ANTIFUNGAL AGENTS

General Introduction to Fungi:

Medical Mycology

1839 - Schnlein and Gruby

- studied the fungus - Trichophyton schoenleinii
same year Langenbeck - reported the yeastlike
microorganism responsible for thrush (C. albicans)
*Gruby- isolated the fungus responsible for favus on potato
slices, rubbed it on the head of a child, and produced the
disease

2 TYPES OF FUNGAL INFECTIONS:

a. Superficial Mycoses
b. Deep-seated Mycoses

A.) Superficial Mycoses

- most common
- caused by a relatively homogenous group of fungi = Dermatophytes
various forms of tinea or ringworm = infections of the hair or hair
follicles, the superficial infections of the intertriginous or flat areas of
hairless skin, and infections of the nails
* lesions are mild, superficial, and restricted
- Causative microbes: specialized saprophytes with the unusual
ability to digest keratin
- reservoir: soil
-frequently transmitted from one host to another (e.g., athletes foot)
-Candida- also produces a dermatophyte like disease.
B.) Systemic Mycoses
- deep-seated, systemic mycoses have a sporadic distribution
- Diseases caused by the systemic organisms: histoplasmosis,
sporotrichosis, blastomycosis, coccidioidomycosis, cryptococcosis,
and paracoccidioidomycosis.
Causative Agent: soil-inhabiting saprophytes with the ability to
adapt to the internal environment of their host
- share common route of infection
* Fungal spores are inhaled into the lung, and a mild, coldlike
condition may result symptom
Asymptomatic = Sensitization detect by skin test / other
immunological procedure
*immune system deals with these infections by walling
them off or by producing the giant cells that are common in type IV
hypersensitivities.
* X-ray / Autopsy reveal lesions
- Recovery = uncertain anamnestic immune response
Opportunistic Fungal Infections
- Patient drug therapy, underlying disease, medical manipulation =
deprived of normal defenses (microbial flora)
allows organisms (normally low inherent
virulence)
exploit the host
Infections = systemic candidiasis, aspergillosis, mucormycosis
* C. albicans = common opportunist
normal microbial flora = vagina
- use of contraceptives
* Fungal flora that inhibit the bowel may develop
superinfection w/ the use of antibiotics (sterilize the bowel
before surgery)

*Oral candidiasis common in poorly nourished persons,

patients on immunosuppressive drugs, persons w/ AIDS.
CUTANEOUS INFECTIONS (DERMATOPHYTOSES)
Dermatophytoses = most common types of human fungal
disease.
superficial infections keratinized epidermis &
epidermal appendages (hair and nails)
Candida spp- cornified tissue of hair, skin and nails.
physiological characteristics -> metabolic use of highly
insoluble scleroprotein keratin.
also gymnoascaceae, few
onygenacea, & certain tineae.
Humans: 1. TRICHOPHYTON
o T. rubrum [nails, beard, smooth skin] [psoriasislike lesions of smooth skin, infections of nails]
o T. tonsurans [scalp, beard, nails]
o T. violaceum [scalp, skin nails]
o T. mentagrophytes [commonest cause of
athletes foot]
o T. verrucosum [scalp, beard]
2. MICROSPORUM
o M. gypseum [scalp]
o M. fulvum [scalp, hairless skin]
o M. canis [scalp, hairless skin]
3. EPIDERMOPHYTON (eczema)
contain most common dermatophytes
Tinea (ringworm)
TABLE 6.4 Locations of the Common Types of Tinea
(Ringworm)
Type
Location
Tinea manuum
Hand
Tinea cruris
Groin
Tinea sycosis
Beard
Tinea capitis
Scalp
Tinea unguium
Nails
Pityrosporum orbiculare = additional type Tinea versicolor
Malassezia furfur - causes yellow to brown patches or continuous
scaling over the trunk and occasionally the legs, face, and neck
* affected areas may be identified by the inability to tan in
the sun.
( Table 6.5 next page )
- treatment is extremely difficult bec. Fungi, like mammalians are
eukaryotes ( cell membrane & biochem. Rxns are nearly identical)
drugs that kill fungus will have toxic effect on Human
cells at normal doses.
** Slight differences in cell membrane:
- lipid bilayers are unstable & unable to hold their shape & support
their functions + Sterols (stiffening agent)
Sterols= Humans cholesterol
Fungi ergosterol

TABLE 6.5 Clinical Types of Fungal Infection

Type
Disease State
Superficial infections
Tinea versicolor
Piedra
Cutaneous infections

Ringworm of scalp, hairless skin, nails

Candidosis of skin, mucous membranes, nails;
sometimes generalized

Subcutaneous infections

Chromomycosis
Mycotic mycetoma
Entomophthoromycosis

Systemic infections

Histoplasmosis
Blastomycosis
Paracoccidioidomycosis
Coccidioidomycosis
Cryptococcosis
Sporotrichosis
Aspergillosis
Mucormycosis
Histoplasmosis duboisii

