Fungi and antifungal therapy, ppt. Basics for medical microbiology

2. Fungi

3. 
 Fungi are eukaryotes, but are quite distinct from
plants and animals.
 They are multinucleate or multicellular organisms
with a thick carbohydrate cell wall containing chitin,
glucans, mannans and glycoproteins.
Fungi?
The FUNGI Kingdom

4. 

5. 

6. 

7. 
Introduction
 Fungi have emerged in the past two
decades as major causes of human
disease, especially among those
individuals who are
immunocompromised or hospitalized
with serious underlying diseases.
 The overall incidence of specific
invasive mycoses continues to increase
with time, and the list of opportunistic
fungal pathogens likewise increases
each year.
There are no
nonpathogenic
fungi!

8. 
How does fungi differentiate
from bacteria?
Bacteria
 Prokaryotic organisms, meaning
they do not possess nucleus.
 Unicellular microorganisms
which can only be seen under a
microscope.
 The key component of the
bacterial cell wall is called
peptidoglycan. The bacterial cell
also has a cell membrane
containing cytoplasm.
 Coccus bacteria are typically
rounded, bacilli are rod-shaped
and spirillum is spiral-shaped.
But there are few bacteria that do
not have cell wall and have no
definite shape and they are
referred as mycoplasma.
Fungi
 Eukaryotic organisms in which
they have well-defined nucleus.
 Fungi are more complex
microorganisms except for yeast.
Most fungi are composed of
networks of long hollow tubes
called hyphae.
 Each hypha is bordered by a rigid
wall usually made of chitin.
 As the mycelium grows, it
produces huge fruiting bodies
and other structures which
contain reproductive spores.
 Fungi appear to have various
shapes and forms from
mushrooms and shelf fungus to
microscopic yeast and mold.

9. 
How does fungi
differentiate
from bacteria?
Bacteria
 Bacteria multiply by way
of binary fission; it is a
process in which each
parent bacterium divides
into two daughter cells of
same sizes.
 Bacteria can either be
heterotrophic or
autotrophic. Autotrophic
bacteria make their own
food from light or
chemical energy.
Fungi
 Fungi are capable of
reproducing both sexually
and asexually. They develop
by branching and
fragmentation, while yeasts
replicate through budding.
Sexual reproduction
happens when specialized
cells, gametes, unite to form
a unique spore.
 Concerning their nutrition,
fungi are known to be
saprophytes, parasites and
symbionts.

10. 
SUMMARY
1. Prokaryotes
2. Single
3. Bacteria can be
autotrophs or
heterotrophs
4. Have 3 distinct shapes
5. Reproduce sexually via
binary fission
1. Eukaryotes
2. Most fungi are
multicellular except for
yeast
3. Heterotrophs
4. Have various shapes
5. Capable of
reproducing both
sexually or asexually

11. 
Growth Forms of Fungi
Yeasts
 Cell that reproduces by
budding or by fission,
where a progenitor or
“mother” cell pinches
off a portion of itself to
produce a progeny or
“daughter” cell.
Molds
 Molds are multicellular
organisms consisting of
threadlike tubular
structures, called hyphae,
that elongate at their tips
by a process known
as apical
extension. Hyphae are
either coenocytic. The
hyphae form together to
produce a mat like
structure called
a mycelium.

12. 
Fungal infection are called Mycoses.
Classified:
 Superficial
 Cutaneous
 Subcutaneous
 Systemic
 Opportunistic
General Aspects of Fungal Disease

13. 
 The superficial mycoses are those infections that are
limited to the very superficial surfaces of the skin
and hair. They are nondestructive and of cosmetic
importance only.
 The clinical infection termed pityriasis versicolor is
characterized by discoloration or depigmentation
and scaling of the skin. Tinea nigra refers to brown
or black pigmented macular patches localized
primarily to the palms. (Malassezia furfur, Hortae
werneckii, Piedraia hortae, and Trichosporon).
Superficial Mycoses

