the Fascinating World of Fungi: A Complete Introduction to Primary Mycology
STRUCTURE & GROWTH
As a result of fungi (yeasts and molds) are eukaryotic organisms,
whereas micro organism are prokaryotic, they differ in a number of funda-
psychological respects (Desk 47–1). Two fungal cell buildings are
necessary medically:
(1) The fungal cell wall consists primarily of chitin (not pep-
tidoglycan as in micro organism); thus, fungi are insensitive to sure
antibiotics, corresponding to penicillins and cephalosporins, that inhibit
peptidoglycan synthesis. Chitin is a polysaccharide composed
of lengthy chains of N-acetylglucosamine. The fungal cell wall
incorporates different polysaccharides as properly, a very powerful of
which is β-glucan, a protracted polymer of d-glucose. The medical
significance of β-glucan is that it’s the web site of motion of the anti-
fungal drug caspofungin.
(2) The fungal cell membrane incorporates ergosterol, in con-
trast to the human cell membrane, which incorporates ldl cholesterol.
The selective motion of amphotericin B and azole medication, corresponding to
fluconazole and ketoconazole, on fungi relies on this differ-
ence in membrane sterols.
There are two kinds of fungi: yeasts and molds. Yeasts develop
as single cells that reproduce by asexual budding. Molds develop
as lengthy filaments (hyphae) and kind a mat (mycelium). Some
hyphae kind transverse partitions (septate hyphae), whereas others
don’t (nonseptate hyphae). Nonseptate hyphae are multinu-
cleated (coenocytic). The expansion of hyphae happens by extension
of the tip of the hypha, not by cell division all alongside the filament.
A number of medically necessary fungi are thermally dimorphic
(i.e., they kind totally different buildings at totally different temperatures).
They exist as molds within the surroundings at ambient temperature
and as yeasts (or different buildings such because the spherules of
Coccidioides) in human tissues at physique temperature.
Most fungi are obligate aerobes; some are facultative anaer-
obes; however none are obligate anaerobes. All fungi require a
preformed natural supply of carbon—therefore their frequent
affiliation with decaying matter. The pure habitat of most
fungi is, subsequently, the surroundings. An necessary exception
is Candida albicans, which is a part of the conventional human flora.
Some fungi reproduce sexually by mating and forming sex-
ual spores (e.g., zygospores, ascospores, and basidiospores).
Zygospores are single massive spores with thick partitions; ascospores
are fashioned in a sac referred to as ascus; and basidiospores are fashioned
externally on the tip of a pedestal referred to as a basidium. The clas-
sification of those fungi relies on their sexual spores. Fungi
that don’t kind sexual spores are termed “imperfect” and are
categorized as fungi imperfecti
ing conidia (asexual spores) from the perimeters or ends of specialised
buildings (Determine 47–1). The form, colour, and association of
conidia support within the identification of fungi. Some necessary
conidia are (1) arthrospores,
1
which come up by fragmentation
of the ends of hyphae and are the mode of transmission of
Coccidioides immitis; (2) chlamydospores, that are rounded,
thick-walled, and fairly resistant (the terminal chlamydospores
of C. albicans support in its identification); (3) blastospores, which
are fashioned by the budding course of by which yeasts reproduce
asexually (some yeasts, e.g., C. albicans, can kind a number of buds
that don’t detach, thus producing sausagelike chains referred to as
pseudohyphae, which can be utilized for identification); and (4)
sporangiospores, that are fashioned inside a sac (sporangium)
on a stalk by molds corresponding to Rhizopus and Mucor.
Though this e book focuses on the fungi which are human
pathogens, it must be remembered that fungi are used within the
manufacturing of necessary meals (e.g., bread, cheese, wine, and
beer). Fungi are additionally answerable for the spoilage of sure
meals. As a result of molds can develop in a drier, extra acidic, and
larger osmotic stress surroundings than micro organism, they have an inclination
to be concerned within the spoilage of fruits, grains, greens, and
jams.