SUBCUTANEOUS FUNGAL INFECTIONS

refers to a group of fungal diseases in w/c both skin &
subcutaneous tissues are involved, but no dissemination to the
internal organs occurs.
* Causative Agent: several unrelated genera
Characteristics: A.) primarily soil saprophytes of very low-grade
virulence and invasive ability
B.) in human & animal infections- they gain
access as a result of a trauma to the tissue
Major disease types:
- chromomycosis, sporotrichosis, mycetoma, lobomycosis,
and entomophthoromycosis
*** dimorphism- accompanies infection by agents. Organisms
undergo a morphogenesis from their saprophytic form into a tissue or
parasitic stage.
TISSUE REACTIONS OF FUNGAL DISEASES
Dermatophyte infection erythema is produced= result of the
irritation of the tissues by organisms.
- sometimes- severe inflammation followed by scar & keloid
formation (exaggerated inflamm. response)
Organisms that invade living tisuue (subcu. & systemic)
uniform acute pyogenic rxn that gives way to chronic dses.
EX: 1. Histoplasma capsulatum- Granuloma with caseation
and fibrocaseous pulmonary granuloma
2. Aspergillosis and Mucormycosis- thrombotic
arteritis (thrombosis characterized by a purulent coagulative necrosis
and invasion of blood vessels)
TOPICAL AGENTS FOR DERMATOPHYTOSES
- Dermatophytoses- tinea/ringworm
Ex: Keratolytic agents such as salicylic acid or other hydroxy cmpds.
1. FATTY ACIDS
-Sebum acidic, fatty substance
natural antifungal agent (part of innate immune system)
-high molecular weight fatty acid have the advantage lower volatility

Causative Organism
Pityrosporum orbiculare
Trichosporon cutaneum (white)
Piedraia hortae (black)
Dermatophytes, Microsporum, Trichophyton,
Epidermophyton
Candida albicans and related forms
Fonsecaea and related forms
Allescheria boydii, Madurella mycetoma, etc.
Basidiobolus haptosporus,
Conidiobolus coronatus
Histoplasma capsulatum
Blastomyces dermatiditis
Paracoccidioides brasiliensis
Coccidioides immitis
Cryptococcus neoformans
Sporothrix schenckii
Aspergillus fumigates
Mucor spp., Absidia spp., Rhizopus spp.
Histoplasma capsulatum var. duboisii

-salt of fatty acids are also fungicidal and provide non volatile form for
topical
a.) Propionic Acid
- antifungal agent non-irritating & nontoxic
- after application- present in perspiration (0.01%)
-salt forms- Sodium, Potassium, Calcium, Ammonium fungicidal
usually used bec. nonvolatile & odorless
b.) Zinc Propionate
- unstable in moisture = -zinc oxide & -propionic acid
- fungicide on adhesive tapes
c.) Sodium Caprylate
- prepared from caprylic acid (component of coconut & palm oils)
- topical tx dermatomycoses caused by C. albicans & Trichophyton,
Microsporum, and Epidermophyton spp.
- sodium salt- solution, powder, and ointment forms

d.) Zinc Caprylate

- topical fungicide
- highly unstable in moisture
e.) Undecylenic Acid
- 10-Undecenoic acid (Desenex, Cruex) from the destructive
distillation of castor oil
- one of the better fatty acids for use as a fungicide, although cure
rates are low
- used in
concentrations up to 10% in solutions, ointments, powders, and
emulsions for topical
- never be applied to mucous membranes because it is a severe
irritant
- traditionally used for athletes foot (tinea pedis)

f.) Triacetin
- Glyceryl triacetate (Enzactin, Fungacetin)
- activity of triacetin is a result of the acetic acid released by
hydrolysis of the compound by esterases present in the skin
- Acid release is a self-limiting process because the esterases are
inhibited below pH 4.

g.) Salicylic Acid and Resorcinol

- Salicylic acid is a strong aromatic acid (pKa 2.5) with both antiseptic
and keratolytic properties
- greater acidity of salicylic acid and its lower solubility in water
compared with p-hydroxybenzoic acid are the consequence of
intramolecular hydrogen bonding
- Salicylic acid is used externally in ointments and solutions for its
antifungal and keratolytic properties. poor antifungal agent.