14. 
Superficial Mycoses
Malassezia furfur

15. 
 Cutaneous mycoses are infections of the keratinized
layer of skin, hair, and nails. These infections may
elicit a host response and become symptomatic.
Signs and symptoms include itching, scaling, broken
hairs, ringlike patches of the skin, and thickened,
discolored nails.
 The Dermatophytes are fungi classified in the genera
Trichophyton, Epidermophyton, and Microsporum .
Cutaneous Mycoses

16. 
Cutaneous
Mycoses

17. 
Subcutaneous mycoses involve the deeper layers of the
skin, including the cornea, muscle, and connective
tissue and are caused by a broad spectrum of
taxonomically diverse fungi. The fungi gain access to
the deeper tissues usually by traumatic inoculation and
remain localized, causing abscess formation,
nonhealing ulcers, and draining sinus tracts.
(Acremonium spp. Fusarium spp., Alternaria spp.,
Cladosporium spp., Exophiala spp).
Subcutaneous Mycoses

18. 
Subcutaneous Mycoses

19. 
 Systemic mycoses - classic dimorphic fungal pathogens
and can cause infection in healthy individuals.
 All of these agents produce a primary infection in the
lung, with subsequent dissemination to other organs and
tissues.
(H. capsulatum, B. dermatitidis, Coccidioides immitis,
Coccidioides posadasii, Paracoccidioides brasiliensis, and
Penicillium marneffe)
Systemic Mycoses

20. 
Systemic
Mycoses

21. 
 The opportunistic mycoses are infections attributable to
fungi that are normally found as human commensals or
in the environment.
 These organisms exhibit inherently low or limited
virulence and cause infection in individuals who are
debilitated, immunosuppressed, or who carry implanted
prosthetic devices or vascular catheters. Virtually any
fungus can serve as an opportunistic pathogen, and the
list of those identified as such becomes longer each year.
 (Candida spp. and C. neoformans , the mold Aspergillus
spp. ).
Opportunistic Mycoses

22. 
Opportunistic Mycoses

23. 
Fungal allergies Fungal toxicoses

24. 
 How do fungi differ from bacteria (size, nucleus,
cytosol, plasma membrane, cell wall, physiology,
generation time)?
 How does the plasma membrane of fungi differ
from that of other eukaryotic (e.g., mammalian)
cells?
 What is the difference between a yeast and a mold?

25. 
 Candida are most important fungi to infect humans.
Candidiasis is the most common systemic mycoses.
 Candida albicans has historically been the most
frequent species to infect human.
 Non-albicans Candida species (C. glabrata), have
become more common isolates in hospitalized
patients.
Why?
Candida

26.  Candida is normal
inhabitant of the mouth,
skin, gastrointestinal tract
and vagina.

27. 
 It is now well established that Candida spp. colonize
the gastrointestinal mucosa and reach the
bloodstream through gastrointestinal translocation
or via contaminated vascular catheters, interact with
host defenses, and exit the intravascular
compartment to invade deep tissues of target organs,
such as the liver, spleen, kidneys, heart, and brain.
 The ability of Candida spp. to adhere to a variety of
tissues and inanimate surfaces is considered
important in the early stages of infection. The
adherence capability of the various species of
Candida is directly related to their virulence ranking

28. 
 The ability of Candida spp. to secrete various
enzymes may also influence the pathogenicity of the
organism. Several species of Candida secrete aspartyl
proteinases that hydrolyze host proteins involved in
defenses against infection, thus allowing the yeasts
to breach connective tissue barriers. Likewise,
phospholipases are produced by most species of
Candida causing infection in humans. These
enzymes damage host cells and are considered
important in tissue invasion.

29. 
 The ability of Candida spp. to rapidly switch from one
morphotype to another
 Phenotypic switching contributes to the virulence of
Candida spp. by allowing the organism to rapidly adapt
to changes in its microenvironment and thereby facilitate
its ability to survive, invade tissues, and escape from host
defenses.
Phenotypic switching?

