Candidiasis
By
Muhammad-Amin Shamall
Muhammad-Amin
Supervised by
Dr. Hero Ismeal
SUMMERY
In the last few decades fungi has become one of the most frequent opportunistic
microorganisms involved in nosocomial infections in hospitalized patients. The most
common fungi involved in fungus infection is Candida, which is a part of the human
skin normal flora, mucosae, gastrointestinal tract, genital and urinary system.
Candidiasis enclose a wide variety of diseases, including superficial infection of skin
and mucosal membranes to disseminated diseases like deep-seated infections including
candidemia, invasive candidiasis and others.
CONTENTS
summery......................................................................................................................... 2
candidiasis ...................................................................................................................... 4
Microbiology.................................................................................................................. 4
pathogenecity mechanism .............................................................................................. 4
Adherence................................................................................................................... 4
Invasion ...................................................................................................................... 5
Secreted hydrolytic enzymes ...................................................................................... 5
Polymorphism ............................................................................................................ 5
Biofilm formation....................................................................................................... 6
Interaction with bacteria ............................................................................................. 6
Phenotypic switching and mating .............................................................................. 6
Metabolic flexibility and nutrition intake................................................................... 6
Stress adaptation ......................................................................................................... 6
Host response ............................................................................................................. 6
Antifungal drug and drug resistance .......................................................................... 7
major types of candidiasis .............................................................................................. 7
Mucosal candidiasis ................................................................................................... 7
Oropharyngeal candidiasis ..................................................................................... 7
Vulvovaginal candidiasis ........................................................................................ 7
Cutaneous candidiasis ................................................................................................ 7
Invasive candidiasis.................................................................................................... 7
Systemic or disseminated candidiasis..................................................................... 7
Candidemia or bloodstream infection..................................................................... 7
risk factors ...................................................................................................................... 8
Candida infection in the intensive care unit (ICU) .................................................... 8
Hematological malignancy, solid organ transplantation, and other
immunosuppressive states .......................................................................................... 8
Neonates ..................................................................................................................... 9
Outbreaks ................................................................................................................... 9
treatment ........................................................................................................................ 9
Some of the drugs used as antifungal and their cellular targets ................................. 9
references ..................................................................................................................... 10
CANDIDIASIS
Candidiasis is the common name for diseases caused by the yeast of the genus Candida.
Candida species are eukaryotic opportunistic pathogens. It is the most abundant yeast
in the human body and one of the normal flora, found in the gastrointestinal tract and
genitourinary tracts, the oral cavity and on the skin of healthy human. If an individual
is immunocompromised Candida especially C.albicans can enter the blood stream and
cause life threatening systemic infection. Candida cause diseases ranging from
superficial mucosal infection to disseminated systemic infections that are often life
threatening. Candidiasis is also known as candidosis, moniliasis and odiomycosis.
MICROBIOLOGY
Candida albicans continue to be the species that cause the largest of cases of candidiasis.
It is followed by C. parapsilosi, C. tropicalis, C. glabarta, C. krusei, C. Lusitaniae, C.
guilliermondii, C. dubliniensis, and the newest one C. auris. Candida species are small
yeasts mainly have a unicellular form with thin wall and ovoid shape, they reproduce
by budding. Candida belong to the class Ascomycetes. Order Sacchromycetales, and
family Sacchromycetes, there are around 200 species but a limited number is
pathogenic. Candida can adapt to adhere to host tissue, pass through epithelial and
endothelia, invade every organ and escape the immune response. Switching from round
yeast to hyphae seem to play an important role in these processes. Hyphal growth also
plays an important role in biofilm production, microbial communities that are attached
to surfaces and resistant to antimicrobial agents. Candida can survive in white variety
of host niches thanks to its ability to for biofilms, drug resistance and stress responses.
PATHOGENECITY MECHANISM
Most infections by Candida originate from biofilms present on medical devices or from
epithelia, most systemic infections arise from the largest C. albicans reservoir, the
gastrointestinal tract. For dissemination, cells have to pass the epithelial barrier and
traverse the endothelia, then they spread though the blood stream and exit by passing
through the endothelium. From there they can invade any internal organ. Candida can
also inter the bloodstream through the epidermis in case of a severe burn, or from
gastrointestinal in case of damage, or via contaminated central venous catheters.
Candida can perfectly adapt to survive in a wide range of host niches and to evade the
immune system, some of the characteristics that helps to adapt to different
environments include, adaptation to pH changes, which helps them to survive in the
blood or some other alkaline environment as well as acidic, a number of strategies and
features explains why Candida is such a successful pathogen. Important factors include
adhesion, secretion of hydrolases, polymorphism, formation of biofilms, metabolic
flexibility and adaptation to stress.