PATHOGENESIS
The response to an infection with many fungi is the formation of
granulomas. Granulomas are produced within the main systemic
fungal illnesses (e.g., coccidioidomycosis, histoplasmosis, and
blastomycosis, in addition to a number of others). The cell-mediated
immune response is concerned in granuloma formation. Acute
suppuration, characterised by the presence of neutrophils within the
exudate, additionally happens in sure fungal illnesses corresponding to aspergil-
losis and sporotrichosis. Fungi would not have endotoxin of their
cell partitions and don’t produce bacterial-type exotoxins.
Activation of the cell-mediated immune system ends in a
delayed hypersensitivity pores and skin check response to sure fungal
antigens injected intradermally. A constructive pores and skin check signifies
publicity to the fungal antigen. It doesn’t suggest present infec-
tion, as a result of the publicity might have occurred previously.
A adverse pores and skin check makes the prognosis unlikely until the
affected person is immunocompromised. As a result of most individuals carry
Candida as a part of the conventional flora, pores and skin testing with Candida
antigens can be utilized to find out whether or not cell-mediated
immunity is regular.
The transmission and geographic places of some impor-
tant fungi are described in Desk 47–2.
Intact pores and skin is an efficient host protection in opposition to sure fungi
(e.g., Candida, dermatophytes), but when the pores and skin is broken, organ-
isms can change into established. Fatty acids within the pores and skin inhibit
dermatophyte progress, and hormone-associated pores and skin adjustments at
puberty restrict ringworm of the scalp attributable to Trichophyton. The
regular flora of the pores and skin and mucous membranes suppress fungi.
When the conventional flora is inhibited (e.g., by antibiotics), over-
progress of fungi corresponding to C. albicans can happen.
Within the respiratory tract, the necessary host defenses are the
mucous membranes of the nasopharynx, which lure inhaled
fungal spores, and alveolar macrophages. Circulating IgG and
IgM are produced in response to fungal an infection, however their
function in safety from illness is unsure. The cell-mediated
immune response is protecting; its suppression can result in reac-
tivation and dissemination of asymptomatic fungal infections
and to illness attributable to opportunistic fungi.
FUNGAL TOXINS & ALLERGIES
Along with mycotic infections, there are two other forms of
fungal illness: (1) mycotoxicoses, attributable to ingested toxins, and
(2) allergic reactions to fungal spores. The most effective-known mycotoxicosis
happens after consuming Amanita mushrooms. These fungi produce
5 toxins, two of which—amanitin and phalloidin—are amongst
essentially the most potent hepatotoxins. The toxicity of amanitin relies
on its skill to inhibit mobile RNA polymerase, which prevents
mRNA synthesis. One other mycotoxicosis, ergotism, is attributable to
the mould Claviceps purpurea, which infects grains and produces
alkaloids (e.g., ergotamine and lysergic acid diethylamide [LSD])
that trigger pronounced vascular and neurologic results.
Different ingested toxins, aflatoxins, are coumarin derivatives
produced by Aspergillus flavus that trigger liver harm and
tumors in animals and are suspected of inflicting hepatic carci-
noma in people. Aflatoxins are ingested with spoiled grains
and peanuts and are metabolized by the liver to the epoxide, a
potent carcinogen. Aflatoxin B1 induces a mutation within the p53
tumor suppressor gene, resulting in a lack of p53 protein and a
consequent lack of progress management within the hepatocyte.
Allergy symptoms to fungal spores, notably these of Aspergillus,
are manifested primarily by an asthmatic response (fast bron-
choconstriction mediated by IgE), eosinophilia, and a “wheal
and flare” pores and skin check response. These medical findings are induced
by a right away hypersensitivity response to the fungal spores.
LABORATORY DIAGNOSIS
There are 4 approaches to the laboratory prognosis of fungal
illnesses: (1) direct microscopic examination, (2) tradition of the
organism, (3) polymerase chain response (PCR) checks, and (4)
serologic checks. Direct microscopic examination of medical speci-
mens corresponding to sputum, lung biopsy materials, and pores and skin scrapings
depends upon discovering attribute asexual spores, hyphae, or
yeasts within the mild microscope. The specimen is both handled
with 10% potassium hydroxide (KOH) to dissolve tissue mate-
rial, leaving the alkali-resistant fungi intact, or stained with
particular fungal stains. Some examples of diagnostically necessary
findings made by direct examination are (1) the spherules of C.
immitis and (2) the extensive capsule of Cryptococcus neoformans seen
in India ink preparations of spinal fluid. Calcofluor white is a
fluorescent dye that binds to fungal cell partitions and is beneficial within the
identification of fungi in tissue specimens. Methenamine silver
stain can also be helpful within the microscopic prognosis of fungi in tissue.