30. 
Thrush
Diaper rash
Esophagitis
Skin lesion
Candidiasis

31. 
 Occurs when Candida enters the bloodstream and
the phagocytic host defenses are inadequate to
control its growth and dissemination.
 Heart candidiasis
 Meningitis
Systemic Candidiasis

32. 
 Depends on localization and severity
 Mucocutaneous candidiasis are usually treated with
topical nystatin or azoles.
 In cases of systemic infections oral of intravenous
antifungal drags are used.
Treanment

33. 
Cryptococcus neoformans
 C. neoformans is an
encapsulated yeast that
causes human infection
throughout the world.
 Although this organism
can infect apparently
normal hosts, it causes
disease much more
frequently and with
greater severity in
immunocompromised
hosts.

34. 
 There are three main lines of defense against
infection by C. neoformans : alveolar macrophages,
inflammatory phagocytic cells, and T-cell and B-
cell responses.
 Development of cryptococcosis largely depends on
the competence of the host's cellular defenses and
the number and virulence of the inhaled yeast cells.

35. 
 The first line of defense is the alveolar macrophages.
These cells are capable of ingesting the yeast cells but
are limited in their ability to kill them.
 Macrophages that contain ingested yeast cells
produce various cytokines for the recruitment of
neutrophils, monocytes, NK cells, and cells from the
bloodstream into the lung. The recruited cells are
effective in killing C. neoformans by intracellular
and extracellular mechanisms.
Defense

36. 
 An effective host response to C. neoformans is a
complex interaction of cellular and humoral immune
factors.
 When these factors are impaired, the infection
disseminates, usually by migration of macrophages
containing viable yeast cells, from the lung to the
lymphatics and the bloodstream to the brain.
 The capsule of C. neoformans protects the cell from
phagocytosis and from cytokines induced by the
phagocytic process; it also suppresses both cellular
and humoral immunity.

37. 

38. 
 Melanin is produced by the
fungus by virtue of a membrane-
bound phenoloxidase enzyme
and is deposited within the cell
wall. It is thought that melanin
enhances the integrity of the cell
wall and increases the net
negative charge of the cell, further
protecting it from phagocytosis.
 Melanization is thought to be
responsible for the neurotropism
of C. neoformans and may protect
the cell from oxidative stress,
temperature extremes, iron
reduction, and microbicidal
peptides.

39. 

40. 

41. 
Treatment
 Amphotericin
followed by
fluconazole

42. 
 Infect only the superficial keratin layer of the skin,
using keratin as a nutritional source.
 Most are unable to grow at 37C or in the presence of
serum
Dermatophytes

43. 
 The term dermatophytosis refers to a complex of
diseases caused by any of several species of
taxonomically related filamentous fungi in the
genera
 Microsporum
 Trichophyton
 Epidermophyton

44. 
Morphology
Epidermophyton
floccosum Trichophyton rubrum

45. 
 In skin biopsies, all of the
dermatophytes are
morphologically similar
and appear as hyaline
septate hyphae, chains of
arthroconidia, or
dissociated chains of
arthroconidia that invade
the stratum corneum, hair
follicles, and hairs.
 When the hair is infected,
the pattern of fungal
invasion can be either
ectothrix, endothrix, or
favic depending on the
dermatophytic species.

46. 
(1) geophilic
(2) zoophilic
(3) anthropophilic
 This classification is quite useful prognostically and
emphasizes the importance of identifying the etiologic
agent of dermatophytoses.
 Species of dermatophytes that are considered
anthropophilic tend to cause chronic, relatively
noninflammatory infections that are difficult to cure.
 The zoophilic and geophilic dermatophytes tend to elicit a
profound host reaction, causing lesions that are highly
inflammatory and respond well to therapy.
Classification (morphological)

47. 
 Clinically, the tineas are classified according to the
anatomic site or structure affected:
 (1) tinea capitis of the scalp, eyebrows, and eyelashes;
 (2) tinea barbae of the beard;
 (3) tinea corporis of the smooth or glabrous skin;
 (4) tinea cruris of the groin;
 (5) tinea pedis of the foot;
 (6) tinea unguium of the nails (also known as
onychomycosis)
Classification (clinical)