Adherence
Adherence is an important factor for commensalism and pathogenesis of Candida. They
adhere to other fungi, bacteria, host cells, and abiotic surfaces, it is a crucial factor for
colonization, tissue invasion, and formation of biofilms. The Candida cell wall plays
an important role in adherence. It is a complex network composed of glycoprotein and
three different carbohydrates. The inner layer contains B-1-3-glucan and chitin which
is covalently attached to the B-1-3-glucan, the inner layer give strength and determines
the cell shape. The outer layer is composed of B-1-6-glucan which is covalently linked
to B-1-3-glucan and proteins that are usually highly glycosylated.
The most extensively characterized adhesion family is agglutinin-like sequence (Als)
family. The ALS family in C. albicans has 8 members. Als3 binds to epithelial and
endothelial cells, gelatin, fibronectin, fibrinogen, type IV collagen and laminin. Als3 is
not only used for adherence, it also plays role in invasion and iron acquisition, and since
all these functions are important for pathogenesis and because Als3 can be found on the
surface of Candida cells but not in human, it is an ideal target for vaccination.
Invasion
Adherence to the host epithelia can be followed by tissue invasion. Candida can cross
the cell epithelia by two ways, induced endocytosis and active penetration. In induced
endocytosis fungal proteins on the surface that mediate invasion bind to proteins
expressed on epithelial surfaces, this association can trigger the formation of
pseudopods that engulf the Candida. In active penetration, hyphae play a key role in it
which is not completely understood. Candida pass between the epithelia by degrading
the extracellular matrix and intracellular junctions, this degradation is catalysed by
secretion of aspartyl proteinases. They also invade into epithelial cells and destroying
them.
Secreted hydrolytic enzymes
Such as proteases, phospholipase and lipases have important roles for Candida
pathogenicity they help in tissue damage, nutrient intake and defence against the host
immune system. The best characterized proteases are the members of aspartyl
proteinases (Saps) family of Candida species of the CTG clade. Saps help in tissue
invasion by depredating extracellular matrix. C. albicans express at least 10 different
genes (SAP 1-10). Sap 1-8 are secreted from the cell where as Sap9 and 10 remain
attached to the cell wall through their GPI anchors. Aspartic proteinases are active at
low pH, optimal pH for Sap activity in C. albicans ranges from 2-7, this range allow
the Candida to survive wide variety of niches including the vagina (pH 4), the blood
(pH 7.4) and the gastrointestinal tract (pH 2-8)
Polymorphism
Several morphological forms have been found in Candida species including, yeast,
pseudohyphae, hyphae, opaque cells and chlamydospores. All major clinically relevant
Candida form yeast cells and pseudohyphae, hyphae have only been described for C.
albicans. The morphology highly depends on the environmental conditions.
It has been suggested that the transition between yeast to hyphae is important for
Candida pathogenicity, but the relationship between morphogenesis and pathogenesis
is still not well understood. A simple view suggest that yeast is needed for dissemination
and hyphae is needed for tissue invasion.
Biofilm formation
Like many other microorganisms, Candida can for biofilms. Biofilms are complex
structured communities, attached to surfaces and surrounded by extracellular matrix.
They are of great importance clinically, they increase resistance against antimicrobial
agents and protect against host immune response. Biofilms might not be composed of
only one species but rather polymicrobial communities. C. albicans biofilms are
composed of yeast and hyphal form and few pseudohyphae, yeast cells are in the basal
layer attached to the surface, hyphal cells are found in the outer layer. The formation of
biofilms can be viewed in steps: first, yeast cells adhere to the surface and divide to
form colonies, then hyphal cells appear, both cells proliferate and produce extracellular
matrix. Mature biofilms release yeast cells into the environment, this probably means
that some hyphal cells turn back to yeast forms.
Interaction with bacteria
Bacteria and fungi compete for space and nutrients on mucosae, skin and medical
devices. These interactions are not well understood and they are complex, it disturbs
and imbalances the normal microbial flora.
Phenotypic switching and mating
Cell morphology changes during phenotypic switching as observed in several C.
albicans strains. The white-opaque switch involves a transition from white colonies,
which are domed and creamy colour, to flat and more grey colonies. The white cells
are ovoid with a smooth surface, whereas the grey colonies appear to be longer and
have a rather uneven surface.
Metabolic flexibility and nutrition intake
Adaptation of the metabolism to the different host niches contributes in the success of
Candida as a pathogen. Glucose is the preferred carbon source for Candida, high levels
of it can be found in the gastrointestinal tract, bloodstream and the brain, also it is found
in the liver as glycogen.
Stress adaptation
Responses to stresses are important for the survival of Candida in the various
environmental ranges in the host, following phagocytosis Candida cells are exposed to
reactive oxygen and nitrogen species. In the gastrointestinal and the urogenital tract
cells have to overcome the pH stress, while in the kidney and oral cavity cells encounter
hard osmotic conditions.