Fungi are steadily cultured on Sabouraud’s agar, which
facilitates the looks of the slow-growing fungi by inhibit-
ing the expansion of micro organism within the specimen. Inhibition of bac-
terial progress is as a result of low pH of the medium and to the
penicillin, streptomycin, and cycloheximide which are steadily
added. The looks of the mycelium and the character of the
asexual spores are steadily enough to establish the organism.
PCR-based checks utilizing DNA probes can establish colonies
rising in tradition at an earlier stage of progress than can checks
based mostly on visible detection of the colonies. Because of this, the diagno-
sis will be made extra quickly. At current, PCR assays can be found
for Coccidioides, Histoplasma, Blastomyces, and Cryptococcus.
Assessments for the presence of antibodies within the affected person’s serum
or spinal fluid are helpful in diagnosing systemic mycoses however
much less so in diagnosing different fungal infections. As is the case for
bacterial and viral serologic testing, a big rise within the
antibody titer should be noticed to verify a prognosis. The
complement fixation check is most steadily utilized in suspected
instances of coccidioidomycosis, histoplasmosis, and blastomycosis.
In cryptococcal meningitis, the presence of the polysaccharide
capsular antigens of C. neoformans within the spinal fluid will be
detected by the latex agglutination check.
ANTIFUNGAL THERAPY
The medication used to deal with bacterial illnesses haven’t any impact on
fungal illnesses. For instance, penicillins and aminoglycosides
inhibit the expansion of many micro organism however don’t have an effect on the expansion
of fungi. This distinction is defined by the presence of sure
buildings in micro organism (e.g., peptidoglycan and 70S ribosomes)
which are absent in fungi.
The simplest antifungal medication, amphotericin B and the
numerous azoles, exploit the presence of ergosterol in fungal cell
membranes that’s not present in bacterial or human cell membranes.
Amphotericin B (Fungizone) disrupts fungal cell membranes on the
web site of ergosterol, and azole medication inhibit the synthesis of ergosterol,
which is a vital part of fungal membranes. One other
antifungal drug, caspofungin (Cancidas), inhibits the synthesis of
β-glucan, which is present in fungal cell partitions however not in bacterial cell
partitions. Human cells would not have a cell wall.
The mechanism of motion of those medication is described beneath.
Desk 47–3 summarizes the mechanism of motion and the impor-
tant hostile results of the key antifungal medication. Determine 47–2
depicts a typical fungal cell exhibiting the positioning of motion of impor-
tant antifungal medication.
Resistance to antifungal medication is changing into clinically necessary
(Desk 47–4). Sure species of Candida, particularly Candida gla-
brata, are proof against fluconazole and to voriconazole. Candida
auris is very drug resistant. Cryptococcus species, particularly
Cryptococcus gattii, are more and more proof against fluconazole.
Aspergillus fumigatus is exhibiting elevated resistance to azole
medication corresponding to itraconazole and voriconazole. Scedosporium
apiospermum, the asexual type of Pseudallescheria boydii, is
proof against nearly all antifungal medication.
MECHANISM OF ACTION OF
ANTIFUNGAL DRUGS
Inhibition of Fungal Cell Wall Synthesis
Echinocandins, corresponding to caspofungin (Cancidas) and micafun-
gin (Mycamine), are lipopeptides that block fungal cell wall
synthesis by inhibiting β-glucan synthase, the enzyme that syn-
thesizes β-glucan (see Determine 47–2). β-Glucan is a polysaccha-
experience composed of lengthy chains of d-glucose, which is an important
part of sure medically necessary fungal pathogens.