48. 
Ringworm
Athlete`s foot
tinea pedis
Clinical symptoms

49.  Darrell, a 24-year-old medical student, just loves his new
bulldog puppy, Delbert. He recently purchased Delbert
from a local “backyard” breeder. Darrell has taken to
giving Delbert frequent “smooches” on his muzzle, which
Delbert loves, because he knows a treat is soon to follow.
After about 3 months of proud puppy ownership and
“smooching,” Darrell noticed that his mustache began
itching, and his upper lip was beginning to swell. Over a
1-week period, his upper lip became swollen and
inflamed, and small pustular areas became apparent
among the sparse hairs of his moustache. Similar changes
were also becoming apparent on Delbert's muzzle. This
concerned Darrell, so he promptly took Delbert to the
veterinarian. The veterinarian took one look at the pair,
wrote a prescription for Delbert, and told Darrell that he
should make a visit to the dermatologist.

50. 
 What was the likely cause of Darrell/Delbert's
affliction? Be specific
 How would you go about making a diagnosis?
 How would you go about treating this infection?
 Who gave what to whom?
Questions

51. 
 1. Both subjects appear to be suffering from a dermatophytosis. Given the
clinical and epidemiologic evidence, one might expect infection with a
zoophilic pathogen, such as M. canis or a Trichophyton species.
 2. The first step in making the diagnosis would be to examine both skin
scrapings and hair using KOH and calcofluor white. A specific etiologic
diagnosis requires culture of hair and skin scrapings, followed by
assessment of the gross and microscopic appearance of the cultured
fungus. In the case of dermatophytes, further identification may be
accomplished by assessing the nutritional requirements of the fungus
using special dermatophyte test media.
 3. This infection, tinea barbae, will require therapy with an agent such as
terbinafine or itraconazole. Further oral-to-muzzle contact should be
discouraged.
 4. The usual transmission of a zoophilic dermatophyte is from animal to
human.
Answers

52. 
 The laboratory diagnosis of dermatophytoses relies on
the demonstration of fungal hyphae by direct
microscopy of skin, hair, or nail samples and the
isolation of organisms in culture. Specimens are
mounted in a drop of 10% to 20% KOH on a glass
slide and examined microscopically. Filamentous,
hyaline hyphal elements characteristic of
dermatophytes may be seen in skin scrapings, nail
scrapings, and hairs.
Laboratory Diagnosis

53. 
Laboratory Diagnosis
 Cultures are always useful
and can be obtained by
scraping the affected areas
and placing the skin, hair,
or nail clippings onto
standard mycologic media
such as Sabouraud agar,
with and without
antibiotics, or
dermatophyte test medium.
Colonies develop within 7
to 28 days.

54. 
Wood`s light

55. 
Treatment

56. 
 Previously well known as Pneumocystis carinii
Pneumocystis jiroveci

57. 
Pneumocystis jiroveci
 The reservoir for P. jirovecii in nature is unknown.
 Airborne transmission has been documented
experimentally among rodents, the rodent strains are
genetically distinct from those of humans, making it
unlikely that rodents serve as a zoonotic reservoir for
human disease.
 Well known that P. carinii produces a form of pneumonia
in individuals with T-cell impairment (patients with
AIDS, solid organ transplant recipients)

58. 
Diagnosis
 The diagnosis of P.
jirovecii infection is
almost entirely based
upon microscopic
examination of clinical
material, including
bronchoalveolar lavage
(BAL) fluid, bronchial
brushing, induced
sputum, and
transbronchial or open-
lung biopsy specimens.

