycosis and is more effective than
griseofulvin or itraconazole
 A/Es – GI upsets, headache, no affect on P450
system, no significant drug interactions
 Polyene macrolide like amphotericin B
 Only used topically, available in creams,
ointments, suppositories, other forms for
applicaation to skin and MMs
 Active against most candida species, most
commonly used for suppression of local
candidal infs
 Common indications are oropharyngeal thrush
and vaginal candidiasis
 2 azoles used topically – clotrimazole and
miconazole
 Used for vulvovaginal candidiasis
 Oral clotrimazole is available for Rx of oral
thrush
 In cream form both agents used for
dermatophytic infs including tinea corporis,
tinea pedis, tinea cruris
 Topical shampoo forms of ketoconazole
available useful in Rx of seborrheic dermatitis
and pityriasis versicolor
Pathogen Primary Secondary

Aspergillus Voriconazole Itraconazole,

fumigatus Caspofungin
Posaconazole
Amphotericin B
Blastomyces Itraconazole or Fluconazole
dermatidis Amphotericin B
Candida albicans Fluconazole Voriconazole,
Amphotericin B Itraconazole,
Caspofungin Ketoconazole
Posaconazole (topical – many)
Anidulafungin
Coccidioides Itraconazole,
immitis Fluconazole or
Amphotericin B
Pathogen Primary Secondary

Cryptococcus Amphotericin B ± Itraconazole or

neoformans Flucytosine Amphotericin B
followed by
Fluconazole
Histoplasma Itraconazole or Fluconazole
capsulatum Amphotericin B
Mucomycosis Amphotericin B Posaconazole

Sporothrix Amphotericin B SSKI*

schenckii Itraconazole
* Saturated solution of potassium iodide Updated from Medical
Letter, 2005
 Importance of these agents in tuberculosis
patients
 Previous assignment on penicillins