The heat shock response is one of the most important stress responses. It isn’t just
induced by increase in temperature but also by oxidative stress, which cause unfolding
and aggregation of proteins, which can in turn lead to severe damage and cell death.
Host response
The host immune system reacts strongly to Candida infections, first by innate response
then by stronger responses including T cells and B cells. The cell wall component of
Candida serves as pathogen-associated molecular pattern (PAMP) that is recognized
by patter recognition receptor (PRR) on the surface of the host immune cells. PAMP
recognition by PRR on the surface of neutrophil and macrophage lead to phagocytosis
and respiratory burst to kill Candida cells. They also produce proinflammatory
cytokinesis. C. albicans are able to escape macrophages but not neutrophils.
Antifungal drug and drug resistance
A relatively small number of antifungals is available at the moment. They fall into four
major classes: azole, polyenes, echinocandins, and pyrimidine. They have fungi
specific target to minimize host toxicity.
MAJOR TYPES OF CANDIDIASIS
Candidiasis is an acute or chronic infection produced by Candida species, but it can
also cause severe and systematic infections.
Mucosal candidiasis
These infections are restricted to the non-sterile mucosal surfaces, like oropharyngeal
and vulvovaginal candidiasis.
Oropharyngeal candidiasis
Oral candidiasis is one of the most common oral infections seen in a person with HIV.
Three general factors may lead to oral candidiasis: immune status of the host, oral
mucosal environment, and specific strains of C. albicans.
The ability of the yeast to overcome the clearance mechanisms and to colonize surfaces
can be considered as a risk factor for oral infections.
Vulvovaginal candidiasis
Disease is usually associated with considerable morbidity, discomfort, pain and sexual
functioning, it is rarely life threatening. The symptoms are eczematoid dermatitis
lesions that sometimes show vesicular and grey-white pseudomembrane vulval pruritis,
burning, erythema and crud like discharge.
Cutaneous candidiasis
This type of candidiasis is usually secondary infection of skin and nail in predisposal
patients. It occurs as a sub-acute or chronic infection.
Invasive candidiasis
Encloses a spectrum of clinical conditions, the most frequent one is candidemia, which
will lead to bloodstream infection, associated with high crude mortality rate. Invasive
candidiasis can involve any organ and the most common cause of it is C. albicans.
Systemic or disseminated candidiasis
Systemic hematogenously disseminated candidiasis is characterized by spreading of the
Candida cells into almost the entire body with chances to create abscesses in vitally
important organs, inducing the organ failure which leads to mortality in about 50% of
all cases.
Candidemia or bloodstream infection
Candidemia has a mortality range about 30-40% in all cases, it extends the duration of
hospital stay and increase the cost. Candida species are the 4th leading cause of hospital
acquired BSIs.
Pathogenesis of Invasive Candidiasis
RISK FACTORS
Candida infection in the intensive care unit (ICU)
Patients in the ICU have the highest rate of getting Candida infection in the hospitals.
Hematological malignancy, solid organ transplantation, and
other immunosuppressive states
These disorders all share a common factor, immunosuppression. Different type of
immunosuppression will attract different risks for the patient.
Neonates
Newborns have no gastrointestinal flora at birth and have to be colonized by
enterobacteria and other microorganisms via maternal breast feeding. Any disturbance
to the processes my lead to colonization by pathogenic microorganism including yeast.
Outbreaks
Candida yeast can survive in inanimate surfaces and in the hands of the healthcare
personnel which alter the risk of outbreak and cross dissemination among high risk
units that we mentioned before.
TREATMENT
Each of the antifungal classes utilizes a different mean to kill or inhibit the growth of
the fungal pathogens. The antifungal mechanisms are either primary or secondary and
are related to intrinsic or acquired characteristics of the fungal pathogen, involving
either interference with the antifungal mechanism of the respective drug or a decrease
in target drug level. Resistance can also occur when environmental factors lead to
colonization or replacement of a susceptible species with resistant species. The
antifungal effect of polyene and azole antifungals are due to their actions on the fungal
cell membrane, where as echinocandins act by disrupting the fungal cell wall.
Some of the drugs used as antifungal and their cellular targets
Chemical classes
1. Azoles, targets Ergosterol synthesis
a. Miconazole
b. Ketoconazole
c. Fluconazole
d. Itraconazole
e. Terconazole
f. Voriconazole
g. Posaconazole
2. Polyenes, targets ergosterol (membrane function)
a. Amphotericin B
b. Nistatin
3. Pyrimidine, targets DNA and RNA synthesis
a. Flucytosine
4. Echinocandins, glucagon synthesis
a. Caspofungin
b. Micanfungin
c. Anidulafungin
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