59. 
 Can be prevented by giving
trimethoprim/sulfomethoxazole (Bactrim) to patient
at risk.
P. jiuroveci prevention

60. 
 Aspergillus is the most important pathogenic mold.
 Aspergillus is ubiquitous in nature is found in large
numbers in rotting plants
Aspergillus

61. 
 Exposure to Aspergillus in the environment may
cause allergic reactions in hypersensitized hosts or
destructive, invasive, pulmonary, and disseminated
disease in highly immunosuppressed individuals.
Aspergillus

62. 
 Approximately 19 species of Aspergillus have been
documented as agents of human disease, the
majority of infections are caused by A. fumigatus , A.
flavus , A. niger , and A. terreus .
Aspergillus

63. 
 Aspergillus spp. grow in culture as hyaline molds.
On a gross level, the colonies of Aspergillus may be
black, brown, green, yellow, white, or other colors,
depending upon the species and the growth
conditions.
Morphology

64. 
 Identification of individual species of Aspergillus
depends in part on the difference in their conidial
heads, including the arrangement and morphology
of the conidia

65. 
Epidemiology
 Within the hospital
environment, Aspergillus
spp. may be found in air,
showerheads, hospital water
storage tanks, and potted
plants.
 The type of host reaction, the
associated pathologic
findings, and the ultimate
outcome of infection depend
more on host factors than on
the virulence or pathogenesis
of the individual Aspergillus
spp.
 The respiratory tract is the
most frequent, and most
important, portal of entry.

66. 
 Respiratory diseases
Bronchopulmonary aspergillosis – asthma, recurrent
chest infiltrates
Tracheobronchitis
Sinusitis
Aspergilloma (“fungus ball”)
Disseminated aspergillosis
Allergy
Diseases

67. 

68. 
 Both the paranasal sinuses and the lower airways
may become colonized with Aspergillus spp.,
resulting in obstructive bronchial aspergillosis and
true aspergilloma (“fungus ball”).

69. 
 Inhalation of spores
 Evasion of pulmonary macrophages
 Local infection in the lung
 Entry into blood vessels
 Dissemination to other sites via blood (brain)
Pathogenesis

70. 

71. 
 Most etiologic agents of aspergillosis grow readily
on routine mycologic media lacking cycloheximide.
 Invasive aspergillosis caused by A. fumigatus and
most other species is rarely documented by positive
blood cultures.
 The rapid diagnosis of invasive aspergillosis has
been advanced by the development of
immunoassays for the Aspergillus galactomannan
antigen in serum.
Laboratory Diagnosis

72. 
 Prevention of aspergillosis in high-risk patients is
paramount. Neutropenic and other high-risk patients
are generally housed in facilities where the air is
filtered to minimize exposure to Aspergillus conidia.
Prevention

73. 
 Specific antifungal therapy of aspergillosis usually
involves the administration of voriconazole or one of
the lipid formulations of amphotericin B.
 Concomitant efforts to decrease immunosuppression
and/or reconstitute host immune defenses are
important components of the treatment of
aspergillosis. Likewise, surgical resection of involved
areas is recommended if possible.
Treatment

74. 
 A number of fungal infection are found in the soil of
specific regions of the country.
 They are typically acquired via respiratory tract and
cause pneumonia or disseminated infection
(especially in immunocompromised patient).
Geographically restricted,
dimorphic fungi

75.  Jane, a 25-year-old unemployed woman from southern
Missouri, was admitted with one-month history of high
persistent fever, weight loss, and fatigue. Her past history,
especially concerning HIV infection, was unknown. She had
been self-medicated with antipyretic drugs but she did not
recover. On physical examination the patient appeared weak,
with fatigue and conjunctival pallor. Her temperature was
38,5°C, with a pulse 30 beats per minute. Her blood pressure
was 80/50 mmHg and she had severe weight loss of more
than 10 kg. No lymphadenopathy was noted. Lung
examination revealed bilateral rales and wheezing; heart
exam demonstrated distant heart sounds. The patient’s
abdomen was distended and tender with a palpable liver tip.
She had difficulties with attention and on neurological
examination she could not walk because of fatigue but she
showed no focal neurologic deficits.

76. Electrocardiogram (ECG) was normal. Chest X-Ray
shows multiple shadows in lungs. Laboratory test results
revealed pancytopenia, hemoglobin of 7.3 g/dL, and
ASAT: 352 IU/L, ALAT: 59 IU/L. HIV1 serology was
positive and CD4 was 7/mm3. Urine culture was sterile.
The peripheral blood film showed the presence of yeast-
like organisms with clear halo and eccentric chromatin, 2
to 4 μm in diameter, inside and next to monocytes. The
patient died just after all the samples were collected.