Caspofungin inhibits the expansion of Aspergillus and Candida
however not Cryptococcus or Mucor. Caspofungin is used for the
therapy of disseminated candidiasis and for the therapy of
invasive aspergillosis that doesn’t reply to amphotericin B.
Micafungin is accredited for the therapy of esophageal can-
didiasis and the prophylaxis of invasive Candida infections in
bone marrow transplant sufferers. Anidulafungin is accredited
for the therapy of esophageal candidiasis and different severe
Candida infections.
Alteration of Fungal Cell Membranes
Amphotericin B & Nystatin
Amphotericin B, a very powerful antifungal drug, is used
within the therapy of a wide range of disseminated fungal illnesses.
It’s a polyene with a collection of seven unsaturated double bonds
in its macrolide ring construction (poly means many, and -ene is a
suffix indicating the presence of double bonds; Determine 47–3). It
disrupts the cell membrane of fungi due to its affinity for
ergosterol, a part of fungal membranes however not of bacte-
rial or human cell membranes. Fungi proof against amphotericin
B have hardly ever been recovered from affected person specimens.
Amphotericin B has important renal toxicity; measurement
of serum creatinine ranges is used to observe the dose. Nephro-
toxicity is considerably decreased when the drug is run
in liposomes, however liposomal amphotericin B is pricey. Fever,
chills, nausea, and vomiting are widespread negative effects.
Nystatin is one other polyene antifungal agent, which, as a result of
of its toxicity, is used topically for infections attributable to the yeast
Candida.
Azoles & Terbinafine
Azoles are antifungal medication that act by inhibiting ergosterol
synthesis. They block cytochrome P450-dependent demeth-
ylation of lanosterol, the precursor of ergosterol. Fluconazole,
ketoconazole, voriconazole, posaconazole, itraconazole, and
HOOC
OH OH OH OH OH O
O
OH
OH
O
HO
HO
NH2
OH
O
O
isavuconazonium (a prodrug of isavuconazole) are used to deal with
systemic fungal illnesses. Clotrimazole and miconazole are used
solely topically as a result of they’re too poisonous to be given systemically.
The 2 nitrogen-containing azole rings of fluconazole will be
seen in Determine 47–4.
Ketoconazole is beneficial within the therapy of blastomycosis,
persistent mucocutaneous candidiasis, coccidioidomycosis, and
pores and skin infections attributable to dermatophytes. Fluconazole is use-
ful within the therapy of candidal and cryptococcal infections.
Itraconazole is used to deal with histoplasmosis and blastomycosis.
Posaconazole is used for the therapy of oropharyngeal candi-
diasis and the prevention of Candida and Aspergillus infections
in immunocompromised people. Isavuconazonium is used
to deal with invasive aspergillosis. Miconazole and clotrimazole,
two different imidazoles, are helpful for topical remedy of Candida
infections and dermatophytoses. Fungi proof against the azole
medication is an rising drawback.
Terbinafine blocks ergosterol synthesis by inhibiting squa-
lene epoxidase. It’s used within the therapy of dermatophyte
infections of the pores and skin, fingernails, and toenails.
Inhibition of Fungal DNA Synthesis
Flucytosine
Flucytosine (5-fluorocytosine, 5-FC) is an antifungal drug
that inhibits DNA synthesis. It’s a nucleoside analogue that’s
metabolized to fluorouracil, which inhibits thymidylate syn-
thetase, thereby limiting the availability of thymidine. It’s utilized in
mixture with amphotericin B within the therapy of dissemi-
nated cryptococcal or candidal infections, particularly cryptococ-
cal meningitis. It’s not used alone as a result of resistant mutants
emerge very quickly.
Extra Antifungal Drug Mechanisms
Griseofulvin is an antifungal drug that’s helpful within the treat-
ment of hair and nail infections attributable to dermatophytes. It
binds to tubulin in microtubules and will act by stopping
formation of the mitotic spindle.
Pentamidine is lively in opposition to fungi and protozoa. It
is extensively used to stop or deal with pneumonia attributable to
Pneumocystis jiroveci. It inhibits DNA synthesis by an unknown
mechanism.