- 3-Iodo-2-propynyl-2,4,5-trichlorophenyl ether (Halotex)

- an ethereal derivative of a phenol
- used: 1% cream for the treatment of superficial tinea infections.
- should be protected from light because the compound is
photosensitive
- 1%- soln and cream
- not the 1st topical agent that should be recommended
- high cure, high price
- lesion typically worsens before it improves
- Inflammation and painful irritation are common

b. Clioquinol
- 5-Chloro-7-iodo-8-quinolinol, 5-chloro8-hydroxy-7iodoquinoline, or iodochlorhydroxyquin (Vioform)
- spongy, light-sensitive, yellowish powder
- used as a substitute for iodoform in the belief that it released iodine
in the tissues
- used as a powder for many skin conditions, such as atopic
dermatitis, eczema, psoriasis, and impetigo
- 3% ointment or cream- vaginally as a treatment for Trichomonas
vaginalis vaginitis
- best use -topical treatment of fungal infections such
as athletes foot and jock itch
- combination with hydrocortisone (Vioform HC) is also available

- m-Hydroxyphenol (resorcinol) - antiseptic and

keratolytic activity

h.) Benzoic Acid

- possesses appreciable antifungal effects, but it cannot penetrate
the outer layer of the skin in infected areas
must be admixed with a keratolytic agent
- BA & SA
- BA & Resorcinol
* old preparation: Whitfields Ointment
Low cure: - 6% BA & SA in petrolatum base
2. PHENOLS AND THEIR DERIVATIVES
- possesses antifungal pptys
hexylresorcinols and parachlorometaxylenol tx tinea infxn
clioquinol and haloprogin- official in the USP
** 3rd agent- ciclopirox olamine- not a phenol but has properties like
those of phenols
- All of these agents appear to interfere with cell membrane integrity
and function in susceptible fungi.

a. Haloprogin

c. Ciclopirox Olamine
-6-Cyclohexyl-1-hydroxyl-4-methyl-2(1H)-pyridinone ethanolamine
salt (Loprox) = broad-spectrum antifungal
agent -topical use only
- active against dermatophytes & pathogenic yeasts (C. albicans) =
causative agents for superficial fungal infections.
- Agent of Choice : tx of cutaneous candidiasis, tinea corporis, tinea
cruris, tinea pedis, and tinea versicolor
- 2nd-line agent- tx of onychomycosis (ringworm of the nails)
- cream and a lotion, each containing 1% of the water-soluble
ethanolamine salt
?MOA: act on cell membranes of susceptible fungi at low
concentrations to block the transport of amino acids into the cells. At
higher concentrations, membrane integrity is lost, and cellular
constituents leak out.

NUCLEOSIDE ANTIFUNGALS
a. Flucytosine
-5-Fluorocytosine, 5-FC, 4-amino-5-fluoro-2(1H)-pyrimidinone, 2hydroxy-4-amino-5-fluoropyrimidine (Ancobon)
- orally active antifungal agent with a very narrow spectrum of activity

- indicated only tx serious systemic infections = caused by

susceptible strains of Candida and Cryptococcus spp.
MOA: book pg 196

ANTIFUNGAL ANTIBIOTICS
- 2 classes: a. Polyenes; b. Griseofulvin
A. POLYENES
- soil bacteria of the genus Streptomyces
** similar- contain a system of conjugated double bonds in
macrocyclic lactone rings.
**differ from the erythromycin-type structures (Macrolides)
-polyene antibiotics
2GROUPS: (size of the macrolide ring)
a. natamycin (pimaricin)- 26-memberedring polyenes
b. amphotericin B and nystatin- 38-membered macrocycles
COMMON IN POLYENES:
(a) a series of hydroxyl groups on the acid-derived portion of the
ring
(b) a glycosidically linked deoxyaminohexose called mycosamine

NUM. DOUBLE BONDS MACROCYCLIC RING

a. Natamycin- pentaene (smallest macrocycle)
b. Nystatin- hexaene
c. Amphotericin B- heptaene.
- No activity against bacteria, rickettsia,/viruses, but they are highly
potent, broad-spectrum antifungal agents.
- protozoa - Leishmania spp
- pathogenic yeasts, molds, and dermatophytes
- low conc. Inhibit = Candida spp., Coccidioides immitis,
Cryptococcus neoformans, H. capsulatum, Blastomyces dermatitidis,
Mucor mucedo, Aspergillus fumigatus, Cephalosporium spp., and
Fusarium spp.
- limit in tx of systemic = toxicities of the drugs, low water solubilities,
& poor chemical stabilities
*** Amphotericin B, the only polyene useful for the treatment of
serious systemic infections, must be solubilized with a detergent.
MOA: three-dimensional shape, a barrel-like nonpolar structure
capped by a polar group (the sugar), they penetrate the fungal
cell membrane, acting as false membrane components, and
bind closely with ergosterol, causing membrane disruption,
cessation of membrane enzyme activity, and loss of cellular
constituents, especially potassium ions.
* Amphotericin B is the loss of potassium ions.
a. Amphotericin B