77. 
Chest X-ray
Severe acute
pulmonary lesion

78. 
 1. What fungal pathogens was Jane exposed to?
 2.What feature is common to all of the endemic
mycoses?
 3.Describe the life cycles of the endemic pathogens.
 4.What do you think is the cause of Jane's
pneumonia, impaired neurological state and
fatigue? How would you make the diagnosis?
 5.What do you think about her immune status?
 6.How would you treat her?

79. 

80. 
 Histoplasma capsulatum
 Coccidioides immitis (dessimination is rare, usually
disease occur like influenza)
 Blastocystes dermatitidis (much less common than
histoplasmosis, may occur to any organ, but
preferentially bones and skin)
Geographically restricted,
dimorphic fungi

81. 
Valley fever (Coccidioides immitis )

82. 
 Coccidioidomycosis is
known as a fungal
parasitic infection,
initially recognized as a
human disease in
Argentina in 1892.

83. 
 Extrapulmonary sites of infection include skin, soft
tissues, bones, joints, and meninges. Persons in
certain ethnic groups (e.g., Filipino, African
American, Native American, and Hispanic) run the
highest risk of dissemination, with meningeal
involvement a common sequela.
 In addition to ethnicity, males (9:1), women in the
third trimester of pregnancy, individuals with a
cellular immunodeficiency (including AIDS, organ
transplantation recipients, and those treated with
tumor necrosis factor antagonists), and persons at
the extremes of age are at high risk for disseminated
disease.
 The mortality in disseminated disease exceeds 90%
without treatment, and chronic infection is common.

84. 
 Immunocompromised patients or others with diffuse
pneumonia should be treated with amphotericin B
followed by an azole (either fluconazole, itraconazole,
posaconazole, or voriconazole) as maintenance therapy.
The total length of therapy should be at least 1 year.
Immunocompromised patients should be maintained on
an oral azole as secondary prophylaxis.
 Primary coccidioidomycosis in the third trimester of
pregnancy or during the immediate postpartum period
requires treatment with amphotericin B.
 Chronic cavitary pneumonia should be treated with an
oral azole for at least 1 year.
Treatment

85. 
 Studies in humans and animals indicate that
infection is acquired after the inhalation of
aerosolized conidia produced by the fungus growing
in soil and leaf litter
Blastocystes dermatitidis

86. 
 Amphotericin B, preferably a lipid formulation, is
the agent of choice for the treatment of life-
threatening or meningeal disease. Mild or moderate
disease may be treated with itraconazole.
Fluconazole, posaconazole, or voriconazole may be
alternatives for those patients unable to tolerate
itraconazole.
Treatment

87. Antifungal drugs

88. 
How does antifungals
work?

89. 
 Antifungal therapy has undergone a tremendous
transformation in recent years.
 Once the sole domain of the agents amphotericin B
and 5-fluorocytosine (flucytosine, 5-FC), which were
toxic and difficult to use, the treatment of mycotic
disease has now been advanced by the availability of
several new, systemically active agents and new
formulations of other older agents that provide
comparable if not superior efficacy with significantly
less toxicity.

90. 
Systemic antifungals
1.Polyens
 Act by binding in the fungal
cytoplasmic membrane, thereby
causing membrane permeability to
increase – it is like penicillin to
fungi.
 Amphotericin B and its lipid
formulations are polyene macrolide
antifungals used in the treatment of
serious life-threatening mycoses.
 Amphotericin B contains seven
conjugated double bonds and may
be inactivated by heat, light, and
extremes of pH. It is poorly soluble
in water and is not absorbed by the
oral or intramuscular route of
administration.

91. 
 Amphotericin B (and its lipid formulations) exerts its
antifungal action by at least two different
mechanisms.
1. The primary mechanism involves the binding of
amphotericin B to ergosterol, the principal
membrane sterol of fungi.
2. An additional mechanism of action of amphotericin
B involves direct membrane damage resulting from
the generation of a cascade of oxidative reactions
triggered by the oxidation of amphotericin B itself.
Mechanism of Action

92. 

93. 

94. 
 Amphotericin B is widely distributed in various
tissues and organs, including liver, spleen, kidney,
bone marrow, and lung.
 The primary clinical indications for amphotericin B
include invasive candidiasis, cryptococcosis,
aspergillosis, mucormycosis, blastomycosis,
coccidioidomycosis, histoplasmosis,
paracoccidioidomycosis, penicilliosis marneffei, and
sporotrichosis.
Indications

95. 
 The main adverse effects of amphotericin B include
nephrotoxicity, as well as infusion-related side
effects, such as fever, chills, myalgias, hypotension,
and bronchospasm.
 The major advantage of the lipid formulations of
amphotericin B are the significantly reduced side
effects, especially nephrotoxicity. The lipid
formulations are not superior to conventional
amphotericin B in terms of efficacy and are much
more expensive.
Side effects

96. 
Systemic antifungals
2.Azoles
 The azole class of
antifungals may be
divided in terms of
structure into the
imidazoles (two nitrogens
in the azole ring) and the
triazoles (three nitrogens
in the azole ring).

97. 
 Among the imidazoles, only ketoconazole has
systemic activity.
 The triazoles all have systemic activity and include
fluconazole, itraconazole, voriconazole, and
posaconazole

98. 
Mechanism of Action
 Both imidazoles and
triazoles exerts its effect by
altering the fungal cell
membrane.
 They inhibits ergosterol
synthesis by interacting with
14-alpha demethylase, a
cytochrome P-450 enzyme
that is necessary for
converting lanosterol to
ergosterol, an essential
component of the membrane.

99. 
Ketoconazole
 Ketoconazole is an orally
absorbed, lipophilic
member of the imidazole
class of antifungal agents.
Its spectrum of activity
includes the endemic
dimorphic pathogens,
Candida spp., C.
neoformans , and
Malassezia spp., although
it is generally less active
than the triazole
antifungal agents

100. 
Fluconazole
 Fluconazole is a first-
generation triazole with
excellent oral
bioavailability and low
toxicity. Fluconazole is
used extensively and is
active against most
species of Candida , C.
neoformans ,
dermatophytes,
Trichosporon spp., H.
capsulatum , C. immitis ,
and P. brasiliensis

101. 
Itraconazole
 Itraconazole is a lipophilic
triazole that may be
administered orally in
capsule or in solution.
Itraconazole has a broad
spectrum of antifungal
activity, including against
Candida spp., C.
neoformans , Aspergillus
spp., dermatophytes,
dematiaceous molds and
the endemic dimorphic
pathogens.

102. 
Voriconazole
 Voriconazole is a new
broad-spectrum
triazole with activity
against Candida spp.,
C. neoformans ,
Trichosporon spp.,
Aspergillus spp.,
Fusarium spp.,
dematiaceous fungi,
and the endemic
dimorphic pathogens

103. 
Posaconazole
 Posaconazole is a triazole
derivative with a
chemical structure similar
to itraconazole.
Posaconazole
demonstrates potent
activity against Candida ,
Cryptococcus , dimorphic
fungi, and filamentous
fungi, including
Aspergillus as well as the
Mucormycetes.

104. 
Imidazoles
 Useful as topical agents
for cutaneous fungi
infections.
 Imidazoles alter the cell
membrane permeability
of susceptible yeasts
and fungi by blocking
the synthesis of
ergosterol

105. 
Systemic antifungals
3. Echinocandins
The echinocandins are a
novel, highly selective,
class of semisynthetic
lipopeptides that inhibit
the synthesis of 1,3-β-
glucans, important
constituents of the
fungal cell wall.

106. 
 The spectrum of activity of the echinocandins is
limited to those fungi in which 1,3-β-glucans
constitute the dominant cell wall glucan component.
 They are active against Candida and Aspergillus
spp. and have variable activity against the
dematiaceous fungi and the endemic dimorphic
pathogens.

107. 
Echinocandins
 Available as
intravenous
formulations only:
 Caspofungine
 Micafungine
 Antidulafungine

108. 
4.Antimetabolites
Flucytosine is the only available antifungal
agent that functions as an antimetabolite.
It is a fluorinated pyrimidine analogue that
exerts antifungal activity by interfering with
the synthesis of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), and proteins in the
fungal cell.
Systemic antifungals

109. 
 Flucytosine is water soluble and has excellent
bioavailability when administered orally.
 Monitoring of serum concentrations of flucytosine is
important in avoiding toxicity.
 Flucytosine is not used as monotherapy, because of the
propensity for secondary resistance.
 Combinations of flucytosine with either amphotericin B
or fluconazole have been shown to be efficacious in
treating both cryptococcosis and candidiasis.

110. 
Systemic antifungals
5. Allylamines
The allylamine class of
antifungal agents includes
terbinafine, which has
systemic activity, and
naftifine, which is a
topical agent.

111. 
Mechanism of Action
 These agents inhibit the
enzyme squalene
epoxidase, which
results in a decrease in
ergosterol and an
increase in squalene
within the fungal cell
membrane.

112. 
Systemic antifungals
 6. Griseofulvine
 Griseofulvin is an oral agent
used in the treatment of
infections caused by the
dermatophytes.
 It is thought to inhibit fungal
growth by interaction with
microtubules within the
fungal cell, resulting in
inhibition of mitosis.

113. 
Mechanism of Action
 Griseofulvine inhibit
fungal growth by
interaction with
microtubules within the
fungal cell, resulting in
inhibition of mitosis.

114. 
 Poorly absorbed, accumulates in the keratinized
tissues
 Griseofulvin is considered a second-line agent in the
treatment of dermatophytoses.

115. 
Topical antifungals
 A wide variety of topical
antifungal preparations is
available for the treatment of
superficial cutaneous and
mucosal fungal infections.
 Topical preparations are
available for most classes of
antifungal agents, including
polyenes (amphotericin B,
nystatin, pimaricin),
allylamines (naftifine and
terbinafine), and numerous
imidazoles and miscellaneous
agents.

116.  Whether one uses topical or systemic therapy for
treatment of cutaneous or mucosal fungal infections
usually depends on the status of the host and the
type and extent of infection.
 Whereas most cutaneous dermatophytic infections
and oral or vaginal candidiasis will respond to
topical therapy, the refractory nature of infections,
such as onychomycosis or tinea capitis (“ringworm”
of the scalp), usually calls for long-term systemic
therapy.

117. 
Nystatin
 Nystatin is a topical polyene
antifungal antibiotic, similar
in structure to amphotericin
B.
 Regular nystatin is not used
to treat systemic fungal
infections because of its
negligible absorption from
the gastrointestinal tract.
 Nystatin is most useful in the
treatment of oropharyngeal,
cutaneous, mucocutaneous,
and vulvovaginal
candidiasis.

118. 
Mechanism of Action
 Nystatin is a polyene
antifungal that binds to
sterols in the cell
membranes of both fungal
and human cells.
 As a result of this binding,
membrane integrity of
both fungal cells and
human cells is impaired,
causing the loss of
intracellular potassium
and other cellular contents.

119. 
Clotrimazole
 Clotrimazole is an
imidazole antifungal agent.
It is used for the treatment
of infections caused by
various species of
pathogenic dermatophytes,
yeasts, and Malassezia
furfur.
 These include ringworm
(dermatophytosis), vaginal
and oral candidiasis, and
tinea infections.

120. 
Mechanism of Action
 Like other azole antifungals,
clotrimazole exerts its effect by
altering the fungal cell
membrane. Clotrimazole
inhibits ergosterol synthesis by
interacting with 14-alpha
demethylase, a cytochrome P-
450 enzyme that is necessary
for converting lanosterol to
ergosterol, an essential
component of the membrane.

121. 
 Clotrimazole is not administered systemically; it is
administered via oral/transmucosal lozenges
(troches), topically, or intravaginally.
 Small amounts absorbed are metabolized in the liver
and excreted in the bile.

122. Thank you!